The Burden of Clostridioides Difficile Infection during the COVID-19 Pandemic: A Retrospective Case-Control Study in Italian Hospitals (CloVid).
Data on the burden of Clostridioides difficile infection (CDI) in Coronavirus Disease 2019 (COVID-19) patients are scant. We conducted an observational, retrospective, multicenter, 1:3 case (COVID-19 patients with CDI)-control (COVID-19 patients without CDI) study in Italy to assess incidence and outcomes, and to identify risk factors for CDI in COVID-19 patients. From February through July 2020, 8402 COVID-19 patients were admitted to eight Italian hospitals; 38 CDI cases were identified, including 32 hospital-onset-CDI (HO-CDI) and 6 community-onset, healthcare-associated-CDI (CO-HCA-CDI). HO-CDI incidence was 4.4 × 10,000 patient-days. The percentage of cases recovering without complications at discharge (i.e., pressure ulcers, chronic heart decompensation) was lower than among controls (p = 0.01); in-hospital stays was longer among cases, 35.0 versus 19.4 days (p = 0.0007). The presence of a previous hospitalisation (p = 0.001), previous steroid administration (p = 0.008) and the administration of antibiotics during the stay (p = 0.004) were risk factors associated with CDI. In conclusions, CDI complicates COVID-19, mainly in patients with co-morbidities and previous healthcare exposures. Its association with antibiotic usage and hospital acquired bacterial infections should lead to strengthen antimicrobial stewardship programmes and infection prevention and control activities.


Does trifluoroethanol affect folding pathways and can it be used as a probe of structure in transition states?
Nonaqueous co-solvents, particularly 2,2,2-trifluoroethanol (TFE), have been used as tools to study protein folding. By analyzing FKBP12, an alpha/beta-protein that folds with two-state kinetics, we have been able to address three key questions concerning the use of TFE. First, does TFE perturb the folding pathway? Second, can the observed changes in the rate of folding and unfolding in TFE be attributed to a change in free energy of a single state? Finally, can TFE be used to infer information on secondary structure formation in the transition state? Protein engineering experiments on FKBP12, coupled with folding and unfolding experiments in 0% and 9.6% TFE, conclusively show that TFE does not perturb the folding pathway of this protein. Our results also suggest that the changes in folding and unfolding rates observed in 9.6% TFE are due to a global effect of TFE on the protein, rather than the stabilization of any elements of secondary structure in the transition state. Thus, studies with TFE and other co-solvents can be accurately interpreted only when combined with other techniques.


Fingertip Strain Plethysmography: Representation of Pulse Information based on Vascular Vibration.
This study presents fingertip strain plethysmography (SPG) as a visual trace of cardiac cycles in peripheral vessels. The setup includes a small, sensitive MEMS strain sensor attached to the fingertip to capture the pulsatile vibrations corresponding to cardiac cycles. SPG is evaluated on 10 healthy subjects for the estimation of heart rate (HR) and heart rate variability (HRV), as well as heartbeat-derived respiratory rate (RR) which is an HRV parameter. The estimated parameters are compared with a simultaneously-recorded electrocardiogram (ECG) for HR and HRV, and an inertial sensor placed on the chest wall for RR. Bland-Altman analyses suggest small estimation biases of 0.03 beats-per-minute (BPM) and 0.38 ms for HR and HRV respectively, demonstrating excellent agreement between fingertip SPG and ECG. The average estimation accuracies of 99.88% (± 0.04), 96.43% (± 1.44), and 92.64% (± 2.30) for HR, HRV, and RR respectively, prove the reliability of SPG for hemodynamic monitoring.Clinical Relevance- Conventional plethysmography sensors are either cumbersome or susceptible to skin color. This effort is a fundamental step towards the augmentation of conventional methods, thus ensuring stable, clinical-grade hemodynamic monitoring.


Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine?
The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine (Flu) (CY-FLU). While cyclophosphamide (CY) possesses lymphotoxic effects, it concurrently preserves regulatory T cell activity, potentially affecting the efficacy of CAR-T cells. Moreover, the use of fludarabine (FLU) has been linked to neurotoxicity, which could complicate the early detection of immune effector cell-associated neurotoxicity syndrome (ICANS) observed in CAR-T cell therapy. Given the ongoing shortage of FLU, alternative lymphodepleting agents have become necessary. To date, only a limited number of studies have directly compared different lymphodepleting regimens, and most of these comparisons have been retrospective in nature. Herein, we review the current literature on lymphodepletion preceding CAR-T cell therapies for lymphoid hematologic malignancies, with a specific focus on the use of bendamustine (BEN). Recent evidence suggests that administering BEN before CAR-T cell infusion yields comparable efficacy, possibly with a more favorable toxicity profile when compared to CY-FLU. This warrants further investigation through randomized prospective studies.


Severe type IV hypersensitivity to 'black henna' tattoo.
A 16-year-old Bangladeshi girl presented with a 9-day history of an extensive pruritic, erythematous, papulovesicular skin eruption to both forearms. Appearance was 5 days following application of a home-made henna preparation. Examination revealed ulceration and scabbing along the whole henna pattern and early keloid formation. A diagnosis of type IV delayed hypersensitivity reaction superimposed by infection was initially made. As in this case, home-made henna preparations commonly combine commercial henna with black hair dye, paraphenylenediamine (PPD). PPD, widely known as 'black henna', darkens the pigment and precipitates the drying process. PPD is a potent contact allergen associated with a high incidence of hypersensitivity reactions. Despite treatment the patient was left with extensive keloid scarring in the pattern of the henna tattoo.


A comparison of infant and toddler feeding practices of mothers with and without histories of eating disorders.
This preliminary study surveyed the feeding practices of mothers with eating disorder histories through evaluation of mothers' reported feeding styles, child diet composition and restrictive special approaches to feeding. For this non-randomised cohort study, 25 mothers with eating disorder histories and 25 mothers with no history of an eating disorder with children ages 6-36 months were selected such that the groups were similar based on child age group and child sex. Mothers were compared on self-reported feeding style using the Infant Feeding Styles Questionnaire and on child diet composition and special feeding approaches using a modified version of the Toddler Diet Questionnaire from the Women, Infants, and Children program. Mothers with eating disorder histories scored lower on the restrictive feeding style subscale than controls. No significant differences were detected between groups in child diet including the percentage of mothers who breastfed, duration of breastfeeding, age at solid food introduction, daily number of meals or snacks or daily frequency of consumption of fruits, vegetables or protein foods. Mothers with eating disorder histories were more likely to report taking a restrictive special approach to feeding such as limiting processed foods or feeding organic foods only. Although mothers with eating disorder histories may not differ greatly from control mothers in terms of child diet composition (smaller effects may not have been detected due to limited sample size), they may be more likely to take restrictive special approaches to feeding which mirror dietary rules common in individuals with eating disorders.


Cell-type specific expression of a dominant negative PKA mutation in mice.
We employed the Cre recombinase/loxP system to create a mouse line in which PKA activity can be inhibited in any cell-type that expresses Cre recombinase. The mouse line carries a mutant Prkar1a allele encoding a glycine to aspartate substitution at position 324 in the carboxy-terminal cAMP-binding domain (site B). This mutation produces a dominant negative RIα regulatory subunit (RIαB) and leads to inhibition of PKA activity. Insertion of a loxP-flanked neomycin cassette in the intron preceding the site B mutation prevents expression of the mutant RIαB allele until Cre-mediated excision of the cassette occurs. Embryonic stem cells expressing RIαB demonstrated a reduction in PKA activity and inhibition of cAMP-responsive gene expression. Mice expressing RIαB in hepatocytes exhibited reduced PKA activity, normal fasting induced gene expression, and enhanced glucose disposal. Activation of the RIαB allele in vivo provides a novel system for the analysis of PKA function in physiology.


A systematic review of the use of aromatherapy in treatment of behavioral problems in dementia.
We aimed to fill the literature gap by identifying the clinical benefits of aromatherapy in older adults with dementia, and its efficacy in reducing behavioral and psychological symptoms of dementia (BPSD) based on available randomized controlled trials (RCT). A systematic review of 11 clinical trials shortlisted from electronic databases from 1995 to 2011 was carried out. The RCT showed that aromatherapy had positive effects on reduction of BPSD, improvement in cognitive functions, increasing quality of life, enhancing independence of activities of daily living and so on. However, adverse effects were noted in some studies. Limitations on methodology are discussed and suggestions on directions of further studies are made. It is recommended that aromatherapy shows the potential to be applied as a therapeutic and safe complementary and alternative therapy for the management of BPSD on more evidence collected from better designed RCT.


Intermetallic Pd3Pb ultrathin nanoplate-constructed flowers with low-coordinated edge sites boost oxygen reduction performance.
Although tremendous efforts have been devoted to exploring non-Pt based electrocatalysts toward the oxygen reduction reaction (ORR), achievements in both catalytic activity and durability are still far from satisfactory. Here, we report a facile approach for the synthesis of intermetallic Pd3Pb ultrathin nanoplate-constructed flowers. Such highly opened hierarchical nanostructures with an ordered phase and low-coordinated edge sites exhibited a substantially enhanced activity toward the ORR. Especially, the intermetallic Pd3Pb nanoflowers achieved a record-breaking mass activity (1.14 mA μgPd-1) in an alkaline solution at 0.9 V vs. a reversible hydrogen electrode among the reported Pd-based ORR electrocatalysts to date, which was 1.8, 3.9 and 11.4 times higher than those of intermetallic Pd3Pb nanocubes, Pd3Pb dendrites and commercial Pt/C, respectively. More importantly, the intermetallic Pd3Pb nanoflowers also showed a higher durability with only 23.7% loss in mass activity after 10 000 cycles compared to the commercial Pt/C (35% loss in mass activity) due to their chemically stable intermetallic structures.


