Do specific antimicrobial stewardship interventions have an impact on carbapenem resistance in Gram-negative bacilli? A multicentre quasi-experimental ecological study: time-trend analysis and characterization of carbapenemases.

BACKGROUND: Carbapenem-resistant Gram-negative bacilli (CR-GNB) are among the most threatening microorganisms worldwide and carbapenem use facilitates their spread. Antimicrobial stewardship programmes (ASPs) can help to optimize the use of antibiotics. This study evaluates the impact of a multifaceted educational ASP on carbapenem use and on the epidemiology of CR-GNB. METHODS: We conducted a quasi-experimental, time-series study in seven hospitals, from January 2014 to September 2018. The key intervention was composed of educational interviews promoting the appropriate use of carbapenems. The primary endpoints were carbapenem consumption and incidence density (ID) of CR-GNB. All non-duplicated CR-GNB clinical isolates were tested using phenotypic assays and PCR for the presence of carbapenemases. Joinpoint regression and interrupted time-series analyses were used to determine trends. RESULTS: A decrease in carbapenem consumption throughout the study period [average quarterly percentage change (AQPC) -1.5%, P < 0.001] and a -8.170 (-16.064 to -0.277) level change following the intervention were observed. The ID of CR-Acinetobacter baumannii decreased (AQPC -3.5%, P = 0.02) and the overall ID of CR-GNB remained stable (AQPC -0.4%, P = 0.52). CR-GNB, CR-Pseudomonas aeruginosa and CR-A. baumannii IDs per hospital correlated with the local consumption of carbapenems. The most prevalent carbapenem resistance mechanisms were OXA-23 for CR-A. baumannii (76.1%), OXA-48 for CR-Klebsiella pneumoniae (66%) and no carbapenemases for CR-P. aeruginosa (91.7%). The epidemiology of carbapenemases was heterogeneous throughout the study, especially for carbapenemase-producing Enterobacteriaceae. CONCLUSIONS: In conclusion, a multifaceted, educational interview-based ASP targeting carbapenem prescribing reduced carbapenem use and the ID of CR-A. baumannii.

Validation of a Histologic Scoring Index for C3 Glomerulopathy.

RATIONALE & OBJECTIVE: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population. STUDY DESIGN: Multicenter, retrospective cohort study. SETTING & PARTICIPANTS: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). PREDICTORS: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score. OUTCOME: Time to kidney failure. ANALYTICAL APPROACH: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines. RESULTS: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure. LIMITATIONS: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding. CONCLUSIONS: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.

A Social-Ecological Approach to Understanding Adolescent Sexting Behavior.

This study examined the extent to which active and passive sexting behaviors are associated with family-, school-, peer-, and romantic-level variables. Young people (N = 3,322; 49.1% female, 48.3% male, 2.6% other) aged 11 to 15 years old (M = 12.84, SD = 0.89) took part, and all attended mainstream secondary schools in Scotland. Participants completed self-report measures of school connectedness, parental love and support, perceived susceptibility to peer- and romantic-pressure (e.g., to display behaviors just to impress others), and their involvement in active and passive sexting. The importance of both school- and family-level factors was evident, though perceived romantic-pressure had the largest effect. However, neither school- nor family-level variables were moderated by either perceived romantic-pressure or perceived peer-pressure. Efforts to reduce sexting or increase its safety should primarily seek to tackle young people's ability to respond effectively to romantic-pressure. It may also be helpful to develop school connectedness and to help families provide support that is constructive and not intrusive.

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment.

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.

Self-(in)compatibility in apricot germplasm is controlled by two major loci, S and M.

