Vaccine approaches for antigen capture by liposomes.
Liposomes have been used as carriers for vaccine adjuvants and antigens due to their inherent biocompatibility and versatility as delivery vehicles. Two vial admixture of protein antigens with liposome-formulated immunostimulatory adjuvants has become a broadly used clinical vaccine preparation approach. Compared to freely soluble antigens, liposome-associated forms can enhance antigen delivery to antigen-presenting cells and co-deliver antigens with adjuvants, leading to improved vaccine efficacy. Several antigen-capture strategies for liposomal vaccines have been developed for proteins, peptides, and nucleic acids. Specific antigen delivery methodologies are discussed, including electrostatic adsorption, encapsulation inside the liposome aqueous core, and covalent and non-covalent antigen capture. Several commercial vaccines include active lipid components, highlighting an increasingly prominent role of liposomes and lipid nanoparticles in vaccine development. Utilizing liposomes to associate antigens offers potential advantages, including antigen and adjuvant dose-sparing, co-delivery of antigen and adjuvant to immune cells, and enhanced immunogenicity. Antigen capture by liposomes has demonstrated feasibility in clinical testing. New antigen-capture techniques have been developed and appear to be of interest for vaccine development.


Microscopical analysis of Candida albicans biofilms on heat-polymerised acrylic resin after chlorhexidine gluconate and sodium hypochlorite treatments.
The ability of Candida albicans to form biofilms on denture surfaces is a significant cofactor in the pathogenesis of denture stomatitis. In this study, we applied a differential staining approach and scanning electron microscopy (SEM) to analyse the effect of sodium hypochlorite and chlorhexidine gluconate on the viability, removal and morphology of C. albicans forming biofilms on denture acrylic using an in vitro model. Immediately after treatment, to distinguish live from dead C. albicans cells in the remaining biofilms, the specimens were stained differentially and analysed by confocal scanning laser microscopy. Moreover, morphological alterations of fungal cells were investigated using scanning electron microscopy. All disinfectant solutions killed all remaining fungal cells on the specimens. Interestingly, 4% chlorhexidine did not remove these cells from the acrylic resin surface whereas sodium hypochlorite solutions (1% and 2%) provided almost complete biofilm removal. Furthermore, treating the specimens with sodium hypochlorite induced cell morphology alterations, as seen in the residual fungal cells. Finally, according to our findings, it can be suggested that sodium hypochlorite solutions are the first choice as denture cleanser when compared with 4% chlorhexidine because those solutions not only killed C. albicans biofilms but also removed them from the heat-polymerised acrylic resin.


[Effect of various factors on the electric conductivity of mixed milk].
The authors evaluated the method of the determination of the electric conductivity of purchased milk for the estimation of the hygienic aspects of milk quality and for mass diagnosis of the inflammatory diseases of dairy cow mammary glands. The variability coefficient of duplicates varied from 1.37 to 3.09%. The study of the dependence of milk conductivity measurement on milk temperature revealed a statistically highly significant positive correlation between the values of these two factors. In the temperature range from 30 degrees C to 35 degrees C the coefficients of correlation ranged from 0.951 to 0.996. Furthermore, interference caused by milk acidity was examined during a five-day incubation of samples at 25 degrees C. A statistically significant difference was observed from the third hour of incubation (P less than 0.05) and a statistically highly significant difference from the fourth hour of incubation (P less than 0.01). The evaluation of the diagnostic value of the method of the measurement of electric conductivity in purchased milk revealed a positive correlation to the content of chloride ions (r = 0.69) and to the number of the cellular elements of milk (r = 0.33).


Frequent allelic losses and mutations of the p53 gene in human ovarian cancer.
The p53 gene on chromosome 17p is considered to be a tumor suppressor gene, and frequent mutations of the p53 gene have been found in a wide variety of human cancers. We examined 31 ovarian cancers for allelic losses and mutations of the p53 gene by polymerase chain reaction-single strand conformation polymorphism analysis as well as restriction fragment length polymorphism analysis. Allelic loss of the p53 gene was detected in 16 of 20 cases (80%). Mutations were detected in 9 of 31 cases (29%): 2 cases in exon 4; 5 cases in exons 5-6; and 2 cases in exons 7-8. In 8 of 9 cases, p53 mutations were accompanied by losses of the normal allele. These alterations of the p53 gene were commonly detected from stage I to stage IV. These results suggest that alterations of the p53 gene play an important role in the development of human ovarian cancers.


Do vaccines make best use of available resources? (in other words are they cost-effective?).
Vaccines are the most popular preventive intervention world-wide and are socially useful interventions. As with all social programmes, the effects of vaccines must be carefully assessed. Their economic significance lies partly in the burden of disease that can be avoided and partly in the competition for resources between vaccines and other interventions. Classic methods of economic evaluation depend on the evaluation of effectiveness and safety of each vaccine being evaluated and can indicate whether vaccination represent a good return for investment, especially if the wider social perspective is taken into account. The use of economic logic can also be applied to prioritize research into vaccines, both on the basis of ability of the target population to benefit and of the availability of good quality evidence.


Low plasma progesterone concentrations are accompanied by reduced luteal blood flow and increased size of the dominant follicle in dairy cows.
To investigate the influence of low plasma progesterone (P(4)) concentrations on luteal and ovarian follicular development as well as endometrial gene expression in the concomitant and subsequent estrous cycle, 20 lactating dairy (Holstein Friesian and Brown Swiss x Holstein Friesian) cows received either a single treatment with 25 mg prostaglandin F(2α) (PGF(2α)) on Day 4 Hour 12 (PG1; n = 8), or two treatments (25 mg PGF(2α) each) on Day 4 Hours 0 and 12 (PG2; n = 12) of the estrous cycle (Day 1, Hour 0 = ovulation). In four cows, ovulation occurred between 4 and 6 d after the second PGF(2α) treatment; these cows and one lame cow were excluded. In the 15 remaining cows with physiological interovulatory intervals (18 to 24 d), P(4), luteal size (LS) and blood flow (LBF), as well as follicular size (FS) and blood flow (FBF), were determined daily until Day 4, immediately prior to (0 h) and 12 h after each PGF(2α) treatment, and then every 2 d, from Day 5 to 8 d after the subsequent ovulation. Because P(4) did not differ (P > 0.05) between PG1 and PG2, cows were regrouped according to their mean P(4) concentration from Days 7 to 15, either P(4) <2 ng/mL (P(4)L; n = 7) or P(4) >2 ng/mL (P(4)H; n = 8). In the treatment cycle, LS was smaller in P(4)L than P(4)H on Days 13 (P = 0.01) and 15 (P = 0.03), and LBF was lower in P(4)L than P(4)H on Day 15 (P = 0.02). The dominant follicle of the first follicular wave was larger in P(4)L than P(4)H on Days 13 (P = 0.03), 15 (P = 0.03), and 17 (P = 0.01). In the subsequent cycle, there were no significant differences between P(4)L and P(4)H for P(4), FS, LS, and LBF; however, FBF was lower (P = 0.01) in P(4)L than P(4)H on Day 7. In Group P(4)L, endometrial expressions of estrogen receptor α and oxytocin receptor were lower (P = 0.05 and P = 0.03, respectively) at the estrus that preceded treatment compared to the post-treatment estrus. In summary, low P(4) during diestrus was associated with smaller LS, reduced LBF, and larger FS in the treatment cycle, but not in the subsequent cycle.


Validation of the Swedish version of the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM).
The purpose of this study was to perform an initial validation of a Swedish translation of the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM). The CORE-OM is a broad self-report instrument of psychological problems, designed as an outcome measure for evaluating the effects of psychological therapy. Participants included a non-clinical group of 229 university students and a clinical group of 619 persons from four primary care sites. The Swedish CORE-OM showed excellent acceptability, high internal consistency and test-retest reliability, as well as acceptable convergent validity. There was strong differentiation of the clinical and non-clinical samples, with the clinical group scoring significantly more psychological problems than the non-clinical group. Sensitivity to change was demonstrated in psychological treatments in primary care. Overall, the psychometric characteristics of the Swedish CORE-OM were very similar to the original UK data. Nevertheless, the validity of the Swedish version needs to be examined more in detail, in larger and more diverse samples. Our results so far, however, provide support for using the Swedish CORE-OM as a psychological problems measure. To our knowledge, there are few other relatively short measures in Swedish that are free to reprint that meet the demands for psychometric properties and utility in primary care settings in which patients typically present a broad range of psychological problems. The Swedish version of the CORE-OM is a valid questionnaire for assessing the severity of a broad range of psychological problems.


Resource utilization of total knee arthroplasty patients cared for on specialty orthopedic surgery units.
The use of specialized orthopedic surgery (SOS) units in total knee arthroplasty (TKA) patients is well established. The number and costs of arthoplasty surgeries continue to increase, requiring institutions to reexamine their existing practices for financial sustainability. The objective of this study was to determine whether having elective TKA patients in SOS units affects resource utilization and outcomes. The study was designed to retrospectively compare elective TKA patients from 1996 to 2004 admitted directly to SOS units with those admitted to nonorthopedic nursing (NON) units. The setting was an academic teaching hospital. Five thousand five hundred and thirty-four patients met inclusion criteria. Of these, 5082 (patients 91.8%) were admitted to SOS units and 452 (8.2%) to NON units. The primary outcomes measured were length of stay (LOS) and costs, adjusted for age, sex, surgical year, comorbidities, and American Society of Anesthesiologists status. Secondary outcomes were 30-day mortality, readmissions, reoperations, and discharge disposition. Mean age of the patients in SOS and NON units was 68.3 and 67.9 years, respectively (P = .50). Adjusted LOS was 0.234 days shorter in SOS units (95% CI: 0.083, 0.385). Adjusted total and hospital cost savings in the SOS unit group were $600 (95% CI: $122, $1079) and $594 (95% CI: $141, $1047), respectively. More NON-unit patients required unanticipated transfers to the intensive care unit (ICU) from the general postoperative nursing unit (3.1% vs. 1.63%; P = .023); however, the mean number of ICU days did not differ between groups. NON-unit patients were more likely to be discharged with home health care (P < .001). There were no differences in 30-day outcomes. Patients on SOS units following elective TKA have a reduced LOS and decreased total and hospital costs. Our results should encourage hospitals to reevaluate postoperative patient flow to optimize resource utilization.