Laboratory and experimental hut trial evaluation of VECTRON ™ T500 for indoor residual spraying (IRS) against insecticide resistant malaria vectors in Burkina Faso.
Background: Malaria cases in some areas could be attributed to vector resistant to the insecticide. World Health Organization recommended insecticides for vector control are limited in number. It is essential to find rotational partners for existing Indoor Residual Spraying (IRS) products. VECTRON ™ T500 is a novel insecticide with broflanilide as active ingredient. It has a mode of action on mosquitoes completely different to usually used. The aim of this study was to determine the optimum effective dose and efficacy of VECTRON TM T500 against susceptible and resistant strains of Anopheles in Burkina Faso. Methods: VECTRON™T500 was sprayed at 50, 100 and 200 mg/m² doses onto mud and concrete blocks using Potter Spray Tower. The residual activity of broflanilide was assessed through cone bioassays 1 week and then monthly up to 14 months post spraying. Its efficacy was evaluated at 100 and 150 mg/m² against wild free-flying mosquitoes in experimental huts on both substrates. Actellic 300CS was applied at 1000 mg/m² as reference product. Cone assays were conducted monthly, using susceptible and resistant mosquito strains. Results: In the laboratory, VECTRON ™ T500 showed residual efficacy (≥80% mortality) on An. gambiae Kisumu up to 12 and 14 months, respectively, on concrete and mud blocks. Similar results were found with 100 and 200 mg/m² using An. coluzzii pyrethroid resistant strain. In experimental huts, a total of 19,552 An. gambiae s.l. were collected. Deterrence, blood-feeding inhibition and exophily with VECTRON™ treated huts were very low. At 100 and 150 mg/m², mortality of wild An. gambiae s.l. ranged between 55% and 73%. Monthly cone bioassay mortality remained >80% up to 9 months. Conclusions: VECTRON™ T500 shows great potential as IRS formulation for malaria vector control. It can be added to the arsenal of IRS products for use in rotations to control malaria and manage mosquito insecticide resistance.


[Direct and mediated action of a permanent magnetic field on biological objects].
The effect of a constant magnetic field (CMF) of H = 2.3 X 10(5) A/m (2900 Oe) on the viability and radiosensitivity of E. coli B and the effect of magnetically activated water (MAW) on the radioresistance of rats were examined. The exposure did not influence the growth kinetics of E. coli B. Cell cultivation in the magnetically pretreated nutrient medium enhanced the bacterial growth. Preliminary exposure of bacterial cells to a CMF for 24 and 48 hrs increased and that for 72 hrs decreased their radioresistance. Twice a day the experimental weanlings were given MAW and the controls--tap water. The postradiation longevity of the MAW rats proved extended as compared to that of the controls. The MAW rats showed a greater osmotic stability of erythrocytes, a higher concentration of nucleic acids, and a larger count of leucocytes.


Leptin as predictor of cardiovascular events and high platelet reactivity in patients undergoing percutaneous coronary intervention.
Leptin is a hormone involved in the regulation of food intake. Previous studies suggested an interplay between leptin, platelet aggregation, and cardiovascular outcome but this issue was not investigated in vivo in patients treated with percutaneous coronary intervention (PCI). We designed a study to evaluate the possible relation between leptin, cardiovascular outcome, and platelet reactivity (PR) in patients undergoing PCI. 155 PCI patients had preprocedural measurements of PR and leptin plasma levels. The latter were assessed by ELISA. Hyperleptinemia was defined as leptin levels ≥14 ng/ml. PR was evaluated by the VerifyNowP2Y12 assay and expressed as P2Y12 reaction units (PRU). Patients were divided into three groups based on PR values and defined as low (LPR), normal (NPR), and high (HPR). Patients were followed for up 8 years. The primary endpoint was the incidence of Major Acute Cardiac Events (MACE) at long-term follow-up according to leptin groups. Secondary endpoints were the evaluation of leptin levels according to PR groups and the incidence of periprocedural myocardial infarction (PMI) according to leptin groups. Long-term follow-up was completed in 140 patients. Patients with hyperleptinemia experienced a higher MACE rate than the normoleptinemic group (HR 2.3; CI 95% 1.14-4.6, P = 0.02). These results remained unchanged after adjusting for Body Mass Index, hypertension, and gender. Leptin levels were significantly different among groups of PR (P = 0.047). Leptin levels were higher in the HPR group (12.61 ± 16.58 ng/ml) compared to the LPR group (7.83 ± 8.87 ng/ml, P = 0.044) and NPR group (7.04 ± 7.03 ng/ml, P = 0.01). The rate of PMI was higher in hyperleptinemia patients (15.1% vs. 6.5%, P = 0.22). This study suggests that high leptin levels are associated with a worse clinical outcome in patients undergoing PCI and with HPR. Further studies are needed to define better the pathophysiological pathways underlying this association.


Latent semantic analysis: a new method to measure prose recall.
The aim of this study was to compare traditional methods of scoring the Logical Memory test of the Wechsler Memory Scale-III with a new method based on Latent Semantic Analysis (LSA). LSA represents texts as vectors in a high-dimensional semantic space and the similarity of any two texts is measured by the cosine of the angle between their respective vectors. The Logical Memory test was administered to a sample of 72 elderly individuals, 14 of whom were classified as cognitively impaired by the Mini-Mental State Examination (MMSE). The results showed that LSA was at least as valid and sensitive as traditional measures. Partial correlations between prose recall measures and measures of cognitive function indicated that LSA explained all the relationship between Logical Memory and general cognitive function. This suggests that LSA may serve as an improved measure of prose recall.


A spectroscopic assessment of static and dynamic disorder in a film of a polythiophene with a planarized backbone.
The optoelectronic performance of organic semiconductor devices is related to the static and dynamic disorder in the film. The disorder can be assessed by considering the linewidth of its optical spectra. We focus on identifying the effect of conjugation length distribution on the static energetic disorder. Hence, we disentangle the contributions of static and dynamic disorder to the absorption and emission spectra of poly(3-(2,5-dioctylphenyl)-thiophene) (PDOPT) by exploring how the linewidth and energy of the spectra evolve upon cooling the sample from 300 K to 5 K. PDOPT has sterically hindered side chains that arrange such as to cause a planarized polymer backbone. This makes it a suitable model for a quasi-one-dimensional molecular system. By modelling the conjugated segments as coupled oscillators we find that the linewidth contribution resulting from the variation of conjugation length decreases linearly with decreasing exciton energy and extrapolates to zero at the energy corresponding to an infinite chain. These results provide a new avenue to the design of low disorder and hence high mobility polymeric semiconductors.


Population genetic structure of the lemon shark (Negaprion brevirostris) in the western Atlantic: DNA microsatellite variation.
DNA microsatellite markers were used to characterize the population genetic structure of the lemon shark, Negaprion brevirostris, in the western Atlantic. This study demonstrates for the first time the usefulness of microsatellites to study population genetic structure and mating systems in the Chondricthyes. Lemon sharks (mostly juveniles) were sampled non-destructively from four locations, Gullivan Bay and Marquesas Key in Florida, Bimini, Bahamas, and Atol das Rocas, Brazil. At least 545 individuals were genotyped at each of four dinucleotide loci. The number of alleles per locus ranged from 19 to 43, and expected heterozygosities ranged from 0.69 to 0.90. Relatively little genetic structure was found in the western Atlantic, with small but significant values for estimators of F(ST) and R(ST) among populations, theta (0.016) and rho (0.026), respectively. No sharp discontinuities were found between the Caribbean sites and Brazil, and most alleles were found at all four sites, indicating that gene flow occurs throughout the western Atlantic with no evidence for distinct stocks.


Conformational analysis of site-specific DNA cross-links of cisplatin-distamycin conjugates.
The requirement for novel platinum antitumor drugs led to the concept of synthesis of novel platinum drugs based on targeting cisplatin to various carrier molecules. We have shown [Loskotova, H., and Brabec, V. (1999) Eur. J. Biochem. 266, 392-402] that attachment of DNA minor-groove-binder distamycin to cisplatin changes several features of DNA-binding mode of the parent platinum drug. Major differences comprise different conformational changes in DNA and a considerably higher interstrand cross-linking efficiency. The studies of the present work have been directed to the analysis of oligodeoxyribonucleotide duplexes containing single, site-specific adducts of platinum-distamycin conjugates. These uniquely modified duplexes were analyzed by Maxam-Gilbert footprinting, phase-sensitive gel electrophoresis bending assay and chemical probes of DNA conformation. The results have indicated that the attachment of distamycin to cisplatin mainly affects the sites involved in the interstrand cross-links so that these adducts are preferentially formed between complementary guanine and cytosine residues. This interstrand cross-link bends the helix axis by approximately 35 degrees toward minor groove, unwinds DNA by approximately 95 degrees and distorts DNA symmetrically around the adduct. In addition, CD spectra of restriction fragments modified by the cisplatin-distamycin conjugates have demonstrated that distamycin moiety in the interstrand cross-links of these compounds interacts with DNA. This interaction facilitates the formation of these adducts. Hence, the structural impact of the specific interstrand cross-link detected in this study deserves attention when biological behavior of cisplatin derivatives targeted by oligopeptide DNA minor-groove-binders is evaluated.


Phenotype analysis impacts testing strategy in patients with Currarino syndrome.
Currarino syndrome (OMIM 175450) presents with sacral, anorectal, and intraspinal anomalies and presacral meningocele or teratoma. Autosomal dominant loss-of-function mutations in the MNX1 gene cause nearly all familial and 30% of sporadic cases. Less frequently, a complex phenotype of Currarino syndrome can be caused by microdeletions of 7q containing MNX1. Here, we report one familial and three sporadic cases of Currarino syndrome. To determine the most efficient genetic testing approach for these patients, we have compared results from MNX1 sequencing, chromosomal microarray, and performed a literature search with analysis of genotype-phenotype correlation. Based on the relationship between the type of mutation (intragenic MNX1 mutations vs 7q microdeletion) and the presence of intellectual disability, growth retardation, facial dysmorphism, and associated malformations, we propose a testing algorithm. Patients with the classic Currarino triad of malformations but normal growth, intellect, and facial appearance should have MNX1 sequencing first, and only in the event of a normal result should the clinician proceed with chromosomal microarray testing. In contrast, if growth delay and/or facial dysmorphy and/or intellectual disability are present, chromosomal microarray should be the first method of choice for genetic testing.