BACKGROUND: Apricot (Prunus armeniaca L.) exhibits a gametophytic self-incompatibility (GSI) system and it is mostly considered as a self-incompatible species though numerous self-compatible exceptions occur. These are mainly linked to the mutated S C-haplotype carrying an insertion in the S-locus F-box gene that leads to a truncated protein. However, two S-locus unlinked pollen-part mutations (PPMs) termed m and m' have also been reported to confer self-compatibility (SC) in the apricot cultivars 'Canino' and 'Katy', respectively. This work was aimed to explore whether other additional mutations might explain SC in apricot as well. RESULTS: A set of 67 cultivars/accessions with different geographic origins were analyzed by PCR-screening of the S- and M-loci genotypes, contrasting results with the available phenotype data. Up to 20 S-alleles, including 3 new ones, were detected and sequence analysis revealed interesting synonymies and homonymies in particular with S-alleles found in Chinese cultivars. Haplotype analysis performed by genotyping and determining linkage-phases of 7 SSR markers, showed that the m and m' PPMs are linked to the same m 0-haplotype. Results indicate that m 0-haplotype is tightly associated with SC in apricot germplasm being quite frequent in Europe and North-America. However, its prevalence is lower than that for S C in terms of frequency and geographic distribution. Structures of 34 additional M-haplotypes were inferred and analyzed to depict phylogenetic relationships and M 1-2 was found to be the closest haplotype to m 0. Genotyping results showed that four cultivars classified as self-compatible do not have neither the S C- nor the m 0-haplotype. CONCLUSIONS: According to apricot germplasm S-genotyping, a loss of genetic diversity affecting the S-locus has been produced probably due to crop dissemination. Genotyping and phenotyping data support that self-(in)compatibility in apricot relies mainly on the S- but also on the M-locus. Regarding this latter, we have shown that the m 0-haplotype associated with SC is shared by 'Canino', 'Katy' and many other cultivars. Its origin is still unknown but phylogenetic analysis supports that m 0 arose later in time than S C from a widely distributed M-haplotype. Lastly, other mutants putatively carrying new mutations conferring SC have also been identified deserving future research.

Protein profile of cotyledon, tegument, and embryonic axis of mature acorns from a non-orthodox plant species: Quercus ilex.

MAIN CONCLUSION: Contrary to the orthodox seeds, recalcitrant Holm oak seeds possess the enzymatic machinery to start germination during the maturation phase. The protein profile of the different parts, mature seeds, of the Holm oak, a non-orthodox plant species, has been characterized using one- and two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption ionization-time of flight mass spectrometry. Protein content and profiles of the three seed tissues (cotyledon, embryonic axis and tegument) were quite different. The embryonic axis showed 4-fold and 20-fold higher protein content than the cotyledon and the tegument, respectively. Two hundred and twenty-six variable proteins among the three seed parts were identified, being classified according to their function into eight main groups. The cotyledon presented the highest number of metabolic and storage proteins (89% of them are legumin) compared to the embryonic axis and tegument. The embryonic axis had the highest number of the species within the protein fate group. The tegument presented the largest number of the defense-/stress-related and cytoskeleton proteins. This distribution is in good agreement with the biological role of the tissues. The study of the seed tissue proteome demonstrated a compartmentalization of pathways and a division of metabolic tasks between embryonic axis, cotyledon and tegument. This compartmentalization uncovered in our study should provide a starting point for understanding, at the molecular level, the particularities of the recalcitrant seeds.

A review of heterogeneous photocatalysis for water and surface disinfection.

Photo-excitation of certain semiconductors can lead to the production of reactive oxygen species that can inactivate microorganisms. The mechanisms involved are reviewed, along with two important applications. The first is the use of photocatalysis to enhance the solar disinfection of water. It is estimated that 750 million people do not have accessed to an improved source for drinking and many more rely on sources that are not safe. If one can utilize photocatalysis to enhance the solar disinfection of water and provide an inexpensive, simple method of water disinfection, then it could help reduce the risk of waterborne disease. The second application is the use of photocatalytic coatings to combat healthcare associated infections. Two challenges are considered, i.e., the use of photocatalytic coatings to give "self-disinfecting" surfaces to reduce the risk of transmission of infection via environmental surfaces, and the use of photocatalytic coatings for the decontamination and disinfection of medical devices. In the final section, the development of novel photocatalytic materials for use in disinfection applications is reviewed, taking account of materials, developed for other photocatalytic applications, but which may be transferable for disinfection purposes.

Importance of Host Feeding in the Biological Control of Insect Pests: Case Study of Egg Parasitoid Species (Hymenoptera: Chalcidoidea: Trichogrammatidae).