Who owns the long term? Perspectives from global business leaders.
Day-to-day management is challenging enough for CEOs. How do they manage for the long term as well? We posed that question to four top executives of global companies. According to Maurice Levy, chairman and CEO of Publicis Groupe, building the future is really about building the present and keeping close to the front line--those who deal with your customers and markets. He also attributes his company's success in large part to knowing when to take action: In a market where clients' needs steer your long-term future, timing is everything. UPS Chairman and CEO Mike Eskew emphasizes staying true to your vision and values over the long run, despite meeting obstacles along the way. It took more than 20 years, and many lessons learned, to produce consistent profits in what is today the company's fastest-growing and most profitable business: international small packages. Wulf H. Bernotat, CEO of E.ON, examines the challenges facing business leaders and politicians as they try to balance energy needs against potential environmental damage. He calls for educating people about consumption and waste, and he maintains that a diverse and reliable mix of energy sources is the only way to ensure a secure supply while protecting our environment. Finally, Marianne Barner, the director of corporate communications and ombudsman for children's issues at IKEA, discusses how the company is taking steps to improve the environment and be otherwise socially responsible. For example, it's partnering with NGOs to address child labor issues and, on its own, is working to help mitigate climate change. IKEA's goals include using renewable sources for 100% of its energy needs and cutting its overall energy consumption by 25%.


Hematopoietic development from human embryonic stem cell lines.
The most common human cell-based therapy applied today is hematopoietic stem cell (HSC) transplantation. Currently, human bone marrow, mobilized peripheral blood, and umbilical cord blood represent the major sources of transplantable HSCs, but their availability for use is limited by both compatibility between donor and recipient and required quantity. Although increasing evidence suggests that somatic HSCs can be expanded to meet current needs, their in vivo potential is concomitantly compromised after ex vivo culture. In contrast, human embryonic stem cells (hESC) possess indefinite proliferative capacity in vitro and have been shown to differentiate into the hematopoietic cell fate, giving rise to erythroid, myeloid, and lymphoid lineages using a variety of differentiation procedures. Human ESC-derived hematopoietic cells emerge from a subset of embryonic endothelium expressing PECAM-1, Flk-1, and VE-Cadherin, but lacking CD45 (CD45negPFV). These CD45negPFV precursors are exclusively responsible for hematopoietic potential of differentiated hESCs. hESC-derived hematopoietic cells show similar clonogenic capacity and primitive phenotype to somatic sources of hematopoietic progenitors and possess limited in vivo repopulating capacity in immunodeficient mice, suggestive of HSC function. Here, we will review current progress in studies of hESC-derived hematopoietic cells and discuss the potential precincts and applications.


Coordinated regulation of growth, activity and transcription in natural populations of the unicellular nitrogen-fixing cyanobacterium Crocosphaera.
The temporal dynamics of phytoplankton growth and activity have large impacts on fluxes of matter and energy, yet obtaining in situ metabolic measurements of sufficient resolution for even dominant microorganisms remains a considerable challenge. We performed Lagrangian diel sampling with synoptic measurements of population abundances, dinitrogen (N2) fixation, mortality, productivity, export and transcription in a bloom of Crocosphaera over eight days in the North Pacific Subtropical Gyre (NPSG). Quantitative transcriptomic analyses revealed clear diel oscillations in transcript abundances for 34% of Crocosphaera genes identified, reflecting a systematic progression of gene expression in diverse metabolic pathways. Significant time-lagged correspondence was evident between nifH transcript abundance and maximal N2 fixation, as well as sepF transcript abundance and cell division, demonstrating the utility of transcriptomics to predict the occurrence and timing of physiological and biogeochemical processes in natural populations. Indirect estimates of carbon fixation by Crocosphaera were equivalent to 11% of net community production, suggesting that under bloom conditions this diazotroph has a considerable impact on the wider carbon cycle. Our cross-scale synthesis of molecular, population and community-wide data underscores the tightly coordinated in situ metabolism of the keystone N2-fixing cyanobacterium Crocosphaera, as well as the broader ecosystem-wide implications of its activities.


Mutational signatures associated with exposure to carcinogenic microplastic compounds bisphenol A and styrene oxide.
Microplastic pollutants in oceans and food chains are concerning to public health. Common plasticizing compounds Bisphenol-A (BPA) and Styrene-7,8-Oxide (SO) are now labeled as carcinogens. We show that BPA and SO cause deoxyribonucleic acid damage and mutagenesis in human cells, and analyze the genome-wide point mutation and genomic rearrangement patterns associated with BPA and SO exposure. A subset of the single- and doublet base substitutions shows mutagenesis near or at guanine, consistent with these compounds' preferences to form guanosine adducts. Presence of other mutational signatures suggest additional mutagenesis probably due to complex effects of BPA and SO on diverse cellular processes. Analyzing data for 19 cancer cohorts, we find that tumors of digestive and urinary organs show relatively high similarity in mutational profiles, and the burden of such mutations increases with age. Even within the same cancer type, proportions of corresponding mutational patterns vary among the cohorts from different countries, as does the amount of microplastic waste in ocean waters. BPA and SO are relatively mild mutagens, and other environmental agents can also potentially generate similar, complex mutational patterns in cancer genomes. Nonetheless, our findings call for systematic evaluation of public health consequences of microplastic exposure worldwide.


Intracerebral hemorrhage outcomes in patients using direct oral anticoagulants versus vitamin K antagonists: a meta-analysis.
The objective of this paper is to assess the clinical outcomes between non-traumatic intracerebral hemorrhage(ICH) in patients using direct oral anticoagulants(DOAC) versus vitamin K antagonists(VKA) for non-valvular atrial fibrillation. We also evaluated the predictors of the poor post-ICH outcomes. We have performed pooled meta-analysis to assess long-term clinical outcomes in patients with DOAC-ICH as compared to those with VKA-ICH. A systematic literature search was conducted by searching the full-text English literature in PubMed, EMBASE, and Cochrane databases for observational studies reporting outcomes on interest. MOOSE guidelines were used to collect data till December 31, 2019 and random effects analysis was carried out to account for heterogeneity. For outcomes, risk ratios(RR) and the mean differences were pooled using a random-effects model and weighted mean differences (WMDs), respectively. Seventeen studies met the inclusion criteria (n = 25,354 patients; DOAC-ICH arms = 5,631; VKA-ICH arm = 19,273). Patients with DOAC-ICH had smaller hematoma volumes (WMD=-9.59; 95%CI=-15.33--3.85; I2 = 68.6%) and reduced mortality rate at discharge (RR = 0.82; 95%CI = 0.71-0.96; I2 = 9.4%). There was no significant difference between the two groups in rate of hematoma expansion (RR = 0.79; 95%CI = 0.56-1.11; I2 = 50.9%), unfavorable functional outcome(Modified Rankin Scale) at discharge (RR = 0.82; 95%CI = 0.56-1.18; I2 = 80.2%), unfavorable outcome at 3-months (RR = 0.77; 95%CI = 0.56-1.06; I2 = 63.9), and mortality at 3-months (RR = 0.90; 95%CI = 0.73-1.10; I2 = 35∙8%). Multivariate meta-regression revealed that the average age of patient population had a significantly negative correlation with(RR=-0.202; p = 0.017) hematoma expansion. We conclude that use of DOAC is associated with reduced hematoma volume and mortality rate at discharge. Age is a predictor of the poor outcome of hematoma expansion.


Mild traumatic brain injury and executive functions in school-aged children.
This study sought to examine the effects of mild traumatic brain injury (TBI) on executive functions in school-aged children. The prospective, longitudinal study involved 8-15 year old children, 186 with mild TBI and 99 with mild orthopaedic injuries (OI). They were administered the Stockings of Cambridge and Spatial Working Memory sub-tests from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) approximately 10 days, 3 months and 12 months post-injury. Parents completed the Behavior Rating Inventory of Executive Functions (BRIEF) on each occasion, with ratings at the initial assessment intended to assess pre-morbid functioning retrospectively. On the CANTAB, the groups did not differ on the Stockings of Cambridge and the mild TBI group unexpectedly performed better than the OI group on Spatial Working Memory. On the BRIEF, children with mild TBI showed a marginally significant trend toward more problems than the OI group on the Metacognition Index composite. The only BRIEF sub-scale on which they demonstrated significantly more problems was Organization of Materials. The presence of intracranial abnormalities on MRI was associated with more problems on the BRIEF Organization of Materials sub-scale at 3 months, but other findings were not consistent with hypothesized effects of TBI severity. The CANTAB sub-tests were significant predictors of later ratings on the BRIEF, but accounted for modest variance. Children with mild TBI show limited evidence of deficits in executive functions, either cognitively or behaviourally, irrespective of injury characteristics. Cognitive tests of executive functions are modest predictors of ratings of executive functions in everyday life, for children both with and without mild TBI.


Complications of ornamental Christmas bulb ingestion. Case report and review of the literature.
Unusual complications ensued when a 14-month-old boy ingested an ornamental Christmas bulb. Profuse rectal bleeding, a large ischiorectal abscess, and an acute condition of the abdomen necessiated a sigmoid colostomy with drainage of the ischiorectal abscess. Following this, repeated episodes of hemorrhage via the colostomy and rectum required multiple operative procedures. The last of these was a total colectomy with an ileostomy and rectal mucous fistula. The patient subsequently developed intestinal obstruction that required lysis of adhesions and drainage of a chronic subhepatic abscess, due to perforation of the terminal part of the ileum. The patient required five months of hospitalization and further surgery to reconstruct gastrointestinal continuity. Hemorrhage is an infrequent complication of foreign body ingestion, as reported in the literature. We theorize that the problems in this case were the result of the extreme thinness (0.033 cm) and the brittleness of the glass fragments.