Latest emerging functions of SPP/SPPL intramembrane proteases.
Signal peptide peptidase (SPP) and the four related SPP-like (SPPL) proteases are homologues of the presenilins, which comprise the catalytic centre of the γ-secretase complex. SPP/SPPL proteases are GxGD-type aspartyl intramembrane proteases selective for substrates with a type II membrane topology. Subcellular localisations of SPP/SPPL proteases range from the early secretory pathway to the plasma membrane and the endocytic system. Similarly diverse are their functional roles at the cellular level covering the turnover of signal peptides and membrane proteins, a contribution to the ERAD pathway as well as the regulation of cellular protein glycosylation and certain signaling pathways. Much less well understood are the physiological functions of SPP/SPPL proteases in complex organisms. Whereas a major role of SPPL2a for homeostasis of B cells and dendritic cells has been documented in mice, in vivo functions of SPP and the other SPPLs remain largely elusive to date. SPP/SPPL proteases contribute to regulated intramembrane proteolysis (RIP), a sequential processing of single-spanning transmembrane proteins by an ectodomain sheddase and an intramembrane-cleaving protease (I-CLIP). However, recent studies reported the cleavage of tail-anchored and multi-pass membrane proteins by SPP as well as the capability of SPPL3 to accept substrates without a preceding ectodomain shedding. This revealed that the mechanistic properties within this family are more diverse than initially thought. With this review, we aim to provide an update on recent achievements in defining the function and (patho-) physiological relevance of SPP/SPPL proteases and to highlight open questions in the field.


Studies on natural killer (NK) cells. II. Serologic evidence for heterogeneity of murine NK cells.
NK cells are divided into 2 subclasses on the basis of cell surface antigens: NKA cells, which preferentially lyse lymphoma cells and which are readily destroyed by treatment with anti-H-2, rabbit anti-mouse, or anti-NK specific antibodies in the presence of C; and NKB cells, which preferentially lyse nonlymphoma tumor cells and which are resistant to anti-NK specific antibodies, partially sensitive to anti-H-2 specific antibodies, and only fully sensitive to rabbit anti-mouse serum and C. Thus, suspensions of spleen cells that were treated with anti-NK-1.2 antibodies and C lost virtually all lytic activity for 6 lymphoma cell lines, whereas lytic activity for 2 nonlymphoma cell lines remained largely intact. It must be noted, however, that unlike NK-1.2 expression, target cell preference is not an absolute indicator of NK cell subclass. Cytotoxic T cells were readily distinguished from NKA and NKB cells on the basis of their sensitivity to monoclonal anti-Thy-1.2 antibodies and resistance to anti-NK-1.2 antiserum and C.


A review of network meta-analysis comparing biologics in the treatment of rheumatoid arthritis.
Even though in recent years significant improvements have been made in the management of patients with rheumatoid arthritis due to the introduction of biologic agents, it is still difficult to identify the most effective and safest available treatment. The choice and comparison between biological agents are a challenge, for only limited head-to-head clinical studies are available. The aim of this manuscript is to review the published network meta-analysis (NMA) to gain a better understanding of efficacy and safety of biological agents and small molecules in the management of RA patients. We used MEDLINE and EMBASE to identify network meta-analyses from 2008 to June 2019 comparing efficacy and safety of licensed biological agents and tsDMARDS at the approved dosages using predefined text words related to the topic. The following scenarios have been investigated: patients not responding to csDMARD (cDMARDs - IR); csDMARD naïve patients; patients not responding to biologics (bDMARDs - IR); patients in biological monotherapy. On the basis of the data present in the literature, we are able to hypothesize some trends of response in terms of efficacy in different subsets of patients, for example patients in monotherapy, bDMARds unresponsive patients, and Methotrexate-naive patients. The differences of the results presented in many works are due to the different inclusion criteria used in the studies, the type of biologics agent used in each study (according to the available molecules in the different years of publication), as well as differences in the methodology of NMA and in the presentation of the data. We suggest that the next NMA follows the indications suggested by the Professional Society for Health Economics and Outcomes Research (ISPOR) so that the results are comparable and comprehensible.


Effectiveness of whole-body vibration exercise and core stabilization exercise in chronic non-specific low back pain: A randomized-controlled study.
The aim of this study was to investigate the effectiveness of whole-body vibration exercise (WBVE) and core stabilization exercise (CSE) on pain, muscle strength, and functional recovery in patients with chronic non-specific low back pain (NLBP). Between June 2016 and July 2017, a total of 74 patients with NLBP (12 males, 62 females; mean age: 44.7±8.9 years; range, 24 to 64 years) were included in this prospective, randomized-controlled study. The patients were randomly assigned to WBVE group (WBVEG, n=25), CSE group (CSEG, (n=25), and home exercise group as the control group (CG, (n=24). All groups performed 24 sessions of exercise for a total of eight weeks. Clinical outcome was measured using the Visual Analog Scale (VAS), Roland-Morris Disability Questionnaire (RMDQ), computerized isokinetic muscle strengths (IMS) and progressive isoinertial lifting evaluation (PILE) test. The VAS and RMDQ scores in WBVEG and CSEG statistically significantly decreased (p<0.05). The difference between the pre-treatment and at three-month VAS scores during intense activity were significantly different in both WBVEG and CSEG than the CG (p<0.05). The IMS values, except for the isokinetic flexion total work (IKFTW), increased significantly in all three groups (p<0.05). The IKFTW values increased significantly in the WBVEG and CSEG (p<0.05). A statistically significant increase in the functional work performance with PILE was observed in all three groups (p<0.05). The differences between the pre-treatment and three-month PILE test (ground to back and back to shoulder) were significantly different in both WBVEG and CSEG than the CG (p<0.05). In the treatment of chronic NLBP, WBVE and CSE appear to be effective in pain and functionality. Although there was a significant improvement in muscle strength and functional work performance in all three groups, greater improvements were observed in the WBVEG and CSEG than the CG.


Novel foods: allergenicity assessment of insect proteins.
Insects represent a promising source of proteins and have been reported as a great potential for being used as novel food and feed proteins. This makes them a valuable source of nutrients to face the increasing demand of food necessitated by the growing global population. The current European food legislation on novel food (EU Reg. 2015/2283), which entered into force in 2018, provides the provisions that should be considered in the applications for the authorisation of novel foods in the European market. Insects, intended as an alternative source of food proteins for human consumption, are considered novel foods. Since food allergens are mostly proteins, the analysis and identification of the potential allergenicity of novel proteins should be a fundamental activity that enables the applicants to fulfil the requirements for the application and authorisation to bring a novel food into the European market and ensures a high level of food safety for the European consumers. The main aims of the work of the EU-FORA fellow were to: (i) Review, assess and identify gaps in the current strategies for predicting allergenicity of novel foods and new alternative protein sources; and (ii) Familiarise, understand and perform an allergenicity assessment of a novel food protein source by: (a) Working on an allergenicity assessment case study of insect proteins from black soldier fly larva (Hermetia Illucens); and (b) Taking into consideration other risk assessment aspects of insects as novel food, including toxicological, nutritional and microbial risks. The project contributed to the continuous learning of the fellow on practical assays and methodologies for the in silico, in vitro and in vivo analysis principles and complemented personal skills related to the food risk assessment requirement for the preparation and submission of an application for authorisation of a novel food.


Routine clinical practice effectiveness of the Glidescope in difficult airway management: an analysis of 2,004 Glidescope intubations, complications, and failures from two institutions.
The Glidescope video laryngoscope has been shown to be a useful tool to improve laryngeal view. However, its role in the daily routine of airway management remains poorly characterized. This investigation evaluated the use of the Glidescope at two academic medical centers. Electronic records from 71,570 intubations were reviewed, and 2,004 cases were identified where the Glidescope was used for airway management. We analyzed the success rate of Glidescope intubation in various intubation scenarios. In addition, the incidence and character of complications associated with Glidescope use were recorded. Predictors of Glidescope intubation failure were determined using a logistic regression analysis. Overall success for Glidescope intubation was 97% (1,944 of 2,004). As a primary technique, success was 98% (1,712 of 1,755), whereas success in patients with predictors of difficult direct laryngoscopy was 96% (1,377 of 1,428). Success for Glidescope intubation after failed direct laryngoscopy was 94% (224 of 239). Complications were noticed in 1% (21 of 2,004) of patients and mostly involved minor soft tissue injuries, but major complications, such as dental, pharyngeal, tracheal, or laryngeal injury, occurred in 0.3% (6 of 2,004) of patients. The strongest predictor of Glidescope failure was altered neck anatomy with presence of a surgical scar, radiation changes, or mass. These data demonstrate a high success rate of Glidescope intubation in both primary airway management and rescue-failed direct laryngoscopy. However, Glidescope intubation is not always successful and certain predictors of failure can be identified. Providers should maintain their competency with alternate methods of intubation, especially for patients with neck pathology.