Over recent decades, intraguild predation (IGP) has attracted special attention, both from the theoretical and practical standpoints. The present paper addresses the interference competition between two Trichogramma species (egg parasitoids)-on the one hand, the extrinsic interactions (i.e., the indirect competition between female T. achaeae and T. brassicae), and on the other, the intrinsic interactions between the larvae of both species. Furthermore, T. achaeae is a better competitor than T. brassicae due to a dual mechanism-the former acts as a facultative hyperparasitoid of the latter, exclusively considering parasitism relationships as well as presenting predation activity by host feeding, which gives preference to eggs previously parasitized by T. brassicae over non-parasitized eggs. Both mechanisms are dependent on the prey density, which is demonstrated by a change in the functional response (i.e., the relationship between the numbers of prey attacked at different prey densities) of T. achaeae adult female-it changes from type II (i.e., initial phase in which the number of attacked targets increases hyperbolically and then reaches an asymptote, reflecting the handling capacity of the predator), in the absence of competition (an instantaneous search rate of a' = 9.996 ± 4.973 days-1 and a handling time of Th = 0.018 ± 0.001 days), to type I (i.e., linear increase in parasitism rate as host densities rise, until reaching a maximum parasitism rate, and an instantaneous search rate of a' = 0.879 ± 0.072 days-1 and a handling time of Th ≈ 0) when interference competition is present. These results show that there is a greater mortality potential of this species, T. achaeae, in conditions of competition with other species, T. brassicae in this case. Based on this, their implications in relation to the biological control of pests by parasitoid species are discussed.

Knowledge domains and emerging trends in non-invasive brain stimulation: A bibliometric analysis via CiteSpace.

INTRODUCTION: In recent decades, new non-invasive brain stimulation techniques and protocols have been developed, such as transcranial magnetic stimulation and transcranial direct current stimulation. OBJECTIVE: To identify and visualize the intellectual structure of non-invasive brain stimulation through document co-citation analysis. MATERIALS AND METHODS: We analyzed 30,854 Web of Science-indexed manuscripts and their 1,615,692 references regarding non-invasive brain stimulation, all published from 1988 to 2022. We drew a document co-citation network map using CiteSpace software. RESULTS: The most productive journal was Clinical Neurophysiology. The most published institution was the University College London, and the country with the most reports was the USA. The most productive author was Alvaro Pascual-Leone and the most cited author in the non-invasive brain stimulation field was J. C. Rothwell. In addition, the most cited study was that of Rossi et al. (2009). The safe application of non-invasive brain stimulation techniques and their effects on motor or executive functions is an emerging trend in this research area. CONCLUSIONS: The current investigation displayed a quantitative scientometric approach and delved into the advancement of non-invasive brain stimulation research by examining the references published in this domain. These findings can be valuable for professionals to picture the patterns of recognition and emerging directions in the field.

Filial cannibalism of Nabis pseudoferus is not evolutionarily optimal foraging strategy.

Using a recursion model with real parameters of Nabis pseudoferus, we show that its filial cannibalism is an optimal foraging strategy for life reproductive success, but it is not an evolutionarily optimal foraging strategy, since it cannot maximize the descendant's number at the end of the reproductive season. Cannibalism is evolutionarily rational, when the number of newborn offspring produced from the cannibalized offspring can compensate the following two effects: (a) The cannibalistic lineage wastes time, since the individuals hatched from eggs produced by cannibalism start to reproduce later. (b) Cannibalism eliminates not only one offspring, but also all potential descendants from the cannibalized offspring during the rest of reproductive season. In our laboratory trials, from conspecific prey Nabis pseudoferus did not produce newborn nymphs enough to compensate the above two effects.

STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia.

Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2, but not its paralog STAG1, are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression, and local chromatin activation, which were not compensated by the remaining STAG1-cohesin. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. Complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs) revealed effects resembling STAG2-mutant AML-specific changes following STAG2 knockdown, not invoked by the depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression, and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis.

A longitudinal study of protective factors against substance use in early adolescence. An ecological approach.