Staphylococcus aureus CC30 Lineage and Absence of sed,j,r-Harboring Plasmid Predict Embolism in Infective Endocarditis.
Staphylococcus aureus induces severe infective endocarditis (IE) where embolic complications are a major cause of death. Risk factors for embolism have been reported such as a younger age or larger IE vegetations, while methicillin resistance conferred by the mecA gene appeared as a protective factor. It is unclear, however, whether embolism is influenced by other S. aureus characteristics such as clonal complex (CC) or virulence pattern. We examined clinical and microbiological predictors of embolism in a prospective multicentric cohort of 98 French patients with monomicrobial S. aureus IE. The genomic contents of causative isolates were characterized using DNA array. To preserve statistical power, genotypic predictors were restricted to CC, secreted virulence factors and virulence regulators. Multivariate regularized logistic regression identified three independent predictors of embolism. Patients at higher risk were younger than the cohort median age of 62.5 y (adjusted odds ratio [OR] 0.14; 95% confidence interval [CI] 0.05-0.36). S. aureus characteristics predicting embolism were a CC30 genetic background (adjusted OR 9.734; 95% CI 1.53-192.8) and the absence of pIB485-like plasmid-borne enterotoxin-encoding genes sed, sej, and ser (sedjr; adjusted OR 0.07; 95% CI 0.004-0.457). CC30 S. aureus has been repeatedly reported to exhibit enhanced fitness in bloodstream infections, which might impact its ability to cause embolism. sedjr-encoded enterotoxins, whose superantigenic activity is unlikely to protect against embolism, possibly acted as a proxy to others genes of the pIB485-like plasmid found in genetically unrelated isolates from mostly embolism-free patients. mecA did not independently predict embolism but was strongly associated with sedjr. This mecA-sedjr association might have driven previous reports of a negative association of mecA and embolism. Collectively, our results suggest that the influence of S. aureus genotypic features on the risk of embolism may be stronger than previously suspected and independent of clinical risk factors.


Low negative affect prior to treatment is associated with a decreased chance of live birth from a first IVF cycle.
Psychological variables, such as anxiety and depression, may have a negative impact on IVF outcomes, but the evidence remains inconclusive. Previous studies have usually measured a single psychological parameter with clinical pregnancy as the outcome. The objective of the current study was to determine whether pretreatment or procedural psychological variables in women undergoing a first IVF cycle affect the chance of achieving a live birth from that cycle. Between February 2002 and February 2004, 391 women with an indication for IVF were recruited at two University Medical Centres in The Netherlands. Pretreatment anxiety and depression were measured with the Hospital Anxiety and Depression Scale. The Daily Record Keeping Chart was used to measure negative and positive affect before treatment and daily during ovarian stimulation. Multiple stepwise forward logistic regression analysis was performed with term live birth as the dependent variable. Regression analysis showed that women who expressed less negative affect at baseline were less likely to achieve live birth (P = 0.03). After one IVF cycle, women who received a standard IVF strategy were more likely to reach live birth delivery than those who received a mild IVF strategy (P = 0.002). A male/female indication for IVF was associated with a higher chance of achieving term live birth than a female only indication (P = 0.03). Age, duration of infertility or type of infertility were not independent predictors of live birth. The relationship between psychological parameters and IVF success rates is more complex than commonly believed. The expression of negative emotions before starting IVF might not be always detrimental for outcomes.


Nanopore Opening at Flat and Nanotip Conical Electrodes during Vesicle Impact Electrochemical Cytometry.
The oxidation of catecholamine at a microelectrode, following its release from individual vesicles, allows interrogation of the content of single nanometer vesicles with vesicle impact electrochemical cytometry (VIEC). Previous to this development, there were no methods available to quantify the chemical load of single vesicles. However, accurate quantification of the content is hampered by uncertainty in the proportion of substituent molecules reaching the electrode surface (collection efficiency). In this work, we use quantitative modeling to calculate this collection efficiency. For all vesicles except those at the very edge of the electrode, modeling shows that ∼100% oxidation efficiency is achieved when employing a 33 μm diameter disk microelectrode for VIEC, independent of the location of the vesicle release pore. We use this to experimentally determine a precise distribution of catecholamine in individual vesicles extracted from PC12 cells. In contrast, we calculate that when a nanotip conical electrode (∼4 μm length, ∼1.5 μm diameter at the base) is employed, as in intracellular VIEC (IVIEC), the current-time response depends strongly on the position of the catecholamine-releasing pore in the vesicle membrane. When vesicle release occurs with the pore opening occurring far from the electrode, lower currents and partial oxidation (∼75%) of the catecholamine are predicted, as compared to higher currents and ∼100% oxidation, when the pore is close to/at the electrode surface. As close agreement is observed between the experimentally measured vesicular content in intracellular and extracted vesicles from the same cell line using nanotip and disk electrodes, respectively, we conclude that pores open at the electrode surface. Not only does this suggest that electroporation of the vesicle membrane is the primary driving force for catecholamine release from vesicles at polarized electrodes, but it also indicates that IVIEC with nanotip electrodes can directly assess vesicular content without correction.


Relationship among antigen contact, alveolitis, and clinical status in farmer's lung disease.
We studied 41 subjects with a history of farmer's lung disease who had been free of acute episodes for at least one year. Twenty-six were still in daily contact with hay (group 1), and 15 had ceased all antigenic exposure (group 2). While the incidence of dyspnea was similar in both groups, coughing and sputum were more frequent in group 1. Inspiratory crackles were frequent in group 1 subjects (15 of 26) and absent in all group 2 subjects. In both groups, a high percentage of lymphocytes was demonstrated by bronchoalveolar lavage: 52.5% +/- 21.1% (mean +/- SD) and 26.3% +/- 18.7%, respectively. Lymphocytic alveolitis (greater than 22% lymphocytes) was more common in group 1 (23 of 26) than in group 2 (6 of 15). There was no relationship between functional abnormalities and the intensity of the alveolitis. We conclude that lymphocytic alveolitis may persist after an acute episode of farmer's lung disease, but the intensity of the alveolitis is not associated with functional alterations.


Control of interstitial pneumonia by drip infusion of megadose vitamin C, dehydroepiandrosterone and cortisol. A short review of our experience.
Interstitial pneumonia can be controlled by the combined use of a prophylactic antibiotic system and the drip infusion system including megadose vitamin C, dehydroepiandrosterone (D) and cortisol (F), a fortified substitute of 3 adrenocortical elements. The response of patients was satisfying with few side-effects of F. It was shown that an excess of vitamin C improved the therapeutic efficacy of D-F complex, and that D and F improved the immunodeficient state of the host. The benefit of D as an adrenal androgen in immunology found another example in the combined use of cyclosporine A (CS) and glucocorticoid (G) in the kidney transplantation clinic: CS and G helps improve graft take by creating a state of androgen excess, as testified in both humans and mice--an alleviation of immune conflict.


Isolation, characterization, and influence of native, nonstarter lactic acid bacteria on Cheddar cheese quality.
To determine whether adventitious nonstarter lactic acid bacteria (NSLAB) might affect cheese flavor and quality, we studied a population of NSLAB present in 30 premium quality Cheddar cheeses (3-mo ripened) produced at a commercial facility in the United States. DNA fingerprinting analysis with a sensitive strategy for arbitrary priming polymerase chain reaction showed that 75 isolates corresponded to at least 18 distinct nonstarter organisms. According to ribotype database comparisons of representatives from the 18 groups, 9 matched Lactobacillus (closest to paracasei species), 8 matched Streptococcus thermophilus, and 1 matched to a Lactococcus species. This finding indicated that among the 75 NSLAB isolates, Lactobacillus made up 64%, S. thermophilus 32%, and Lactococcus 4%. Isolates representing 11 NSLAB groups were characterized for protease, peptidase, and diacetyl production. Based on this phenotypic analysis, two Lactobacillus isolates were evaluated as adjuncts in Cheddar cheese. All of the NSLAB identified from the adjunct cheese at 3 mo by DNA fingerprinting consisted of the adjunct lactobacilli, showing that the adjunct strains predominated throughout the early stages of ripening. The impact of adjunct lactobacilli was evident after 6 mo when free amino acids significantly increased and sensory scores improved in adjunct cheese as compared with a control cheese. The largest impact was found in adjunct cheese containing a blend of both lactobacilli strains. These results show that certain adventitious NSLAB positively contribute to flavor development.


Shape-dependent cellular processing of polyelectrolyte capsules.
Particle shape is emerging as a key design parameter for tailoring the interactions between particles and cells. Herein, we report the preparation of rod-shaped layer-by-layer (LbL)-assembled polymer hydrogel capsules with tunable aspect ratios (ARs). By templating spherical and rodlike silica particles, disulfide-stabilized poly(methacrylic acid) hydrogel capsules (PMA HCs) with different ARs (from 1 to 4) are generated. The influence of capsule AR on cellular internalization and intracellular fate was quantitatively investigated by flow cytometry, imaging flow cytometry, and fluorescence deconvolution microscopy. These experiments reveal that the cellular internalization kinetics of PMA HCs are dependent on the AR, with spherical capsules being internalized more rapidly and to a greater extent compared with rod-shaped capsules. In contrast, the capsules with different ARs are colocalized with the lysosomal marker LAMP1, suggesting that the lysosomal compartmentalization is independent of shape for these soft polymer capsules.