Epidemiology of limb trauma interventions in France: current state and future projections.
The distributions and projections of trauma, treated according to the anatomical region, have not been studied in France. The objectives of this study were to obtain French epidemiological data specific to trauma procedures in orthopedic surgery, as well as to establish a statistical trend on the evolution of medical and surgical procedures resulting from this, since 2013 and over the years to come. Our hypothesis was that an increasing trend in trauma procedures since 2013 exists, with an epidemiological forecast of a continuing increase over 50 years, mainly in the context of the management of osteoporotic fractures related to the ageing French population. We conducted a retrospective study using national data to obtain completion of procedures between the start of 2013 and the end of 2021. From 2013 to 2021, we noted a total of 5,216,567 procedures related to orthopedic traumatology for an average of 579,618 procedures per year. We noted an overall increase in all procedures, continuing from 2013 to 2019, with an average annual increase of 1.125%. The most commonly performed procedure was osteosynthesis, with an average of 276,989 procedures per year. This was followed by wound sutures with an average of 185,023 procedures, orthopedic reductions of fractures and/or dislocations at an average of 62,960, then arthroplasties with 25,425 procedures per year, musculotendinous ruptures were 19,755 procedures per year, surgical reductions of fractures and/or dislocations represented 6,920 procedures per year, and fasciotomies with 2,848 procedures. From 2013 to 2021, there was an annual average of 276,989 osteosynthesis procedures. Open osteosynthesis, with an average of 146,547 procedures per year, represented 55% of osteosynthesis procedures. Fractures of the proximal end of the femur represented 79,549 procedures on average per year, including 46,621 (58%) involving the trochanter, while 32,852 (41%) were of the femoral neck. Wrist fractures accounted for an annual average of 55,300. Hand fractures represented an annual average of 38,444, of which 52.2% were closed (17,778). On average, 1000 fractures per year involved the carpus without scaphoid involvement, and 2177 scaphoid fractures. Ankle fractures represented 37,951 procedures on average per year, including 74% of the malleolar complex (28,199). Leg fractures represented 17,613 procedures per year, 58% tibial diaphysis (10,091), 41% tibial plateau (6,857). The strengths of this study are the exhaustiveness of the data, presenting all the Common Classification of Medical Procedures (CCAM) chosen during the defined period. This study allowed us to establish, to our knowledge, the first epidemiological database of French orthopedic traumatology. IV; epidemiological descriptive study.


The diagnostic challenge of metastatic linitis plastica. Two cases and a consideration of the problem.
Linitis plastica of the stomach is usually difficult to diagnose preoperatively and can extend locally and metastasize widely before recognition. This insidious manner of spread may cause unusual presentations in organs distant from the stomach. The authors recently treated two patients who were initially found to have radiologic abnormalities of the colon and bladder, respectively. One patient was surgically explored with a view towards the resection of a primary colonic tumor, the other to determine the nature of a bladder tumor. Intraoperative histologic interpretation of frozen tissue samples from the gastric wall in each case radically altered the surgical approach and the prognosis. The clinical presentations illustrate that it may be difficult to obtain preoperative diagnostic tissue samples in such cases and that it is important for the surgeon to inspect and palpate the stomach wall during all abdominal explorations for cancer.


Occurrence and profiling of multiple nitrosamines in source water and drinking water of China.
The occurrence of multiple nitrosamines was investigated in 54 drinking water treatment plants (DWTPs) from 30 cities across major watersheds of China, and the formation potential (FP) and cancer risk of the dominant nitrosamines were studied for profiling purposes. The results showed that N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosodi-n-butylamine (NDBA) were the most abundant in DWTPs, and the concentrations in source water and finished water samples were not detected (ND) -53.6ng/L (NDMA), ND -68.5ng/L (NDEA), ND -48.2ng/L (NDBA). The frequencies of detection in source waters were 64.8%, 61.1% and 51.8%, and 57.4%, 53.7%, and 37% for finished waters, respectively. Further study indicated that the FPs of the three main nitrosamines during chloramination were higher than those during chlorination and in drinking water. The results of Principal Components Analysis (PCA) showed that ammonia was the most closely associated factor in nitrosamine formation in the investigated source water; however, there was no significant correlation between nitrosamine-FPs and the values of dominant water-quality parameters. The advanced treatment units (i.e., ozonation and biological activated carbon) used in DWTPs were able to control the nitrosamine-FPs effectively after disinfection. The target pollutants posed median and maximum cancer risks of 2.99×10(-5) and 35.5×10(-5) to the local populations due to their occurrence in drinking water.


Impaired adrenocortical function in very low birth weight infants after multiple pregnancies.
To evaluate the differences in adrenal function between very low birth weight (VLBW) infants from singleton and multiple pregnancies. Forty infants of birth weights less than 1500 g underwent an ACTH test. Thirty infants born from singleton pregnancies (singleton group) and ten born from multiple pregnancies (multiple group) were enrolled. A baseline blood sample was drawn for cortisol measurement and thereafter serum cortisol was measured 1 and 2 h after an i.v. injection of ACTH. In multiple pregnancies, the median basal cortisol level of the infants was significantly lower than that in the singletons. The median cortisol level at 1 and 2 h after administration of ACTH was significantly lower in infants from multiple gestations than in singletons. Of infants from the multiple gestation group six, and of the singleton infants 12, had baseline cortisol levels lower than the reference values (P=0.48). One hour after ACTH stimulation all multiple and 53% of the singleton group infants showed a subnormal (<500 nmol/l, P=0.007) cortisol response. Two hours after ACTH, nine multiple group patients and 43% of the singletons had subnormal (<500 nmol/l, P=0.01) stimulated cortisol levels. We have concluded that VLBW infants from multiple gestations seem to be at an increased risk of insufficient postnatal adrenocortical function. In the future, specific attention should be paid to evaluate further newborn infants from multiple pregnancies with regard to a possible benefit of hydrocortisone substitution in stressful clinical situations.


[Sonographic assessment of tumor spread in rectal cancer].
The authors present the combined method of sonographic assessment of rectal carcinomas in respect of spread of tumour as well as metastasising, using linear rectal sounds (Aloka-Hellige) and rotating rectal sounds (Brüel-Kjear). This method involves further diagnostic progress compared with the methods employed to date. The article comprises application in 24 patients with histologically confirmed carcinoma of the rectum.


Treatment of Invasive Brain Tumors Using a Chain-like Nanoparticle.
Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood-tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment.


Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system.
As a potent therapeutic agent, small interfering RNA (siRNA) has been exploited to silence critical genes involved in tumor initiation and progression. However, development of a desirable delivery system is required to overcome the unfavorable properties of siRNA such as its high degradability, molecular size, and negative charge to help increase its accumulation in tumor tissues and promote efficient cellular uptake and endosomal/lysosomal escape of the nucleic acids. In this study, we developed a new activatable cell-penetrating peptide (ACPP) that is responsive to an acidic tumor microenvironment, which was then used to modify the surfaces of siRNA-loaded liposomes. The ACPP is composed of a cell-penetrating peptide (CPP), an acid-labile linker (hydrazone), and a polyanionic domain, including glutamic acid and histidine. In the systemic circulation (pH 7.4), the surface polycationic moieties of the CPP (polyarginine) are "shielded" by the intramolecular electrostatic interaction of the inhibitory domain. When exposed to a lower pH, a common property of solid tumors, the ACPP undergoes acid-catalyzed breakage at the hydrazone site, and the consequent protonation of histidine residues promotes detachment of the inhibitory peptide. Subsequently, the unshielded CPP would facilitate the cellular membrane penetration and efficient endosomal/lysosomal evasion of liposomal siRNA. A series of investigations demonstrated that once exposed to an acidic pH, the ACPP-modified liposomes showed elevated cellular uptake, downregulated expression of polo-like kinase 1, and augmented cell apoptosis. In addition, favorable siRNA avoidance of the endosome/lysosome was observed in both MCF-7 and A549 cells, followed by effective cytoplasmic release. In view of its acid sensitivity and therapeutic potency, this newly developed pH-responsive and ACPP-mediated liposome system represents a potential platform for siRNA-based cancer treatment.


[Learning how to prepare the child to face difficult experiences].
This paper presents some considerations about the importance of nursing students learning to prepare children to face difficult situations. The author focuses on her experience as an instructor of undergraduate nursing students in a children's emergency room. She tells how she perceives the students and his learning experience in preparing children for these situations. She describes how facilitates this learning process for the student, by promoting an atmosphere of understanding, respect, trust and freedom to perceive, reflect and act.


Evidence-based asthma management.
In 2002 the National Asthma Education and Prevention Program published evidence-based guidelines for the diagnosis and management of asthma, but there are some unresolved asthma-management issues that need further research. For asthmatic children inhaled corticosteroids are more beneficial than as-needed use of beta(2) agonists, long-acting beta(2) agonists, theophylline, cromolyn sodium, nedocromil, or any combination of those. Leukotriene modifiers are an alternative but not a preferred treatment; they should be considered if the medication needs to be administered orally rather than via inhalation. Cromolyn sodium and nedocromil are effective long-term asthma-control medications, but they are not as effective as inhaled corticosteroids. There is insufficient evidence to determine whether cromolyn benefits maintenance of childhood asthma. Cromolyn sodium and nedocromil are alternatives, but not preferred treatments for mild persistent asthma. Cromolyn may be useful as a preventive therapy prior to exertion or unavoidable exposure to allergens. Regular inhalation of corticosteroids controls asthma significantly better than as-needed beta(2) agonists. No studies have examined the long-term impact of regular inhaled corticosteroids on lung function in children <or= 5 years old. As monotherapy, inhaled corticosteroids are more effective than long-acting beta(2) agonists. The asthma-control benefit of inhaled corticosteroids decidedly outweighs the risks from inhaled corticosteroids. There is no high-level evidence that low-to-medium-dose inhaled corticosteroids have ocular toxicity or important effects on hypothalamic-pituitary-adrenal function in children. Antibiotic therapy has no role in asthma management unless there is a bacterial comorbidity, but further research is needed on the relationship between sinusitis and asthma exacerbation. The asthma care plan should include a written asthma action plan for the patient, but there is inadequate evidence as to whether the asthma action plan should be based on symptoms or on peak flow monitoring. There is low-level evidence that helium-oxygen mixture (heliox) may be of benefit in the first hour of an acute asthma attack but less advantageous after that first hour. Metered-dose inhalers are no more or less effective, overall, than other aerosol-delivery devices for the delivery of beta(2) agonists or inhaled corticosteroids, so the least expensive delivery method should be chosen.