BACKGROUND: Adolescent substance use has been widely related to different individual, school, family and community factors. Yet, the number of studies with all these variables together in a model from an ecological perspective is still low, and they rarely used a longitudinal design. The aim of this study was to explore, from an ecological perspective, the prospective impact of different individual, school, family and neighbourhood factors on adolescent substance use. METHODS: This was a longitudinal study with a one-year follow up. There were 881 participants (Mage = 12.57; 48.1% females) at wave 1, of which 686 (Mage = 13.51; 51.8% females) were followed-up at wave 2. Validated questionnaires were used for data collection. RESULTS: Regression analyses showed that higher substance use was predicted by high family socio-economic status cross-sectionally and longitudinally, and it was related to low neighbourhood socio-economic status cross-sectionally only. Participants who disliked school and had a poor academic performance were more likely to use substances, both cross-sectionally and longitudinally. CONCLUSIONS: The inclusion of families in substance use prevention programmes could be a key component in these interventions. Moreover, promotion of a positive school climate could protect adolescents from using substances.

Intratumoral BO-112 in combination with radiotherapy synergizes to achieve CD8 T-cell-mediated local tumor control.

BACKGROUND: Radioimmunotherapy combines irradiation of tumor lesions with immunotherapy to achieve local and abscopal control of cancer. Most immunotherapy agents are given systemically, but strategies for delivering immunotherapy locally are under clinical scrutiny to maximize efficacy and avoid toxicity. Local immunotherapy, by injecting various pathogen-associated molecular patterns, has shown efficacy both preclinically and clinically. BO-112 is a viral mimetic based on nanoplexed double-stranded RNA (poly I:C) which exerts immune-mediated antitumor effects in mice and humans on intratumoral delivery. BO-112 and focal irradiation were used to make the proof-of-concept for local immunotherapy plus radiation therapy combinations. METHODS: Murine transplantable tumor cell lines (TS/A, MC38 and B16-OVA) were used to show increased immunogenic features under irradiation, as well as in bilateral tumor models in which only one of the lesions was irradiated or/and injected with BO-112. Flow cytometry and multiplex tissue immunofluorescence were used to determine the effects on antitumor immunity. Depletions of immune cell populations and knockout mice for the IFNAR and BATF-3 genes were used to delineate the immune system requirements for efficacy. RESULTS: In cultures of TS/A breast cancer cells, the combination of irradiation and BO-112 showed more prominent features of immunogenic tumor cell death in terms of calreticulin exposure. Injection of BO-112 into the tumor lesion receiving radiation achieved excellent control of the treated tumor and modest delays in contralateral tumor progression. Local effects were associated with more prominent infiltrates of antitumor cytotoxic tumor lymphocytes (CTLs). Importantly, local irradiation plus BO-112 in one of the tumor lesions that enhanced the therapeutic effects of radiotherapy on distant irradiated lesions that were not injected with BO-112. Hence, this beneficial effect of local irradiation plus BO-112 on a tumor lesion enhanced the therapeutic response to radiotherapy on distant non-injected lesions. CONCLUSION: This study demonstrates that local BO-112 immunotherapy and focal irradiation may act in synergy to achieve local tumor control. Irradiation plus BO-112 in one of the tumor lesions enhanced the therapeutic effects on distant irradiated lesions that were not injected with BO-112, suggesting strategies to treat oligometastatic patients with lesions susceptible to radiotherapy and with at least one tumor accessible for repeated BO-112 intratumoral injections.

Alpha-synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis.

Alpha-synuclein is a synaptic modulatory protein implicated in the pathogenesis of Parkinson disease. The precise functions of this small cytosolic protein are still under investigation. alpha-Synuclein has been proposed to regulate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in vesicle fusion. Interestingly, alpha-synuclein fails to interact with SNARE proteins in conventional protein-binding assays, thus suggesting an indirect mode of action. As the structural and functional properties of both alpha-synuclein and the SNARE proteins can be modified by arachidonic acid, a common lipid regulator, we analysed this possible tripartite link in detail. Here, we show that the ability of arachidonic acid to stimulate SNARE complex formation and exocytosis can be controlled by alpha-synuclein, both in vitro and in vivo. Alpha-synuclein sequesters arachidonic acid and thereby blocks the activation of SNAREs. Our data provide mechanistic insights into the action of alpha-synuclein in the modulation of neurotransmission.

Effectiveness of a cognitive behavioral intervention in patients with medically unexplained symptoms: cluster randomized trial.