Fluorescent cell tracer dye permits real-time assessment of re-epithelialization in a serum-free ex vivo human skin wound assay.
Ex vivo wounded human skin organ culture is an invaluable tool for translationally relevant preclinical wound healing research. However, studies incorporating this system are still underutilized within the field because of the low throughput of histological analysis required for downstream assessment. In this study, we use intravital fluorescent dye to lineage trace epidermal cells, demonstrating that wound re-epithelialization of human ex vivo wounds occurs consistent with an extending shield mechanism of collective migration. Moreover, we also report a relatively simple method to investigate global epithelial closure of explants in culture using daily fluorescent dye treatment and en face imaging. This study is the first to quantify healing of ex vivo wounds in a longitudinal manner, providing global assessments for re-epithelialization and tissue contraction. We show that this approach can identify alterations to healing with a known healing promoter. This methodological study highlights the utility of human ex vivo wounds in enhancing our understanding of mechanisms of human skin repair and in evaluating novel therapies to improve healing outcome.


A bridge to recovery: Acute amantadine prior to environmental enrichment after brain trauma augments cognitive benefit.
Environmental enrichment (EE) facilitates motor and cognitive recovery after traumatic brain injury (TBI). Historically, EE has been provided immediately and continuously after TBI, but this paradigm does not model the clinic where rehabilitation is typically not initiated until after critical care. Yet, treating TBI early may facilitate recovery. Hence, we sought to provide amantadine (AMT) as a bridge therapy before commencing EE. It was hypothesized that bridging EE with AMT would augment motor and cognitive benefits. Anesthetized adult male rats received a cortical impact (2.8 mm deformation at 4 m/s) or sham surgery and then were housed in standard (STD) conditions where they received intraperitoneal AMT (10 mg/kg or 20 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 h after surgery and once daily during the 6-day bridge phase or once daily for 19 days for the non-bridge groups (i.e., continuously STD-housed) to compare the effects of acute AMT plus EE vs. chronic AMT alone. Abbreviated EE, which was presented to closer emulate clinical rehabilitation (e.g., 6 h/day), began on day 7 for the AMT bridge and chronic EE groups. Motor (beam-walking) and cognition (acquisition of spatial learning and memory) were assessed on days 7-11 and 14-19, respectively. Cortical lesion volume and hippocampal cell survival were quantified on day 21. EE, whether provided in combination with VEH or AMT, and AMT (20 mg/kg) + STD, benefitted motor and cognition vs. the STD-housed VEH and AMT (10 mg/kg) groups (p < 0.05). The AMT (20 mg/kg) + EE group performed better than the VEH + EE, AMT (10 mg/kg) + EE, and AMT (20 mg/kg) + STD groups in the acquisition of spatial learning (p < 0.05) but did not differ in motor function (p > 0.05). All groups receiving EE exhibited decreased cortical lesion volumes and increased CA3 neuron survival relative to the STD-housed groups (p < 0.05) but did not differ from one another (p > 0.05). The added cognitive benefit achieved by bridging EE with AMT (20 mg/kg) supports the hypothesis that the temporal separation of combinational therapies is more effective after TBI.


Coping with Africa's increasing tuberculosis burden: are community supervisors an essential component of the DOT strategy? Directly observed therapy.
Tuberculosis incidence in Africa is increasing dramatically and fragile health systems are struggling to cope. Potential coping capacity may lie within affected communities but this capacity needs to be harnessed if tuberculosis is to be controlled. Since 1991 all patients with tuberculosis in Hlabisa health district, South Africa have been eligible for community-based directly observed therapy (DOT). Patients are supervised either by a health worker (HW) in a village clinic, or in the community by a community health worker (CHW) or a volunteer lay person (VLP). Tuberculosis incidence increased from 312 cases in 1991 to 1250 cases in 1996. By December 1995, 2622 (87%) of 3006 patients had received DOT, supervised mainly by VLP (56%) but also by HW (28%) and CHW (16%). The proportion supervised by HW fell from 46% in 1991 to 26% in 1995 (P < 0.0001). More patients supervised by VLP (85%) and CHW (88%) than by HW (79%, P = 0.0008) completed treatment. Case-holding by HW declined more between 1991 and 1995 (84% to 71%, P = 0.02) than did case-holding by both CHW (95% to 90%. P = 0.7) and VLP (88% to 84%, P = 0.4). Mortality was similar (4-6%) and stable over time, irrespective of the supervisor. High tuberculosis treatment completion rates are achievable and sustainable for several years in resource-poor settings despite a massively increased case load if community resources are harnessed. Patients may be more effectively supervised by voluntary lay people than by health workers under these circumstances, without being placed at increased risk. These findings suggest that community supervisors may be an essential component of any DOT strategy.


Weekly low-dose treatment with intravenous iron sucrose maintains iron status and decreases epoetin requirement in iron-replete haemodialysis patients.
Haemodialysis patients need sustained treatment with intravenous iron because iron deficiency limits the efficacy of recombinant human epoetin therapy in these patients. However, the optimal intravenous iron maintenance dose has not been established yet. We performed a prospective multicentre clinical trial in iron-replete haemodialysis patients to evaluate the efficacy of weekly low-dose (50 mg) intravenous iron sucrose administration for 6 months to maintain the iron status, and to examine the effect on epoetin dosage needed to maintain stable haemoglobin values in these patients. Fifty patients were enrolled in this prospective, open-label, single arm, phase IV study. Forty-two patients (84%) completed the study. After 6 months of intravenous iron sucrose treatment, the mean ferritin value showed a tendency to increase slightly from 405 +/- 159 at baseline to 490 +/- 275 microg/l at the end of the study, but iron, transferrin levels and transferrin saturation did not change. The haemoglobin level remained stable (12 +/- 1.1 at baseline and 12.1 +/- 1.5 g/dl at the end of the study). The mean dose of darbepoetin alfa could be reduced from 0.75 to 0.46 microg/kg/week; epoetin alfa was decreased from 101 to 74 IU/kg/week; and the mean dose of epoetin beta could be reduced from 148 to 131 IU/kg/week at the end of treatment. A regular 50 mg weekly dosing schedule of iron sucrose maintains stable iron stores and haemoglobin levels in haemodialysed patients and allows considerable dose reductions for epoetins. Low-dose intravenous iron therapy may represent an optimal approach to treat the continuous loss of iron in dialysis patients.


Yeast telomerase subunit Est1p has guanine quadruplex-promoting activity that is required for telomere elongation.
Telomeres are eukaryotic protein-DNA complexes found at the ends of linear chromosomes that are essential for maintaining genome integrity and are implicated in cellular aging and cancer. The guanine (G)-rich strand of telomeric DNA, usually elongated by the telomerase reverse transcriptase, can form a higher-order structure known as a G-quadruplex in vitro and in vivo. Several factors that promote or resolve G-quadruplexes have been identified, but the functional importance of these structures for telomere maintenance is not well understood. Here we show that the yeast telomerase subunit Est1p, known to be involved in telomerase recruitment to telomeres, can convert single-stranded telomeric G-rich DNA into a G-quadruplex structure in vitro in a Mg(2+)-dependent manner. Cells carrying Est1p mutants deficient in G-quadruplex formation in vitro showed gradual telomere shortening and cellular senescence, indicating a positive regulatory role for G-quadruplex in the maintenance of telomere length.


Internal growth of nonsolid lung nodules: radiologic-pathologic correlation.
To determine whether computed tomographic (CT) attenuation values correlate with the histologic measurements of a lung cancer manifesting as a nonsolid nodule and to quantify the extent to which the tumor replaces the airspace within the nodule. Informed consent was obtained to analyze images from CT and pathologic examination under an institutional review board-approved protocol. Fifteen patients who had undergone resection of nonsolid lung cancer were evaluated. On the basis of the CT attenuation values of nonsolid nodules, nonneoplastic lung, soft tissue, and air, the overall proportion of soft tissue in the nodule and nonneoplastic lung and the difference between these two measures were calculated. The analogous measures were obtained from a representative digitized histologic slide. The area of each nodule and the proportion of air within it were measured, and the proportion of soft tissue in the nodule and nonneoplastic lung and the difference between the two were calculated. The difference between the two proportions at CT and histologic examination are the proportions attributable to the cancer on the basis of CT and histologic examinations, respectively. Linear regression was performed to assess the relationship between these measures. The average proportions of soft tissue in the nodule at CT and histologic examination were 48% and 69%, respectively, and they showed significant correlation with each other (P = .02); in addition, each showed significant correlation with the attenuation of the nodule (P < .0001 and P = .02, respectively). The difference between the proportions of soft tissue in nodule and nonneoplastic lung at CT and histologic examination were 37% and 30%, respectively, and both were independent of the tumor diameter (P = .26 and P = .41). The proportion of soft tissue within a nonsolid nodule is correlated with attenuation at CT. This allows for measurement of change within the nodule. An increase of 100 HU in nodule attenuation represents an approximately 10% increase in tumor volume.


Automated Recognition of Regional Wall Motion Abnormalities Through Deep Neural Network Interpretation of Transthoracic Echocardiography.
Automated interpretation of echocardiography by deep neural networks could support clinical reporting and improve efficiency. Whereas previous studies have evaluated spatial relationships using still frame images, we aimed to train and test a deep neural network for video analysis by combining spatial and temporal information, to automate the recognition of left ventricular regional wall motion abnormalities. We collected a series of transthoracic echocardiography examinations performed between July 2017 and April 2018 in 2 tertiary care hospitals. Regional wall abnormalities were defined by experienced physiologists and confirmed by trained cardiologists. First, we developed a 3-dimensional convolutional neural network model for view selection ensuring stringent image quality control. Second, a U-net model segmented images to annotate the location of each left ventricular wall. Third, a final 3-dimensional convolutional neural network model evaluated echocardiographic videos from 4 standard views, before and after segmentation, and calculated a wall motion abnormality confidence level (0-1) for each segment. To evaluate model stability, we performed 5-fold cross-validation and external validation. In a series of 10 638 echocardiograms, our view selection model identified 6454 (61%) examinations with sufficient image quality in all standard views. In this training set, 2740 frames were annotated to develop the segmentation model, which achieved a Dice similarity coefficient of 0.756. External validation was performed in 1756 examinations from an independent hospital. A regional wall motion abnormality was observed in 8.9% and 4.9% in the training and external validation datasets, respectively. The final model recognized regional wall motion abnormalities in the cross-validation and external validation datasets with an area under the receiver operating characteristic curve of 0.912 (95% CI, 0.896-0.928) and 0.891 (95% CI, 0.834-0.948), respectively. In the external validation dataset, the sensitivity was 81.8% (95% CI, 73.8%-88.2%), and specificity was 81.6% (95% CI, 80.4%-82.8%). In echocardiographic examinations of sufficient image quality, it is feasible for deep neural networks to automate the recognition of regional wall motion abnormalities using temporal and spatial information from moving images. Further investigation is required to optimize model performance and evaluate clinical applications.