Designer probiotics: Opening the new horizon in diagnosis and prevention of human diseases.
Probiotic microorganisms have been used for therapeutic purposes for over a century, and recent advances in biotechnology and genetic engineering have opened up new possibilities for developing therapeutic approaches using indigenous probiotic microorganisms. Diseases are often related to metabolic and immunological factors, which play a critical role in their onset. With the help of advanced genetic tools, probiotics can be modified to produce or secrete important therapeutic peptides directly into mucosal sites, increasing their effectiveness. One potential approach to enhancing human health is through the use of designer probiotics, which possess immunogenic characteristics. These genetically engineered probiotics hold promise in providing novel therapeutic options. In addition to their immunogenic properties, designer probiotics can also be equipped with sensors and genetic circuits, enabling them to detect a range of diseases with remarkable precision. Such capabilities may significantly advance disease diagnosis and management. Furthermore, designer probiotics have the potential to be used in diagnostic applications, offering a less invasive and more cost-effective alternative to conventional diagnostic techniques. This review offers an overview of the different functional aspects of the designer probiotics and their effectiveness on different diseases and also, we have emphasized their limitations and future implications. A comprehensive understanding of these functional attributes may pave the way for new avenues of prevention and the development of effective therapies for a range of diseases.


In vivo targets of Salmonella FinO include a FinP-like small RNA controlling copy number of a cohabitating plasmid.
FinO-domain proteins represent an emerging family of RNA-binding proteins (RBPs) with diverse roles in bacterial post-transcriptional control and physiology. They exhibit an intriguing targeting spectrum, ranging from an assumed single RNA pair (FinP/traJ) for the plasmid-encoded FinO protein, to transcriptome-wide activity as documented for chromosomally encoded ProQ proteins. Thus, the shared FinO domain might bear an unusual plasticity enabling it to act either selectively or promiscuously on the same cellular RNA pool. One caveat to this model is that the full suite of in vivo targets of the assumedly highly selective FinO protein is unknown. Here, we have extensively profiled cellular transcripts associated with the virulence plasmid-encoded FinO in Salmonella enterica. While our analysis confirms the FinP sRNA of plasmid pSLT as the primary FinO target, we identify a second major ligand: the RepX sRNA of the unrelated antibiotic resistance plasmid pRSF1010. FinP and RepX are strikingly similar in length and structure, but not in primary sequence, and so may provide clues to understanding the high selectivity of FinO-RNA interactions. Moreover, we observe that the FinO RBP encoded on the Salmonella virulence plasmid controls the replication of a cohabitating antibiotic resistance plasmid, suggesting cross-regulation of plasmids on the RNA level.


Novel insights on the relationship between T-tubular defects and contractile dysfunction in a mouse model of hypertrophic cardiomyopathy.
Abnormalities of cardiomyocyte Ca(2+) homeostasis and excitation-contraction (E-C) coupling are early events in the pathogenesis of hypertrophic cardiomyopathy (HCM) and concomitant determinants of the diastolic dysfunction and arrhythmias typical of the disease. T-tubule remodelling has been reported to occur in HCM but little is known about its role in the E-C coupling alterations of HCM. Here, the role of T-tubule remodelling in the electro-mechanical dysfunction associated to HCM is investigated in the Δ160E cTnT mouse model that expresses a clinically-relevant HCM mutation. Contractile function of intact ventricular trabeculae is assessed in Δ160E mice and wild-type siblings. As compared with wild-type, Δ160E trabeculae show prolonged kinetics of force development and relaxation, blunted force-frequency response with reduced active tension at high stimulation frequency, and increased occurrence of spontaneous contractions. Consistently, prolonged Ca(2+) transient in terms of rise and duration are also observed in Δ160E trabeculae and isolated cardiomyocytes. Confocal imaging in cells isolated from Δ160E mice reveals significant, though modest, remodelling of T-tubular architecture. A two-photon random access microscope is employed to dissect the spatio-temporal relationship between T-tubular electrical activity and local Ca(2+) release in isolated cardiomyocytes. In Δ160E cardiomyocytes, a significant number of T-tubules (>20%) fails to propagate action potentials, with consequent delay of local Ca(2+) release. At variance with wild-type, we also observe significantly increased variability of local Ca(2+) transient rise as well as higher Ca(2+)-spark frequency. Although T-tubule structural remodelling in Δ160E myocytes is modest, T-tubule functional defects determine non-homogeneous Ca(2+) release and delayed myofilament activation that significantly contribute to mechanical dysfunction.


A highly color-stability white organic light-emitting diode by color conversion within hole injection layer.
We demonstrated a novel-structure white organic light-emitting devices (WOLEDs) composed of a greenish blue fluorescent emitting layer and a red fluorescent dye-doped hole injection layer. The spectra of WOLEDs show no change at a wide range current density operation and long-term continuous operation. We concluded that carriers recombined inside the emitting layer in the WOLEDs to produce a greenish blue electroluminescence (EL), and a part of the EL was absorbed by the red fluorescent guest doped hole injection layer and converted into red photoluminescence (PL); the whole white emission from the device was a mixture of the greenish blue EL and red PL.


Elevated Black Carbon Concentrations and Atmospheric Pollution around Singrauli Coal-Fired Thermal Power Plants (India) Using Ground and Satellite Data.
The tropospheric NO₂ concentration from OMI AURA always shows high concentrations of NO₂ at a few locations in India, one of the high concentrations of NO₂ hotspots is associated with the locations of seven coal-fired Thermal Power plants (TPPs) in Singrauli. Emissions from TPPs are among the major sources of black carbon (BC) soot in the atmosphere. Knowledge of BC emissions from TPPs is important in characterizing regional carbonaceous particulate emissions, understanding the fog/haze/smog formation, evaluating regional climate forcing, modeling aerosol optical parameters and concentrations of black carbon, and evaluating human health. Furthermore, elevated BC concentrations, over the Indo-Gangetic Plain (IGP) and the Himalayan foothills, have emerged as an important subject to estimate the effects of deposition and atmospheric warming of BC on the accelerated melting of snow and glaciers in the Himalaya. For the first time, this study reports BC concentrations and aerosol optical parameters near dense coal-fired power plants and open cast coal mining adjacent to the east IGP. In-situ measurements were carried out in Singrauli (located in south-east IGP) at a fixed site about 10 km from power plants and in transit measurements in close proximity to the plants, for few days in the month of January and March 2013. At the fixed site, BC concentration up to the 95 μgm-3 is observed with strong diurnal variations. BC concentration shows two maxima peaks during early morning and evening hours. High BC concentrations are observed in close proximity to the coal-fired TPPs (>200 μgm-3), compared to the outside domain of our study region. Co-located ground-based sunphotometer measurements of aerosol optical depth (AOD) show strong spatial variability at the fixed site, with AOD in the range 0.38⁻0.58, and the highest AOD in the range 0.7⁻0.95 near the TPPs in transit measurements (similar to the peak of BC concentrations). Additionally, the Angstrom exponent was found to be in the range 0.4⁻1.0 (maximum in the morning time) and highest in the proximity of TPPs (~1.0), suggesting abundance of fine particulates, whereas there was low Angstrom exponent over the surrounding coal mining areas. Low Angstrom exponent is characterized by dust from the unpaved roads and nearby coal mining areas. MODIS derived daily AOD shows a good match with the MICROTOPS AOD. The CALIPSO derived subtypes of the aerosol plot shows that the aerosols over Singrauli region are mainly dust, polluted dust, and elevated smoke. The preliminary study for few days provides information about the BC concentrations and aerosol optical properties from Singrauli (one of the NO₂ hotspot locations in India). This preliminary study suggests that long-term continuous monitoring of BC is needed to understand the BC concentrations and aerosol optical properties for better quantification and the estimation of the emission to evaluate radiative forcing in the region.


An earthquake gap south of Istanbul.
Over the last century the North Anatolian Fault Zone in Turkey has produced a remarkable sequence of large earthquakes. These events have now left an earthquake gap south of Istanbul and beneath the Marmara Sea, a gap that has not been filled for 250 years. Here we investigate the nature of the eastern end of this gap using microearthquakes recorded by seismographs primarily on the Princes Islands offshore Istanbul. This segment lies at the western terminus of the 1999 Mw7.4 Izmit earthquake. Starting from there, we identify a 30-km-long fault patch that is entirely aseismic down to a depth of 10 km. Our evidence indicates that this patch is locked and is therefore a potential nucleation point for another Marmara segment earthquake-a potential that has significant natural hazards implications for the roughly 13 million Istanbul residents immediately to its north.


TDGF1 is a novel predictive marker for metachronous metastasis of colorectal cancer.
Teratocarcinoma-derived growth factor 1 (TDGF1) is a member of the epidermal growth factor-cripto FRL1 cryptic protein family and is involved in the activation of several different signaling pathways during embryonic development and cellular transformation. Previous reports show that TDGF1 regulates the activation of several signaling pathways and controls cellular transformation in embryonic status, whereas its significance in colorectal cancer (CRC) is not yet fully understood. The present study comprised 55 patients who underwent surgery for CRC, as well as two cell lines derived from human CRC. The correlation of gene expression with clinical parameters in patients was assessed. The biological significance of TDGF1 expression was evaluated by knockdown experiments in the cell lines. Seventeen of 55 (30.9%) cases exhibited a higher TDGF1 expression in cancerous regions than in marginal non-cancerous regions. Patients with high TDGF1 expression were statistically susceptible to a recurrence of the disease, and showed poorer disease-free survival than those with low expression. The assessment of TDGF1 knock-down in the 2 cell lines demonstrated that the siRNA inhibition resulted in a statistically significant reduction in cell growth and invasion. In conclusion, the present data strongly suggest the usefulness of TDGF1 as a predictive marker for metachronous metastasis in CRC patients.


Complementation analysis and deletion mapping of Escherichia coli mutants defective in chemotaxis.
Motile, but generally nonchemotactic (che) mutants of Escherichia coli were examined for complementation and recombination with specialized lambdafla transducing phages. The complex complementation behavior of these mutants found previously in F-prime tests could largely be accounted for by intragenic complementation and by polarity effects. Mutants of the "cheA" class defined two genes, cheA and cheW, which appeared to be contranscribed. Mutants of the "cheB" class defined four genes, cheX, cheB, cheY, and cheZ, which also constituted a transcriptional unit. Mutants defective in cheA, cheW, cheX, or cheY function swam smoothly, with little or no tumbling, whereas cheB or cheZ mutants exhibited very high tumbling rates. These functions are probably involved in initiating of controlling changes in flagellar rotation in response to chemotactic stimuli.