BACKGROUND: Medically unexplained symptoms are an important mental health problem in primary care and generate a high cost in health services.Cognitive behavioral therapy and psychodynamic therapy have proven effective in these patients. However, there are few studies on the effectiveness of psychosocial interventions by primary health care. The project aims to determine whether a cognitive-behavioral group intervention in patients with medically unexplained symptoms, is more effective than routine clinical practice to improve the quality of life measured by the SF-12 questionary at 12 month. METHODS/DESIGN: This study involves a community based cluster randomized trial in primary healthcare centres in Madrid (Spain). The number of patients required is 242 (121 in each arm), all between 18 and 65 of age with medically unexplained symptoms that had seeked medical attention in primary care at least 10 times during the previous year. The main outcome variable is the quality of life measured by the SF-12 questionnaire on Mental Healthcare. Secondary outcome variables include number of consultations, number of drug (prescriptions) and number of days of sick leave together with other prognosis and descriptive variables. Main effectiveness will be analyzed by comparing the percentage of patients that improve at least 4 points on the SF-12 questionnaire between intervention and control groups at 12 months. All statistical tests will be performed with intention to treat. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in this analysis. DISCUSSION: This study aims to provide more insight to address medically unexplained symptoms, highly prevalent in primary care, from a quantitative methodology. It involves intervention group conducted by previously trained nursing staff to diminish the progression to the chronicity of the symptoms, improve quality of life, and reduce frequency of medical consultations. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01484223 [http://ClinicalTrials.gov].

Erosive pustular dermatosis of the scalp after photodynamic therapy.

Erosive pustular dermatosis of the scalp is a rare condition that tends to occur mainly in elderly patients. Clinically it is characterized by the presence of pustules, chronic crusted erosions with progressive scarring alopecia, and skin atrophy. Although etiology remains unclear, it seems to be triggered by local trauma such as surgical procedures, skin graft, ultraviolet light exposure, cryotherapy, craniotomy, or radiotherapy. To our knowledge, erosive pustular dermatosis of the scalp after photodynamic therapy has been seldom reported. We described a 81-year-old woman presenting with erosive pustular dermatosis of the scalp after photodynamic therapy for actinic keratosis.

Temporary alopecia after embolization of an arteriovenous malformation.

Alopecia after head and neck radiotherapy has been extensively reported in the literature. However, alopecia after endovascular procedures is seldom reported in the dermatological literature. Prolonged fluoroscopic imaging during these procedures may cause serious radiation injuries to the skin, such as dermatitis or alopecia. Radiation-induced temporary alopecia is a peculiar form of radiodermitis that occurs over the areas of the scalp that receive the highest doses of radiation. Although repopulation of alopecic patches occurs spontaneously without treatment, it is important to recognize this disorder to establish a correct diagnosis and inform patients about this transient side effect. We report a 44-year-old woman presenting with temporary alopecia after embolization of an arteriovenous malformation.

Vascular malformation of the glans penis successfully treated with Nd:YAG laser.

Penile venous malformations are uncommon and those located on the glans are even rarer. Treatment of venous malformations of the glans is currently controversial. Neodynium (Nd):YAG laser treatment may be a useful option.

Effect of Relative Humidity on the Population Dynamics of the Predator Amblyseius swirskii and Its Prey Carpoglyphus lactis in the Context of Slow-Release Sachets for Use in Biological Control in Greenhouses.

Amblyseius swirskii is a predatory mite that is widely used for biological control in greenhouses. One way this predator is released is in a formulation in slow-release sachets. These sachets are prepared with the predatory mite, the factitious prey mite Carpoglyphus lactis, and a food substrate for the latter. The objective of the present study was to study the effects of microclimatic conditions in this type of formulation on the population dynamics of mites inside the sachets and on the release of predatory mites. These experiments were conducted under laboratory conditions in two trials. The ambient relative humidity affected the water content of the food substrate of the prey mite inside the sachets, with an initial value of 21.49 ± 0.42%, which was reduced to values of 4.7 ± 0.25%, 10.87 ± 1.03% and 17.27 ± 0.82% after 21 days of trials when they were exposed to low, medium and high ambient relative humidity levels, respectively. Relative humidity significantly altered the dynamics of the populations of both species inside the sachets and the exits of the predator from the sachets to the external environment.