Phase transitions and lattice dynamics in perovskite-type hydride [Formula: see text].
First principles calculations have been used to investigate the structural phase transitions and lattice dynamics in the alloy [Formula: see text]. The density functional perturbation theory and the virtual crystal approximation are employed, within the generalized gradient approximation. Our total energy and formation enthalpy results show that [Formula: see text] undergoes a phase transition from the orthorhombic Pnma phase to the polar R3c one at a lithium concentration of x = 0.7. Under pressure the system in the R3c structure exhibits a phase transition to the Pnma one and the values of the transition pressure are 0.32, 1.79 and 4.07 GPa for x = 0.7, 0.75 and 0.8, respectively. The calculated phonon dispersion curves for different lithium concentration show a softening of the B2u mode at the zone center ([Formula: see text] point) which vanishes at x =0.8 in the polar R3c phase confirming the transition of the system from the non polar Pnma structure to the polar R3c one. The phonon frequencies at the zone center for the Raman-active and infrared-active modes are predicted for both structures for different lithium concentrations. The heat capacity is evaluated from the calculated phonon spectra and density of states in function of temperature and lithium concentration in both phases.


Identification, purification, and functional reconstitution of the cyclic GMP-dependent channel from rod photoreceptors.
The cyclic GMP-dependent cation channel from bovine rod outer segments has been purified to greater than 90% homogeneity by a rapid two-step chromatographic procedure. The purified channel has an apparent molecular mass of 63 kDa as determined by NaDodSO4/gel electrophoresis. When incorporated into the membrane of liposomes, the purified protein mediates the cyclic GMP-dependent efflux of entrapped Ca2+. The reconstituted channel protein exhibits properties similar to the cyclic GMP-dependent channel observed in excised patches of the plasma membrane and in disk membranes. Cyclic GMP activated the channel cooperatively (Hill coefficient n = 3.1) with an apparent Michaelis constant of approximately 11 microM. After reconstitution of the purified protein into a planar lipid bilayer, we recorded cyclic GMP-stimulated single-channel activity. The single-channel conductance at physiological salt concentrations and in the absence of divalent cations was 26 pS. The drug l-cis-diltiazem, shown to block the cyclic GMP-dependent channel in excised patches of the plasma membrane and in isolated disks of rod outer segments, was ineffective against the purified channel.


Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy.
Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.


Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells.
Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response.


Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex.
The Cdk12/CycK complex promotes expression of a subset of RNA polymerase II genes, including those of the DNA damage response. CDK12 is among only nine genes with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, the influence of these mutations on the Cdk12/CycK complex and their link to cancerogenesis remain ill-defined. Here, we show that most mutations prevent formation of the Cdk12/CycK complex, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations reveals coordinated downregulation of genes critical to the homologous recombination DNA repair pathway. Moreover, we establish that the Cdk12/CycK complex occupies these genes and promotes phosphorylation of RNA polymerase II at Ser2. Accordingly, we demonstrate that the mutant Cdk12 proteins fail to stimulate the faithful DNA double strand break repair via homologous recombination. Together, we provide the molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations may elicit defects in multiple DNA repair pathways, leading to genomic instability underlying the genesis of the cancer.


[Successful treatment of bradyarrhythmia associated with obstructive sleep apnea syndrome by continuous positive airway pressure].
Obstructive Sleep Apnea Syndrome (OSAS) is an additional independent factor of growth of cardiovascular mortality. Special role disturbances of respiration during sleep play in development of nocturnal cardiac arrhythmias. Approaches to correction of OSAS associated nocturnal bradyarrhythmias have substantially changed during recent years. We present report of a clinical case in which we detected relation of nocturnal bradyarrhythmias to OSAS. Adequate correction of OSAS by continuous positive airway pressure therapy resulted in complete elimination of bradyarrhythmias during night time. This allowed to avoid implantation of permanent pacemaker.


FHLdb: A Comprehensive Database on the Molecular Basis of Familial Hemophagocytic Lymphohistiocytosis.
Background: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders. The lack of comprehensive disease-specific mutation databases may hinder or delay classification of the genetic variants found in samples from these patients. This is especially true for familial hemophagocytic lymphohistiocytosis (FHL), a life-threatening PID classically considered an autosomal recessive condition, but with increasingly demonstrated genetic heterogeneity. Objective: The aim of this study was to build an open-access repository to collect detailed information on the known genetic variants reported in FHL. Methods: We manually reviewed more than 120 articles to identify all reported variants related to FHL. We retrieved relevant information about the allelic status, the number of patients with the same variant, and whether functional assays were done. We stored all the data retrieved in a PostgreSQL database and then built a website on top of it, using the Django framework. Results: The database designed (FHLdb) (https://www.biotoclin.org/FHLdb) contains comprehensive information on reported variants in the 4 genes related to FHL (PRF1, UNC13D, STXBP2, STX11). It comprises 240 missense, 69 frameshift, 51 nonsense, 51 splicing, 10 in-frame indel, 7 deep intronic, and 5 large rearrangement variants together with their allelic status, carrier(s) information, and functional evidence. All genetic variants have been classified as pathogenic, likely pathogenic, uncertain significance, likely benign or benign, according to the American College of Medical Genetics guidelines. Additionally, it integrates information from other relevant databases: clinical evidence from ClinVar and UniProt, population allele frequency from ExAC and gnomAD, and pathogenicity predictions from well-recognized tools (e.g., PolyPhen-2, SIFT). Finally, a diagram depicts the location of the variant relative to the gene exon and protein domain structures. Conclusion: FHLdb includes a broad range of data on the reported genetic variants in familial HLH genes. It is a free-access and easy-to-use resource that will facilitate the interpretation of molecular results of FHL patients, and it illustrates the potential value of disease-specific databases for other PIDs.


Ochratoxin A Producing Fungi, Biosynthetic Pathway and Regulatory Mechanisms.
Ochratoxin A (OTA), mainly produced by Aspergillus and Penicillum species, is one of the most important mycotoxin contaminants in agricultural products. It is detrimental to human health because of its nephrotoxicity, hepatotoxicity, carcinogenicity, teratogenicity, and immunosuppression. OTA structurally consists of adihydrocoumarin moiety linked with l-phenylalanine via an amide bond. OTA biosynthesis has been putatively hypothesized, although several contradictions exist on some processes of the biosynthetic pathway. We discuss recent information on molecular studies of OTA biosynthesis despite insufficient genetic background in detail. Accordingly, genetic regulation has also been explored with regard to the interaction between the regulators and the environmental factors. In this review, we focus on three aspects of OTA: OTA-producing strains, OTA biosynthetic pathway and the regulation mechanisms of OTA production. This can pave the way to assist in protecting food and feed from OTA contamination by understanding OTA biosynthetic pathway and regulatory mechanisms.


A triple gene mutant of BoHV-1 administered intranasally is significantly more efficacious than a BoHV-1 glycoprotein E-deleted virus against a virulent BoHV-1 challenge.
Bovine herpesvirus 1 (BoHV-1) causes respiratory infections and abortions in cattle, and is an important component of bovine respiratory disease complex, which causes a considerable economic loss worldwide. Several efforts have been made to produce safer and more effective vaccines. One of these vaccines is a glycoprotein E (gE)-deleted marker vaccine which is currently mandated for use in EU countries. In the present study, we have constructed a three-gene-mutated BoHV-1 vaccine virus (UL49.5 luminal domain residues 30-32 and cytoplasmic tail residues 80-96 deleted, gE cytoplasmic tail- and entire Us9-deleted) and compared its protective vaccine efficacy in calves after intranasal vaccination with that of a gE-deleted virus. Following vaccination, both the triple mutant and gE-deleted vaccine virus replicated well in the nasal epithelium of the calves. The vaccinated calves did not show any clinical signs. Four weeks post-vaccination, the animals were challenged intranasally with a virulent BoHV-1 wild-type virus. Based on clinical signs, both the gE-deleted and triple mutant group were protected equally against the virulent BoHV-1 challenge. However, based on the quantity and duration of nasal viral shedding, virus neutralizing antibody and cellular immune responses, the triple mutant virus vaccine induced a significantly better protective immune response than the gE-deleted virus vaccine. Notably, after the virulent BoHV-1 challenge, the triple mutant virus vaccinated group cleared the challenge virus three days earlier than the BoHV-1 gE-deleted virus vaccinated group.