European Census on Pediatric Surgery.
Detailed data on the distribution of pediatric surgical institutions in Europe are sparse. Therefore, the Section and Board of Pediatric Surgery of the Union of European Medical Specialists (UEMS) and the European Pediatric Surgeons' Association (EUPSA) jointly organized the first official census of the European centers of pediatric surgery (PS). After obtaining a list of pediatric surgical centers in Europe, a specialized questionnaire was created and made available on the Internet. General, workload, staff, and ancillary data were collected for the centers. Total 215 out of 431 centers answered. PS center density is 1 in every 177,000 children or 1 in every 1,142,000 inhabitants. Approximately 77% of the centers (167 out of 215) are training centers in PS. Every center has an average inpatients procedures/year equal to 1,588, and 92.6 neonatal procedures/year. There are 3.9 surgeons/100,000 children, and 1,662 neonates for every surgeon. In average every EU surgeon performs 202 procedures/year, of which 11 procedures are on neonates. Trainees represent the 38% of the total workforce, and there are 2.3 trainees for every staff aged > 60 years. The paper aims to offer a more grounded basis on which the future of PS in our Continent should be planned. Presented data will provide an invaluable help to all our colleagues, as well as national policy makers, to press for and to make better informed and well-grounded sound political choices in the field of PS.


[Novel site-specific endonuclease from Acinetobacter species M strain].
Site-specific endonuclease R. AspMI was isolated and purified to apparent functional homogeneity from Acinetobacter species (strain M). The enzyme recognizes symmetrical DNA sequence 5'-AGG decreases CCT-3' and cleaves it at the site indicated by the arrow forming blind DNA ends. The endonuclease is an isoschizomer of the StuI endonuclease. Cleavage of the DNA site was inhibited by dcm-methylation. AspMI is approximately equal to 30 kD monomer.


Hippo pathway deficiency reverses systolic heart failure after infarction.
Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.


Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.
Detectable levels of cardiac troponin T (cTnT) are strongly associated with structural heart disease and increased risk of death and adverse cardiovascular events; however, cTnT is rarely detectable in the general population using standard assays. To determine the prevalence and determinants of detectable cTnT in the population using a new highly sensitive assay and to assess whether cTnT levels measured with the new assay associate with pathological cardiac phenotypes and subsequent mortality. Cardiac troponin T levels were measured using both the standard and the highly sensitive assays in 3546 individuals aged 30 to 65 years enrolled between 2000 and 2002 in the Dallas Heart Study, a multiethnic, population-based cohort study. Mortality follow-up was complete through 2007. Participants were placed into 5 categories based on cTnT levels. Magnetic resonance imaging measurements of cardiac structure and function and mortality through a median of 6.4 (interquartile range, 6.0-6.8) years of follow-up. In Dallas County, the prevalence of detectable cTnT (≥0.003 ng/mL) was 25.0% (95% confidence interval [CI], 22.7%-27.4%) with the highly sensitive assay vs 0.7% (95% CI, 0.3%-1.1%) with the standard assay. Prevalence was 37.1% (95% CI, 33.3%-41.0%) in men vs 12.9% (95% CI, 10.6%-15.2%) in women and 14.0% (95% CI, 11.2%-16.9%) in participants younger than 40 years vs 57.6% (95% CI, 47.0%-68.2%) in those 60 years and older. Prevalence of left ventricular hypertrophy increased from 7.5% (95% CI, 6.4%-8.8%) in the lowest cTnT category (<0.003 ng/mL) to 48.1% (95% CI, 36.7%-59.6%) in the highest (≥0.014 ng/mL) (P < .001); prevalence of left ventricular systolic dysfunction and chronic kidney disease also increased across categories (P < .001 for each). During a median follow-up of 6.4 years, there were 151 total deaths, including 62 cardiovascular disease deaths. All-cause mortality increased from 1.9% (95% CI, 1.5%-2.6%) to 28.4% (95% CI, 21.0%-37.8%) across higher cTnT categories (P < .001). After adjustment for traditional risk factors, C-reactive protein level, chronic kidney disease, and N-terminal pro-brain-type natriuretic peptide level, cTnT category remained independently associated with all-cause mortality (adjusted hazard ratio, 2.8 [95% CI, 1.4-5.2] in the highest category). Adding cTnT categories to the fully adjusted mortality model modestly improved model fit (P = .02) and the integrated discrimination index (0.010 [95% CI, 0.002-0.018]; P = .01). In this population-based cohort, cTnT detected with a highly sensitive assay was associated with structural heart disease and subsequent risk for all-cause mortality.


Evaluation of methods for endoscopic staging of nasal polyposis.
Endoscopy is needed for reliable evaluation of the treatment of nasal polyposis. In this study, we compared the reproducibility of various score systems for staging nasal polyposis and the inter-individual variations between investigators. The mass of the polyps was assessed by five methods, three new techniques (numbers 1, 2 and 3) and two established ones (numbers 4 and 5). These were: 1, lateral imaging projecting the extension of the polyps by drawing on a schematic picture of the lateral wall of each nasal cavity; 2, assessment of polyp obstruction estimating the proportion of the total nasal cavity volume occupied by polyps; 3, nasal airway patency--determining the relationship between the patient's patent airway lumen and an imaginary maximal nasal airway lumen; 4, a score system with four steps ad modum Lildholdt et al.--determining their relationship to fixed anatomical landmarks; and 5, a score system with three steps ad modum Lund and Mackay--determining their relationship to the middle meatus. High correlations were found between the first and the second assessments by a given investigator with all five methods used to score nasal polyposis. High correlations were also shown between the various methods. When three investigators examined a given patient, there were no significant differences between the investigators using score systems 1, 3 and 4. However, with score systems 2 and 5, there was insufficient agreement between the investigators. The patient's symptom of nasal blockage was not a good indicator of the size of the polyps, especially as regards small polyps. Two of the best methods tested (1 and 4) were selected for further clinical studies regarding evaluation of the sensitivity of score systems to detect changes in polyp size during treatment.


[Treatment of "difficult" duodenal stump].
The Plenk method in the author's modification was successfully applied in resection of the stomach "for exclusion" in 22 patients. When there was a threatening incompetence of the duodenal stump sutures, to prevent generalization of peritonitis the stump in 24 patients was covered with a "hood" of the greater omentum and external drainage of this space was installed; the procedure was an alternative of duodenostomy. Incompetence occurred in 3 cases with subsequent recovery. In resection of the stomach for recurrent ulcer after previous vagotomy combined with gastroduodenostomy after Jaboulay, the defects in the duodenal wall were closed with a demucosed antral-pyloric gastric segment after the author's method. The operation was conducted on 4 patients.


Periapical bone response to bacterial lipopolysaccharide is shifted upon cyclooxygenase blockage.
Infection, inflammation and bone resorption are closely related events in apical periodontitis development. Therefore, we sought to investigate the role of cyclooxygenase (COX) in osteoclastogenesis and bone metabolism signaling in periapical bone tissue after bacterial lipopolysaccharide (LPS) inoculation into root canals. Seventy two C57BL/6 mice had the root canals of the first molars inoculated with a solution containing LPS from E. coli (1.0 mg/mL) and received selective (celecoxib) or non-selective (indomethacin) COX-2 inhibitor. After 7, 14, 21 and 28 days the animals were euthanized and the tissues removed for total RNA extraction. Evaluation of gene expression was performed by qRT-PCR. Statistical analysis was performed using analysis of variance (ANOVA) followed by post-tests (α=0.05). LPS induced expression of mRNA for COX-2 (Ptgs2) and PGE2 receptors (Ptger1, Ptger3 and Ptger4), indicating that cyclooxygenase is involved in periapical response to LPS. A signaling that favours bone resorption was observed because Tnfsf11 (RANKL), Vegfa, Ctsk, Mmp9, Cd36, Icam, Vcam1, Nfkb1 and Sox9 were upregulated in response to LPS. Indomethacin and celecoxib differentially modulated expression of osteoclastogenic and other bone metabolism genes: celecoxib downregulated Igf1r, Ctsk, Mmp9, Cd36, Icam1, Nfkb1, Smad3, Sox9, Csf3, Vcam1 and Itga3 whereas indomethacin inhibited Tgfbr1, Igf1r, Ctsk, Mmp9, Sox9, Cd36 and Icam1. We demonstrated that gene expression for COX-2 and PGE2 receptors was upregulated after LPS inoculation into the root canals. Additionally, early administration of indomethacin and celecoxib (NSAIDs) inhibited osteoclastogenic signaling. The relevance of the cyclooxygenase pathway in apical periodontitis was shown by a wide modulation in the expression of genes involved in both bone catabolism and anabolism.


Glomerular volume and clinicopathologic features related to disease severity in renal biopsies of African Americans and whites in the southeastern United States.
African Americans have a 4-fold greater risk than whites for developing end-stage renal disease. Glomerulomegaly, possibly related to obesity, has been identified in high-risk populations and is suggested to be a marker for end-stage renal disease risk. To investigate differences in glomerular size and patient clinical characteristics at the time of renal biopsy for the major diseases contributing to end-stage renal disease. Mean glomerular tuft volumes were estimated by the Weibel-Gomez method (1964) in native renal biopsies of 203 African American and 100 white patients 18 years of age and older by point counting on a stereologic grid. Glomerulosclerosis was graded on individual glomeruli from 0 to 4, and a glomerular sclerosis index was calculated for each biopsy. Relationships between the mean volume of nonsclerotic glomeruli, age, sex, race, sclerosis index, cortical fibrosis, estimated glomerular filtration rate, body mass index, and disease diagnosis were analyzed. Racial differences in mean volume of nonsclerotic glomeruli and body mass index were not significant in any disease category, and African Americans had more severe disease as determined by sclerosis index, cortical fibrosis, and estimated glomerular filtration rate only in focal segmental glomerulosclerosis. For all patients, increased sclerosis index and cortical fibrosis and lower estimated glomerular filtration rate were best predicted by increased age (P < .001). For approximately the same severity of disease, African Americans were 10 years or more younger than whites with the difference being seen in all disease categories except membranous glomerulonephritis and diabetes. Glomerulomegaly relative to whites was not a distinguishing feature of African American renal biopsies.


Effects of synergistic Fenton-microwave treatment on the antioxidant stress of soluble polysaccharides and the physicochemical properties of insoluble polysaccharides from Gelidium amansii.
In this study, we individually obtained crude Gelidium amansii water-soluble polysaccharides and water-insoluble polysaccharides (GAIPs) using an improved Fenton-microwave synergistic treatment. The former were purified by alcohol precipitation and deproteinization to obtain Gelidium amansii water-soluble polysaccharides (GASPs), and their effects on the oxidative stress resistance of Caenorhabditis elegans were investigated. GAIPs were studied for their physicochemical properties, including hydration characteristics, adsorption, and cation-exchange capacity. The results showed that compared with the negative control, 1.0 mg/mL GASPs significantly upregulated (>1.70-fold) the expression of antioxidant-related genes, such as daf-16, sir-2.1, and skn-1 (p < 0.05), which prolonged the mean survival time and increased the mean number of head bobbing (p < 0.05). The hydration characteristics and oil-holding capacity of GAIPs were lower than those of G. amansii powder (GAP) and G. amansii filtrate residue (GADP). However, the adsorption capacity of GAIPs for cholesterol (pH 7.0) and sodium cholate and the cation-exchange capacity were significantly better than those of GAP (5.17, 13.16 & 1.63 times, p < 0.05) and GADP (8.42, 6.39, & 2.05 times, p < 0.05). To conclude, the synergistic Fenton-microwave treatment contributed to the increase in the oxidative stress resistance of GASPs and improved the adsorption capacity and cation-exchange capacity of GAIPs.


4D Flow with MRI.
Magnetic resonance imaging (MRI) has become an important tool for the clinical evaluation of patients with cardiac and vascular diseases. Since its introduction in the late 1980s, quantitative flow imaging with MRI has become a routine part of standard-of-care cardiothoracic and vascular MRI for the assessment of pathological changes in blood flow in patients with cardiovascular disease. More recently, time-resolved flow imaging with velocity encoding along all three flow directions and three-dimensional (3D) anatomic coverage (4D flow MRI) has been developed and applied to enable comprehensive 3D visualization and quantification of hemodynamics throughout the human circulatory system. This article provides an overview of the use of 4D flow applications in different cardiac and vascular regions in the human circulatory system, with a focus on using 4D flow MRI in cardiothoracic and cerebrovascular diseases.


A simplified metabolic network reconstruction to promote understanding and development of flux balance analysis tools.
GEnome-scale Network REconstructions (GENREs) mathematically describe metabolic reactions of an organism or a specific cell type. GENREs can be used with a number of constraint-based reconstruction and analysis (COBRA) methods to make computational predictions on how a system changes in different environments. We created a simplified GENRE (referred to as iSIM) that captures central energy metabolism with nine metabolic reactions to illustrate the use of and promote the understanding of GENREs and constraint-based methods. We demonstrate the simulation of single and double gene deletions, flux variability analysis (FVA), and test a number of metabolic tasks with the GENRE. Code to perform these analyses is provided in Python, R, and MATLAB. Finally, with iSIM as a guide, we demonstrate how inaccuracies in GENREs can limit their use in the interrogation of energy metabolism.


Can a tablet-based cancellation test identify cognitive impairment in older adults?
There has been a growing interest in using computerized cognitive assessment to detect age-related cognitive disorders. We have developed a tablet-based cancellation test (e-CT), previously shown as a reliable measure of executive functions and free of effect of familiarity with computer-based devices in healthy older adults. This study aimed to investigate the influence of demographics and current daily use of computer-based devices in older adults with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). We further studied the ability of the e-CT to discriminate MCI and AD patients from older adults with normal cognition (NC). The e-CT was administered to 325 older adults (NC = 112, MCI = 129, AD = 84). Subjects also performed the K-T test, a paper-and-pencil cancellation test from which the e-CT was developed. Multiple linear regression analyses were conducted to assess the contribution of demographics and current daily use of computer-based devices on the e-CT in patient groups. The Receiver Operating Characteristic (ROC) curves and the Area Under the Curve (AUC) were established to compare the efficacy of the e-CT and the K-T test to classify subjects into diagnostic groups. In the MCI group, age (B = -0.37, p<0.001) and current daily use of computer-based devices (B = 5.85, p<0.001) were associated with the number of correct cancellations of the e-CT. In the AD group, only current daily use of a computer-based device was a significant contributor (B = 6.28, p<0.001). The e-CT (AUC = 0.811; 95% confidence interval [CI]: 0.756-0.867) and the K-T (AUC = 0.837; CI: 0.787-0.887) showed good and comparable diagnostic accuracy to discriminate between MCI and NC subjects. To discriminate between NC and AD, both tests showed high diagnostic accuracy, with the AUC values of 0.923 (CI: 0.876-0.971) and 0.929 (95%CI: 0.886-0.972) for the e-CT and the K-T, respectively. The e-CT presents satisfying discriminative validity and is a promising tool for detection of early cognitive impairment in older adults.


[Expert assessment of work disability--do we realize the effects?].
Three inquiries on the results of medical expertises concerning incapacitation for work in cases where employers had doubted this fact, seem to establish that the Medical Service of the Social Health Insurance (MDK) is quite capable of keeping improper use of the epithet "unfit for work" in check. If the design of the studies is critically analysed, it becomes evident that most problems are still unsolved. More clarity regarding the sense or nonsense of this work-intensive topic may result from a carefully and completely planned randomised trial. Such a study appears mandatory, the more so since the economic benefit of the expertises does not seem to be very bright, taking several hypotheses into consideration.


TSC1 regulates the balance between effector and regulatory T cells.
Mammalian target of rapamycin (mTOR) plays a crucial role in the control of T cell fate determination; however, the precise regulatory mechanism of the mTOR pathway is not fully understood. We found that T cell-specific deletion of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted in augmented Th1 and Th17 differentiation and led to severe intestinal inflammation in a colitis model. Conditional Tsc1 deletion in Tregs impaired their suppressive activity and expression of the Treg marker Foxp3 and resulted in increased IL-17 production under inflammatory conditions. A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stronger effector-like phenotype compared with Tsc1-/- Foxp3+ Tregs. Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of the mTOR target S6K1. Moreover, IL-17 production was enhanced by Treg-specific double deletion of Tsc1 and Foxo3a. Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination.


Effect of radiologists' experience with an adaptive statistical iterative reconstruction algorithm on detection of hypervascular liver lesions and perception of image quality.
To prospectively evaluate whether clinical experience with an adaptive statistical iterative reconstruction algorithm (ASiR) has an effect on radiologists' diagnostic performance and confidence for the diagnosis of hypervascular liver tumors, as well as on their subjective perception of image quality. Forty patients, having 65 hypervascular liver tumors, underwent contrast-enhanced MDCT during the hepatic arterial phase. Image datasets were reconstructed with filtered backprojection algorithm and ASiR (20%, 40%, 60%, and 80% blending). During two reading sessions, performed before and after a three-year period of clinical experience with ASiR, three readers assessed datasets for lesion detection, likelihood of malignancy, and image quality. For all reconstruction algorithms, there was no significant change in readers' diagnostic accuracy and sensitivity for the detection of liver lesions, between the two reading sessions. However, a 60% ASiR dataset yielded a significant improvement in specificity, lesion conspicuity, and confidence for lesion likelihood of malignancy during the second reading session (P < 0.0001). The 60% ASiR dataset resulted in significant improvement in readers' perception of image quality during the second reading session (P < 0.0001). Clinical experience using an ASiR algorithm may improve radiologists' diagnostic performance for the diagnosis of hypervascular liver tumors, as well as their perception of image quality.


The evolving algorithm of biological selection in severe asthma.
New therapeutic options for severe asthma have recently emerged, mostly in the form of monoclonal antibodies ("biologicals") targeting relevant inflammatory pathways. Currently available agents target different aspects of "Type 2" immunity, and their indications often include overlapping patient groups. We present a round-table discussion that took place during the Annual Meeting of the Respiratory Effectiveness Group (REG), on the reasoning behind the use of different add-on medications for severe asthma, and crucially, on selection strategies. The proposed rational is based on current evidence, including real-life studies, as well as on the appreciation of the relevant complexities. Direct head-to-head comparisons of biologicals are lacking; therefore, algorithms for initial choice and potential switch between agents should be based on understanding the key characteristics of different options and the development of a clear plan with predefined targets and shared decision-making, in a structured way.


Healthcare Ethics During a Pandemic.
As clinicians and support personnel struggle with their responsibilities to treat during the current COVID-19 pandemic, several ethical issues have emerged. Will healthcare workers and support staff fulfill their duty to treat in the face of high risks? Will institutional and government leaders at all levels do the right things to help alleviate healthcare workers risks and fears? Will physicians be willing to make hard, resource-allocation decisions if they cannot first husband or improvise alternatives?With our healthcare facilities and governments unprepared for this inevitable disaster, front-line doctors, advanced providers, nurses, EMS, and support personnel struggle with acute shortages of equipment-both to treat patients and protect themselves. With their personal and possibly their family's lives and health at risk, they must weigh the option of continuing to work or retreat to safety. This decision, made daily, is based on professional and personal values, how they perceive existing risks-including available protective measures, and their perception of the level and transparency of information they receive. Often, while clinicians get this information, support personnel do not, leading to absenteeism and deteriorating healthcare services. Leadership can use good risk communication (complete, widely transmitted, and transparent) to align healthcare workers' risk perceptions with reality. They also can address the common problems healthcare workers must overcome to continue working (ie, risk mitigation techniques). Physicians, if they cannot sufficiently husband or improvise lifesaving resources, will have to face difficult triage decisions. Ideally, they will use a predetermined plan, probably based on the principles of Utilitarianism (maximizing the greatest good) and derived from professional and community input. Unfortunately, none of these plans is optimal.


Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma.
Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and extra-terminal domain (BET) proteins are activated in a noncanonical fashion by TGFβ, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (P < 0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (P < 0.001), with associated perturbations in the cell cycle leading to cell-cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.