Stigma Toward Bariatric Surgery in the Netherlands, France, and the United Kingdom: Protocol for a Cross-cultural Mixed Methods Study.
Bariatric surgery is an effective procedure for the treatment of obesity. Despite this, only 0.1% to 2% of eligible individuals undergo surgery worldwide. The stigma surrounding surgery might be a reason for this. Thus far, no research has systematically studied the nature and implications of bariatric surgery stigma. The limited studies on bariatric surgery stigma are often conducted from the perspective of the public or health care professions and either use small and nonrepresentative samples or fail to capture the full essence and implications of the stigma altogether, including attitudes toward patients and perpetrators of the stigma. In addition, studies from patients' perspectives are limited and tend to address bariatric surgery stigma superficially or implicitly. Finally, the extent to which cultural factors shape and facilitate this stigma and the experiences of patients have not yet been researched. This study aimed to explore the perceptions, experiences, and consequences of bariatric surgery stigma from the perspective of the public, health care professionals, and patients before and after bariatric surgery. Furthermore, although the concept of stigma is universal, every society has specific cultural norms and values that define acceptable attributes and behaviors for its members. Therefore, this study also aimed to explore the extent to which cultural factors influence bariatric surgery stigma by comparing the Netherlands, France, and the United Kingdom. This paper describes the protocol for a multiphase mixed methods research design. In the first part, we will conduct a scoping review to determine the current knowledge on bariatric surgery stigma and identify knowledge gaps. In the second part, semistructured interviews among patients before and after bariatric surgery will be conducted to explore their experiences and consequences of bariatric surgery stigma. In the third part, surveys will be conducted among both the public and health care professionals to determine the prevalence, nature, and impact of bariatric surgery stigma. Surveys and interviews will be conducted in the Netherlands, France, and the United Kingdom. Finally, data integration will be conducted at the interpretation and reporting levels. The study began in September 2020 and will continue through September 2025. With the results of the review, we will create an overview of the current knowledge regarding bariatric surgery stigma from patients' perspectives. Qualitative data will provide insights into patients' experiences with bariatric surgery stigma. Quantitative data will provide information related to the prevalence and nature of bariatric surgery stigma from the perspective of the public and health care professionals. Both qualitative and quantitative data will be compared for each country. The findings from this study will lead to new insights that can be used to develop strategies to reduce bariatric surgery stigma and improve access, use, and outcomes of bariatric surgery. PRR1-10.2196/36753.


Medication errors of nurses in the emergency department.
Patient safety is one of the main concepts in the field of healthcare provision and a major component of health services quality. One of the important stages in promotion of the safety level of patients is identification of medication errors and their causes. Medical errors such as medication errors are the most prevalent errors that threaten health and are a global problem. Execution of medication orders is an important part of the treatment and care process and is regarded as the main part of the nurses' performance. The purpose of this study was to explore the medication error reporting rate, error types and their causes among nurses in the emergency department. In this descriptive study, 94 nurses of the emergency department of Imam Khomeini Hospital Complex were selected based on census in 2010-2011. Data collection tool was a researcher-made questionnaire consisting of two parts: demographic information, and types and causes of medication errors. After confirming content-face validity, reliability of the questionnaire was determined to be 0.91 using Cronbach's alpha test. Data analyses were performed by descriptive statistics and inferential statistics. SPSS-16 software was used in this study and P values less than 0.05 were considered significant. The mean age of the nurses was 27.7 ± 3.4 years, and their working experience was 7.3 ± 3.4 years. Of participants 46.8% had committed medication errors in the past year, and the majority (69.04%) had committed the errors only once. Thirty two nurses (72.7%) had not reported medication errors to head nurses or the nursing office. The most prevalent types of medication errors were related to infusion rates (33.3%) and administering two doses of medicine instead of one (23.8%). The most important causes of medication errors were shortage of nurses (47.6%) and lack of sufficient pharmacological information (30.9%). This study showed that the risk of medication errors among nurses is high and medication errors are a major problem of nursing in the emergency department. We recommend increasing the number of nurses, adjusting the workload of the nursing staff in the emergency department, retraining courses to improve the staff's pharmacological information, modification of the education process, encouraging nurses to report medical errors and encouraging hospital managers to respond to errors in a constructive manner in order to enhance patient safety.


Structural insights into the mechanism of single domain VHH antibody binding to cortisol.
To date, few structural models of VHH antibody binding to low molecular weight haptens have been reported. Here, we report the crystal structure of cortisol binding to its VHH antibody NbCor at pH 3.5 and 10.5. Cortisol binds to NbCor mainly by burying itself under the tunnel formed by the complementarity determining region 1 (CDR1) of NbCor. The affinity of NbCor binding to cortisol and similar compounds was also verified by a microscale thermophoresis assay. Combining our findings with several previously reported structures of hapten-VHH antibody complexes, we propose that VHH antibodies exhibit a special mechanism of binding small haptens by encapsulating them in a tunnel formed by CDR1. Our findings provide useful structural information for the further development and optimization of hapten-specific VHH antibodies.


Achieving High Performance with FPGA-Based Computing.
Numerous application areas, including bioinformatics and computational biology, demand increasing amounts of processing capability. In many cases, the computation cores and data types are suited to field-programmable gate arrays. The challenge is identifying the design techniques that can extract high performance potential from the FPGA fabric.


Anal cloacogenic carcinoma: classification and clinical behavior.
A retrospective study of 35 patients with anal cloacogenic carcinomas showed that the histological characteristics of the tumors were correlated with their biological behavior. The basaloid squamous type of cloacogenic carcinoma was more common in women (3.6:1) and had a more favorable course in both men and women, with a mean survival of 5.0 years. Glandular variants of these tumors, with an adenocystic or mucoepidermoid pattern, occurred predominantly in men and had a more aggressive course, manifested by early metastases to inguinal and mesenteric lymph nodes, liver, and lung, with mean survival limited to 2.5 years. Nine of the 11 patients who survived longer than five years had the basaloid squamous histological pattern and were treated by abdominoperineal resection or pelvic exenteration; five of these patients also received postoperative therapy with radiation. The overall actual five-year survival for patients with anal cloacogenic carcinoma was 41% in this study. The histological pattern of anal cloacogenic carcinoma provides useful prognostic information to the clinician.


[Corticotropin-releasing hormone in the regulation of adaptive behavior].
Recent findings on the role of corticotropin-releasing hormone (CRH) in the regulation of stress and its consequences are summarized and analyzed in the review. Being involved in stress-activating system this neurohormone is referred to as a neurochemical factor triggering and integrating both endocrine and behavioral functions. The CRH distribution in hypothalamus and extrahypothalamic brain regions relevant to its involvement in the controlling of endocrine processes and behavior is viewed in details. Distinct behavioral outcomes of stress and the contribution of amygdalar, hippocampal, and striatal CRH-structures, implicated in general organism response to external influences, are widely discussed. From this viewpoint the mechanisms involved in the development of post-stress psychopathology, as well as drug addiction and alcoholism are treated.


Predictors of Posttraumatic Growth Among University Students Who Experienced a Recent Earthquake.
A 5.8 magnitude earthquake hit Gyeongju City, South Korea, in 2016, traumatising and psychologically panicking residents. The purpose of this study was to identify predictive factors for posttraumatic growth (PTG) among university students who experienced South Korea's largest earthquake. A cross-sectional descriptive survey was distributed to a convenience sample of 493 university students in Gyeongju City. Data were collected via 5 self-report questionnaires. PTG was found to be positively correlated with posttraumatic stress disorder (PTSD), resilience and social support. Multiple regression analysis showed that PTSD (β = 0.519, p < .001), resilience (β = 0.213, p < .001), religion (β = 0.125, p = .001) and sex (female; β = 0.090, p = .010) were identified as predictive factors of PTG. These results illustrate a need for health care providers to include individual internal resources such as resilience in intervention strategies to promote PTG and decrease posttraumatic experiences in those who have experienced traumatic events such as earthquakes. A longitudinal study is needed to obtain more definitive evidence of PTSD progression and PTG over time.


Distribution of HIV-1 resistance-conferring polymorphic alleles SDF-1-3'A, CCR2-64I and CCR5-Delta32 in diverse populations of Andhra Pradesh, South India.
Polymorphic allelic variants of chemokine receptors CCR2 and CCR5, as well as of stromal-derived factor-1 SDF-1, the ligand for the chemokine receptor CXCR4, are known to have protective effects against HIV-1 infection and to be involved with delay in disease progression. We have studied the DNA polymorphisms at the loci that encode these proteins in 525 healthy individuals without any history of HIV-1 infection from 11 diverse populations of Andhra Pradesh, South India. The two protective alleles SDF-1-3'A and CCR2-64I at the SDF-1 and CCR2 loci, respectively, are present in all populations studied, although their frequencies differ considerably across populations (from 17% to 35% for the SDF-1-3'A allele, and from 3% to 17% for CCR2-64I). In contrast the CCR5-Delta32 allele is observed only in three populations (Yamani, Pathan and Kamma), all in low frequencies (i.e. 1% to 3%). The mean number of mutant alleles (for the three loci together) carried by each individual varies from 0.475 (in Vizag Brahmins) to 0.959 (in Bohra Muslims). The estimated relative hazard values for the populations, computed from the three-locus genotype data, are comparable to those from Africa and Southeast Asia, where AIDS is known to be widespread.


Evolvability and genetic constraint in Dalechampia blossoms: genetic correlations and conditional evolvability.
The short-term evolvability of a character is closely related to its level of additive genetic variation. However, a large component of the variation in any one character may be pleiotropically linked to other characters under the influence of different selective factors. Therefore, the organization of the organism into quasi-independent modules may be an important prerequisite for evolvability. In this paper we propose to study character evolvability in terms of conditional genetic variation. By estimating the amount of genetic variation in a character, y, that is independent of other characters, x, we can assess the evolvability of y when there is stabilizing selection on x. We suggest that systematic use of conditioning may help build a picture of modular organization and quasi-independent evolvability. As an illustration, we use this approach to assess the evolvability of floral characters in Dalechampia scandens (Euphorbiaceae). Although our study population had relatively low levels of genetic variation at the outset, we find evidence that conditioning may lead to substantial further reduction in the genetic variation available for independent adaptation. This provides additional evidence that the D. scandens blossom is constrained in its short-term evolvability.


Comparative efficacy of clorsulon and albendazole against Fasciola hepatica in cattle.
In a dosage-confirmation trial, anthelmintic activities of clorsulon and albendazole against Fasciola hepatica were evaluated and compared. Twenty-eight cattle (8 to 12 months old) with natural F hepatica infections were randomly allotted to 4 groups of 7 cattle each: group 1, no treatment (controls); group 2, clorsulon suspension given orally at 3.5 mg/kg of body weight; group 3, clorsulon suspension given orally at 7 mg/kg; and group 4, albendazole paste given orally at 10 mg/kg. At necropsies, performed 7 and 8 days after treatment, control cattle harbored a geometric mean of 133.2 F hepatica, 16.0 of which were immature. Clorsulon administered at 3.5 mg/kg or 7 mg/kg resulted in greater than 99% removal of F hepatica, including immatures. Albendazole treatment resulted in a 76% overall reduction in F hepatica, including a 91% reduction of immatures. Fascioloides magna also were found in the cattle, but neither clorsulon nor albendazole caused significant reductions of the parasite. Adverse reactions to the 2 drugs were not observed.


The clinical impact of continuing to prescribe antiretroviral therapy in patients with advanced AIDS who manifest no virologic or immunologic benefit.
Despite the efficacy and tolerability of modern antiretroviral therapy (ART), many patients with advanced AIDS prescribed these regimens do not achieve viral suppression or immune reconstitution as a result of poor adherence, drug resistance, or both. The clinical outcomes of continued ART prescription for such patients have not been well characterized. We examined the causes and predictors of all-cause mortality, AIDS-defining conditions, and serious non-AIDS-defining events among a cohort of participants in a clinical trial of pre-emptive therapy for CMV disease. We focused on participants who, despite ART had failed to achieve virologic suppression and substantive immune reconstitution. 233 ART-receiving participants entered with a median baseline CD4+ T cell count of 30/mm(3) and plasma HIV RNA of 5 log10 copies/mL. During a median 96 weeks of follow-up, 24.0% died (a mortality rate of 10.7/100 patient-years); 27.5% reported a new AIDS-defining condition, and 22.3% a new serious non-AIDS event. Of the deaths, 42.8% were due to an AIDS-defining condition, 44.6% were due to a non-AIDS-defining condition, and 12.5% were of unknown etiology. Decreased risk of mortality was associated with baseline CD4+ T cell count ≥25/mm(3) and lower baseline HIV RNA. Among patients with advanced AIDS prescribed modern ART who achieve neither virologic suppression nor immune reconstitution, crude mortality percentages appear to be lower than reported in cohorts of patients studied a decade earlier. Also, in contrast to the era before modern ART became available, nearly half of the deaths in our modern-era study were caused by serious non-AIDS-defining events. Even among the most advanced AIDS patients who were not obtaining apparent immunologic and virologic benefit from ART, continued prescription of these medications appears to alter the natural history of AIDS--improving survival and shifting the causes of death from AIDS- to non-AIDS-defining conditions.


NIT24 and NIT29-mediated IAA synthesis of Xanthomonas oryzae pv. oryzicola suppresses immunity and boosts growth in rice.
Auxin plays a pivotal role in the co-evolution of plants and microorganisms. Xanthomonas oryzae pv. oryzicola (Xoc) stands as a significant factor that affects rice yield and quality. However, the current understanding of Xoc's capability for indole 3-acetic acid (IAA) synthesis and its mechanistic implications remains elusive. In this study, we performed a comprehensive genomic analysis of Xoc strain RS105, leading to the identification of two nitrilase enzyme family (NIT) genes, designated as AKO15524.1 and AKO15829.1, subsequently named NIT24 and NIT29, respectively. Our investigation unveiled that the deletion of NIT24 and NIT29 resulted in a notable reduction in IAA synthesis capacity within RS105, thereby impacting extracellular polysaccharide production. This deficiency was partially ameliorated through exogenous IAA supplementation. The study further substantiated that NIT24 and NIT29 have nitrilase activity and the ability to catalyse IAA production in vitro. The lesion length and bacterial population statistics experiments confirmed that NIT24 and NIT29 positively regulated the pathogenicity of RS105, suggesting that NIT24 and NIT29 may regulate Xoc invasion by affecting IAA synthesis. Furthermore, our analysis corroborated mutant strains, RS105_ΔNIT24 and RS105_ΔNIT29, which elicited the outbreak of reactive oxygen species, the deposition of callose and the upregulation of defence-related gene expression in rice. IAA exerted a significant dampening effect on the immune responses incited by these mutant strains in rice. In addition, the absence of NIT24 and NIT29 affected the growth-promoting effect of Xoc on rice. This implies that Xoc may promote rice growth by secreting IAA, thus providing a more suitable microenvironment for its own colonization. In summary, our study provides compelling evidence for the existence of a nitrilase-dependent IAA biosynthesis pathway in Xoc. IAA synthesis-related genes promote Xoc colonization by inhibiting rice immune defence response and affecting rice growth by increasing IAA content in Xoc.


Protected polymorphisms and evolutionary stability of patch-selection strategies in stochastic environments.
We consider a population living in a patchy environment that varies stochastically in space and time. The population is composed of two morphs (that is, individuals of the same species with different genotypes). In terms of survival and reproductive success, the associated phenotypes differ only in their habitat selection strategies. We compute invasion rates corresponding to the rates at which the abundance of an initially rare morph increases in the presence of the other morph established at equilibrium. If both morphs have positive invasion rates when rare, then there is an equilibrium distribution such that the two morphs coexist; that is, there is a protected polymorphism for habitat selection. Alternatively, if one morph has a negative invasion rate when rare, then it is asymptotically displaced by the other morph under all initial conditions where both morphs are present. We refine the characterization of an evolutionary stable strategy for habitat selection from Schreiber (Am Nat 180:17-34, 2012) in a mathematically rigorous manner. We provide a necessary and sufficient condition for the existence of an ESS that uses all patches and determine when using a single patch is an ESS. We also provide an explicit formula for the ESS when there are two habitat types. We show that adding environmental stochasticity results in an ESS that, when compared to the ESS for the corresponding model without stochasticity, spends less time in patches with larger carrying capacities and possibly makes use of sink patches, thereby practicing a spatial form of bet hedging.


RANKL/RANK/OPG Pathway: A Mechanism Involved in Exercise-Induced Bone Remodeling.
Bones as an alive organ consist of about 70% mineral and 30% organic component. About 200 million people are suffering from osteopenia and osteoporosis around the world. There are multiple ways of protecting bone from endogenous and exogenous risk factors. Planned physical activity is another useful way for protecting bone health. It has been investigated that arranged exercise would effectively regulate bone metabolism. Until now, a number of systems have discovered how exercise could help bone health. Previous studies reported different mechanisms of the effect of exercise on bone health by modulation of bone remodeling. However, the regulation of RANKL/RANK/OPG pathway in exercise and physical performance as one of the most important remodeling systems is not considered comprehensive in previous evidence. Therefore, the aim of this review is to clarify exercise influence on bone modeling and remodeling, with a concentration on its role in regulating RANKL/RANK/OPG pathway.


Marriage and mortality after noncardiac surgery.
Marriage is linked to substantial societal and economic benefits, and it has been associated with improved outcomes following acute illness. However, it is not known if being married confers benefit to patients undergoing noncardiac surgical procedures. Patients undergoing any noncardiac surgical procedure were included over a period of 19 months. All-cause mortality at 2 years was determined by linking patient records to the National Death Index. Risk adjustment was performed using Cox modeling and the Cleveland Clinic risk stratification index. Of the 11,588 patients included, 7830 (68.0%) were married at the time of surgery. There was a significant interaction between sex and marital status (P = 0.03), so the remainder of the analysis was performed separately by sex. Among men, not being married was associated with significantly worse survival (hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.06, 1.63), whereas among women, there was no significant association between marital status and survival (HR: 0.94, 95% CI: 0.77, 1.15). Furthermore, divorced men (HR: 1.76, 95% CI: 1.25, 2.51) and never married men (HR: 1.53, 95% CI: 1.14, 2.05) had significantly worse survival than married men, whereas there was no significant difference between widowed men and married men, nor when comparing widowed, divorced, or never married women to married women. Among a diverse group of surgical patients, being married at the time of surgery is associated with significantly improved survival only among men. Focused efforts to improve social support for unmarried male patients may improve outcomes.


Analysis of translocations in stable cells and their implications in retrospective biological dosimetry.
The aim of the present study was to evaluate the influence of the exclusion of cells with unstable aberrations in the elaboration of dose-effect curves for translocations and their implications in biological dosimetry of past exposures. To establish dose-effect curves, peripheral blood samples were irradiated with 60Co gamma rays at ten different doses and the yield of translocations analyzed by FISH was considered in all cells and in stable cells (those without dicentrics, acentrics or rings). To discriminate transmissible translocations, the dose- effect curve for total apparently simple translocations in stable cells was chosen as the reference. In stable cells, dose- effect curves for apparently simple translocations without pseudosimple and complex-derived one-way patterns, tAbtBa and total translocations were obtained. None of these curves differed from the reference curve. When all cells were considered, only the curve for total translocations was significantly different from the reference curve. From the results obtained it can be concluded that the use of dose-effect curves for apparently simple translocations in stable cells and in all cells will give similar dose estimates in retrospective biological dosimetry studies. However, the use of dose-effect curves for total translocations in all cells will lead to underestimations of the dose mainly at high doses.


Mechanisms of new-onset psychosis during the COVID-19 pandemic: What ignited the fire?
The coronavirus disease 2019 (COVID-19) pandemic has been associated with the emergence of various psychiatric illnesses, although very little literature has focused on the effect of COVID-19 on psychosis. Preliminary data have shown possible increases in new-onset psychosis. Using MEDLINE, we performed a review of the current literature to identify the mechanisms by which pandemics may increase psychosis risk and generate evidence-based recommendations to control surges of psychosis. We identified 85 relevant studies, of which 34 were case reports on psychosis during the COVID-19 pandemic. Underlying mechanisms of psychosis include "direct viral mechanisms," such as neuroinflammation linked with the coronavirus, and "nonviral mechanisms," such as stress, isolation, and uncertainty. Improvement of our understanding of the pathophysiology of psychosis related to COVID-19 along with implementation of strategies to fight against stress and social isolation in addition to awareness campaigns regarding new-onset psychotic symptoms are much needed to optimize early detection and management of psychosis.