Holmium laser enucleation of the prostate: comparison of outcomes according to prostate size in 97 Japanese patients.
To review the outcomes associated with holmium laser enucleation of the prostate (HoLEP) to identify the efficacy and safety in relation to the prostate size in subjects with symptomatic benign prostatic hyperplasia (BPH). A retrospective review was conducted of the data from 97 patients who had undergone HoLEP combined with mechanical morcellation. All patients completed both the preoperative and the 6-month postoperative assessment. The morbidity and improvement in the outcome variables were compared in groups classified according to the baseline prostate volume: <50 cm3 (group 1), >or=50 cm3-<100 cm3 (group 2), and >or=100 cm3 (group 3). The peak urinary flow rate (Qmax), postvoiding residual urine volume (PVR), International Prostate Symptom Score (IPSS) and quality of life (QoL) score all improved significantly after HoLEP, and no significant differences were observed among the groups. The mean total operation times were 70.3, 99.1, and 155.5 minutes for groups 1, 2, and 3, respectively (P < 0.0001 group 1 v group 2 v group 3). The mean times required to complete the enucleation and morcellation were 44.7 v 66.5 v 107.3 minutes (P < 0.0001) and 8.6 v 10.9 v 23.8 minutes (P < 0.0001), respectively. The efficacy for tissue enucleation and morcellation was 0.44 v 0.57 v 0.75 g/min (P < 0.0001) and 2.5 v 3.3 g/min (P = 0.016) v 3.2 g/min (P = 0.035). The mean hemoglobin loss after HoLEP was greater in group 3 than in group 1 (P = 0.036), but it was still low (1.8 g/dL). Major complications included bladder-muscle injury in one patient in group 2 and one in group 3 and long-lasting urinary incontinence in one patient in group 1 and one in group 2 (2.1%). No blood transfusion or transurethral resection syndrome was observed in any of the groups. Holmium laser enucleation is an effective treatment for symptomatic BPH independent of prostate size.


The Prevalence and Cost of Medicare Beneficiaries Diagnosed and At Risk for Opioid Abuse, Dependence, and Poisoning.
Reliance on prescription opioids to manage pain has been associated with increases in diversion, overdose, and addiction. Prevalence of misuse and abuse has been shown to be higher among government-insured populations than commercially insured populations. However, the prevalence and costs of misuse/abuse among the Medicare fee-for-service (FFS) population has not been studied. To (a) determine the prevalence and costs of prescription opioid misuse/abuse and (b) evaluate the prevalence and costs associated with those identified as at risk for opioid misuse/abuse in Medicare FFS beneficiaries. This retrospective case-control study used Medicare claims data for the calendar years of 2010 and 2011 and included Medicare beneficiaries aged at least 18 years. The index date was the date of first diagnosed misuse/abuse or at risk for abuse and had to occur between July 1, 2010, and June 30, 2011, and beneficiaries had to have at least 6 months continuous eligibility before and after the index date. Matching (1:1) was used for comparing opioid misusers/abusers with nonabuser controls, as well as comparing patients at risk for opioid abuse with controls not at risk for abuse. Controls were matched to cases by gender, age, disability, and geographic region. The index date of the control patient was set equal to the index date of the matched case. Prevalence of misuse/abuse in the Medicare FFS population was 13.1 per 1,000 persons, with the majority among patients receiving Medicare based on disability (76.2%). The prevalence of at risk for misuse/abuse was 117.4 per 1,000 persons. Approximately half of the Medicare FFS patients used an opioid. Overall total annual unadjusted mean costs of health care resources were significantly greater for abusers than for matched controls ($46,194 vs. $21,964; P < 0.0001), with a mean annual excess cost of $24,230. The overall total adjusted 6-month post-index mean costs of health care resources for abusers was significantly greater than that of matched controls ($33,942 vs. $10,754; P < 0.0001), with a mean excess cost of $23,188. The prevalence of diagnosed abuse among Medicare FFS population (13.1 per 1,000 persons) was higher than other payer groups studied using similar ICD-9-CM codes, and the majority of abuse was among those receiving Medicare based on disability (76.2%). The prevalence of at-risk abuse was 9 times higher than the prevalence of diagnosed abuse. As with other studies, health care resource utilization and costs were significantly greater for diagnosed abuse than matched controls. This study was sponsored by Pfizer. Roland is a Pfizer employee and stockholder and was involved in all aspects of the study as part of a mid-career fellowship in pharmacoeconomics with the University of Utah. Ye and Stevens are employees of University of Utah, and Oderda was an employee of University of Utah, which received financial support from Pfizer in connection with the development of this manuscript. Oderda also reports consulting fees from Pfizer, Trevena, and Pacira, unrelated to this study. The results of this study were presented at the Academy of Managed Care Pharmacy Nexus 2015; October 26-29, 2015; Orlando, FL, and the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2016; April 19-22, 2016; San Francisco, CA.


The asymptomatic carotid bruit.
Management of the asymptomatic carotid bruit remains a controversial subject. The purpose of this study is to determine whether or not such bruits are important risk factors in the evolution of stroke. Since April 1977, 87 patients with 131 asymptomatic carotid bruits were evaluated with the Gee oculoplethysmography (OPG). Eleven bruits (8.4%) were hemodynamically significant (ophthalmic artery/brachial artery systolic pressure index below 0.69 or a difference of 5 mm Hg or more between the eyes). The patients were reevaluated at 6-month intervals. The mean follow-up was 34 months (range, 1-60 months). During this period, 14 bruits (11.6%) that initially were nonhemodynamically significant (NHS) later became hemodynamically significant (HS). Patients with asymptomatic carotid bruits had a stroke incidence of 10.3 per cent. Patients with HS bruits had a stroke incidence of 24 per cent and a transient ischemic attack (TIA) incidence of 16 per cent, which were significantly higher (P greater than 0.01) compared to the patients with NHS bruits (4.8% incidence of stroke and 3.2% incidence of TIA). Nine patients (10.3%) developed strokes without antecedent TIA and six patients (6.9%) developed TIA. The strokes occurred in the cerebral hemisphere supplied by the carotid artery with HS bruit in three of six patients. The strokes in three patients with NHS bruits were on the same side of the bruits. The TIAs developed in four patients with HS bruits and in two patients with NHS bruits. The authors conclude that the patient with an asymptomatic HS carotid bruit has a high risk of developing a stroke and that surgical treatment is warranted.


Guessing with a Bit of Help.
What is the value of just a few bits to a guesser? We study this problem in a setup where Alice wishes to guess an independent and identically distributed (i.i.d.) random vector and can procure a fixed number of k information bits from Bob, who has observed this vector through a memoryless channel. We are interested in the guessing ratio, which we define as the ratio of Alice's guessing-moments with and without observing Bob's bits. For the case of a uniform binary vector observed through a binary symmetric channel, we provide two upper bounds on the guessing ratio by analyzing the performance of the dictator (for general k ≥ 1 ) and majority functions (for k = 1 ). We further provide a lower bound via maximum entropy (for general k ≥ 1 ) and a lower bound based on Fourier-analytic/hypercontractivity arguments (for k = 1 ). We then extend our maximum entropy argument to give a lower bound on the guessing ratio for a general channel with a binary uniform input that is expressed using the strong data-processing inequality constant of the reverse channel. We compute this bound for the binary erasure channel and conjecture that greedy dictator functions achieve the optimal guessing ratio.


Monocyte-derived CD1a+ and CD1a- dendritic cell subsets differ in their cytokine production profiles, susceptibilities to transfection, and capacities to direct Th cell differentiation.
We describe a phenotypically and functionally novel monocyte-derived dendritic cell (DC) subset, designated mDC2, that lacks IL-12 synthesis, produces high levels of IL-10, and directs differentiation of Th0/Th2 cells. Like conventional monocyte-derived DC, designated mDC1, mDC2 expressed high levels of CD11c, CD40, CD80, CD86, and MHC class II molecules. However, in contrast to mDC1, mDC2 lacked expression of CD1a, suggesting an association between cytokine production profile and CD1a expression in DC. mDC2 could be matured into CD83+ DC cells in the presence of anti-CD40 mAbs and LPS plus IFN-gamma, but they remained CD1a- and lacked IL-12 production even upon maturation. The lack of IL-12 and CD1a expression by mDC2 did not affect their APC capacity, because mDC2 stimulated MLR to a similar degree as mDC1. However, while mDC1 strongly favored Th1 differentiation, mDC2 directed differentiation of Th0/Th2 cells when cocultured with purified human peripheral blood T cells, further indicating functional differences between mDC1 and mDC2. Interestingly, the transfection efficiency of mDC2 with plasmid DNA vectors was significantly higher than that of mDC1, and therefore mDC2 may provide improved means to manipulate Ag-specific T cell responses after transfection ex vivo. Taken together, these data indicate that peripheral blood monocytes have the capacity to differentiate into DC subsets with different cytokine production profiles, which is associated with altered capacity to direct Th cell differentiation.


Anticancer Effect and Mechanism of Hydroxygenkwanin in Oral Squamous Cell Carcinoma.
The incidence and mortality of oral squamous cell carcinoma (OSCC) are high, and the number of oral cancers had risen in the world. However, chemotherapy drugs have numerous side effects. There is an urgent requirement to develop a novel drug that can be used to treat oral cancer. Hydroxygenkwanin (HGK) is a nature flavonoid extracted from Daphne genkwa Sieb. et Zucc. (Thymelaeaceae). Previous studies had demonstrated that HGK exhibits anticancer effect, but the effect is still unclear in oral cancer. HGK inhibited cell growth dose-dependently in SAS and OCEM1 cells. The functional enrichment analysis showed the significant pathway in cellular movement, cell cycle and cellular growth and proliferation. We further demonstrated the HGK induced the cell cycle arrest by flow cytometry and inhibited colony formation ability and cell movement. The western blot showed that HGK induced cell cycle arrest through p21 activation and caused intrinsic cell apoptosis pathway. HGK inhibited the cell invasion and migration through down-regulation vimentin. HGK might be an effective natural product for oral cancer therapy.