Treatment of Intracranial Aneurysm with Bare Stent only.
Typical treatment of intracranial aneurysm includes: surgical clipping, intrasacular packing, and parent artery occlusion. The treatment of a fusiform aneurysm is often parent artery occlusion, and keeping patency of the parent artery is difficult.We report our experience in the treatment of 3 cases of intracranial fusiform aneurysm with stent placement inside the parent artery only, without coil packing of the aneurysm lumen. All 3 patients had a non-hemorrhagic dissecting aneurysm in the vertebral artery. They were treated with 2 Helistents, 3 Neuroform stents, and 2 Neuroform stents, respectively. These aneurysms disappeared after treatment at their follow-up angiograms. Treatment with a bare stent may induce obliteration or reduction in the size of some aneurysms. This technique is useful in the treatment of non-hemorrhagic fusiform-shaped aneurysms or non-hemorrhagic dissecting aneurysms to preserve the patency of these parent arteries.


Inhibitory circuits of the mammalian main olfactory bulb.
Synaptic inhibition critically influences sensory processing throughout the mammalian brain, including the main olfactory bulb (MOB), the first station of sensory processing in the olfactory system. Decades of research across numerous laboratories have established a central role for granule cells (GCs), the most abundant GABAergic interneuron type in the MOB, in the precise regulation of principal mitral and tufted cell (M/TC) firing rates and synchrony through lateral and recurrent inhibitory mechanisms. In addition to GCs, however, the MOB contains a vast diversity of other GABAergic interneuron types, and recent findings suggest that, while fewer in number, these oft-ignored interneurons are just as important as GCs in shaping odor-evoked M/TC activity. Here I challenge the prevailing centrality of GCs. In this review, I first outline the specific properties of each GABAergic interneuron type in the rodent MOB, with particular emphasis placed on direct interneuron recordings and cell type-selective manipulations. On the basis of these properties, I then critically reevaluate the contribution of GCs vs. other interneuron types to the regulation of odor-evoked M/TC firing rates and synchrony via lateral, recurrent, and other inhibitory mechanisms. This analysis yields a novel model in which multiple interneuron types with distinct abundances, connectivity patterns, and physiologies complement one another to regulate M/TC activity and sensory processing.


Primary care providers' use of and attitudes towards placebos: An exploratory focus group study with US physicians.
To examine how primary care physicians define placebo concepts, use placebos in clinical practice, and view open-label placebos (OLPs). Semi-structured focus groups that were audio-recorded and content-coded. Two focus groups with a total of 15 primary care physicians occurred at medical centres in the New England region of the United States. Prior experience using placebo treatments and attitudes towards open-label placebos were explored. Themes were analysed using an inductive data-driven approach. Physicians displayed a nuanced understanding of placebos and placebo effects in clinical contexts which sometimes focused on relational factors. Some respondents reported that they prescribed treatments with no known pharmacological effect for certain conditions and symptoms ('impure placebos') and that such prescriptions were more common for pain disorders, functional disorders, and medically unexplained symptoms. Opinions about OLP were mixed: Some viewed OLPs favourably or considered them 'harmless'; however, others strongly rejected OLPs as disrespectful to patients. Other issues in relation to OLPs included the following: lack of guidelines, legal and reputational concerns, and the notion that such treatments would run counter to customary medical practice. A number of physicians reported prescribing impure placebos in clinical care. Although some primary care physicians were resistant to the possibility of recommending OLPs, others regarded OLPs more favourably, viewing them as potential treatments, albeit with restricted potential. Statement of contribution What is already known? Many physicians report prescribing drugs for the purposes of eliciting a placebo effect. Initial evidence for the efficacy of open-label placebos is promising. What does this study add? A more nuanced description of the circumstances under which primary care physicians report placebo prescribing. A qualitative account of physician attitudes about using open-label placebos in clinical practice.


Gut microbiota, probiotics and diabetes.
Diabetes is a condition of multifactorial origin, involving several molecular mechanisms related to the intestinal microbiota for its development. In type 2 diabetes, receptor activation and recognition by microorganisms from the intestinal lumen may trigger inflammatory responses, inducing the phosphorylation of serine residues in insulin receptor substrate-1, reducing insulin sensitivity. In type 1 diabetes, the lowered expression of adhesion proteins within the intestinal epithelium favours a greater immune response that may result in destruction of pancreatic β cells by CD8+ T-lymphocytes, and increased expression of interleukin-17, related to autoimmunity. Research in animal models and humans has hypothesized whether the administration of probiotics may improve the prognosis of diabetes through modulation of gut microbiota. We have shown in this review that a large body of evidence suggests probiotics reduce the inflammatory response and oxidative stress, as well as increase the expression of adhesion proteins within the intestinal epithelium, reducing intestinal permeability. Such effects increase insulin sensitivity and reduce autoimmune response. However, further investigations are required to clarify whether the administration of probiotics can be efficiently used for the prevention and management of diabetes.


Transforaminal percutaneous endoscopic discectomy in the treatment of far-lateral and foraminal lumbar disc herniations.
Far-lateral (extraforaminal) and foraminal disc herniations comprise up to 11% of all herniated intervertebral discs. Operative management can be technically difficult, and the optimum surgical treatment remains controversial. Accessing these lateral disc herniations endoscopically via a percutaneous transforaminal approach offers several theoretical advantages over the more traditional procedures. The object of this study was to assess the safety and efficacy of treating patients with far-lateral and foraminal disc herniations via a percutaneous transforaminal endoscopic approach. A retrospective analysis was performed of 47 consecutive patients who underwent surgery via this approach. All procedures were performed after induction of a local anesthetic on an outpatient basis. Outcome was measured with Macnab criteria and by determining a patient's return-to-work status. The median follow-up period was 18 months (range 4-51 months). Excellent or good outcome was obtained in 40 (85%) of 47 patients. Of the 38 patients working before the onset of symptoms, 34 (90%) returned to work. Five patients (11%) experienced poor outcomes and subsequently underwent open procedures at the same level. Of the 10 recipients of Workers' Compensation, Macnab criteria indicated a significantly worse outcome (70% excellent or good), but an excellent return-to-work status was maintained (90%). There were no complications. Transforaminal percutaneous endoscopic discectomy is safe and efficacious in the treatment of far-lateral and foraminal disc herniations.


Seize the moment to learn about epilepsy in people with cancer.
Seizures are common neurologic complications of cancer and can occur at any point in the disease trajectory. Despite this, the exact pathophysiologic basis of seizures related to cancer is not known. The etiology of seizures is thought to be multifactorial, including the presence of tumors within the cranial cavity, metabolic derangements, and the direct effect of medications on the central nervous system. Seizure management often employs anticonvulsant medications and interventions to promote patient safety. Oncology nurses must be aware of the potential seriousness of this complication and implement appropriate strategies to assist patients in maintaining safety and quality of life.


Barriers to fertility regulation: a review of the literature.
The evidence in the demographic and family planning literature of the range and diversity of the barriers to fertility regulation in many developing countries is reviewed in this article from a consumer perspective. Barriers are defined as the constraining factors standing between women and the realistic availability of the technologies and correct information they need in order to decide whether and when to have a child. The barriers include limited method choice, financial costs, the status of women, medical and legal restrictions, provider bias, and misinformation. The presence or absence of barriers to fertility regulation is likely an important determinant of the pace of fertility decline or its delay in many countries. At the same time, barriers inhibit women's ability to avoid unintended pregnancy. Problems of quantifying barriers limit understanding of their importance. New ways to quantify them and to identify misinformation, which is often concealed in survey data, are needed for future research.


Electric current paths in a Si:P delta-doped device imaged by nitrogen-vacancy diamond magnetic microscopy.
The recently-developed ability to control phosphorous-doping of silicon at an atomic level using scanning tunneling microscopy, a technique known as atomic precision advanced manufacturing (APAM), has allowed us to tailor electronic devices with atomic precision, and thus has emerged as a way to explore new possibilities in Si electronics. In these applications, critical questions include where current flow is actually occurring in or near APAM structures as well as whether leakage currents are present. In general, detection and mapping of current flow in APAM structures are valuable diagnostic tools to obtain reliable devices in digital-enhanced applications. In this paper, we used nitrogen-vacancy (NV) centers in diamond for wide-field magnetic imaging (with a few-mm field of view and micron-scale resolution) of magnetic fields from surface currents flowing in an APAM test device made of a P delta-doped layer on a Si substrate, a standard APAM witness material. We integrated a diamond having a surface NV ensemble with the device (patterned in two parallel mm-sized ribbons), then mapped the magnetic field from the DC current injected in the APAM device in a home-built NV wide-field microscope. The 2D magnetic field maps were used to reconstruct the surface current densities, allowing us to obtain information on current paths, device failures such as choke points where current flow is impeded, and current leakages outside the APAM-defined P-doped regions. Analysis on the current density reconstructed map showed a projected sensitivity of ∼0.03 A m-1, corresponding to a smallest-detectable current in the 200μm wide APAM ribbon of ∼6μA. These results demonstrate the failure analysis capability of NV wide-field magnetometry for APAM materials, opening the possibility to investigate other cutting-edge microelectronic devices.


Neurocysticercosis: is serology useful in the absence of brain imaging?
Neurocysticercosis (NCC) is endemic in most parts of the world and is now recognised as an important contributor to neurological disease. Serological diagnosis of NCC improved greatly in the past two decades and contributed to demonstrating previously unsuspected regions of endemicity. Claims for an accurate serological screening tool for human cysticercosis are frequently raised. However, after symptomatic therapeutics are applied, management of NCC is driven by the characteristics of the central nervous system infection in terms of viability, number, location size and evolutionary stage of parasites, as well as by the resulting inflammation. It is unclear whether, in the absence of neuroimaging, serological confirmation of aetiology of suspected cases (neurologically symptomatic) or detection of asymptomatic cases in population screening would affect their management or prognosis.