Complementary feeding approaches and risk of choking: A systematic review.

There are two main complementary feeding (CF) approaches: traditional spoon-feeding (TSF) and baby-led weaning (BLW). Many parents and healthcare professionals have concerns about the risk of choking associated with BLW. Since asphyxia is one of infants' main causes of death, this study aims to understand the influence of the CF approach adopted by caregivers on infants' risk of choking. A systematic review was performed. The search was conducted through PubMed, Scopus, and Web of Science databases. We included randomized controlled trials or observational studies published between January 2010 and November 2023, with a clear definition of the intervention and directly assessing the risk of choking. After the selection procedure, 7 of the 165 studies initially identified were included. No study reported statistically significant differences in the risk of choking between babies following BLW, baby-led introduction to solids (BLISS), and TSF. In five studies, although not statistically significant, infants in the TSF group had more choking episodes than those in the BLW or BLISS groups. The risk of choking does not seem to be associated with the CF approach. Instead, it may be related to the familiarity of the baby with each texture and the parent's understanding of the information about how to minimize the risk of choking. Recall bias may be present in all included studies. Advice on how to modify foods to make them safer needs to be clearer and reinforced to all parents.

Synergistic Effect of Venetoclax and Bendamustine in Early T-cell Precursor Acute Lymphoblastic Leukemia.

BACKGROUND/AIM: To date, therapeutic options for T-cell acute lymphoblastic leukemia (T-ALL) remain very limited. This study evaluated the efficacy of monotherapies and combination therapies including a selective BCL-2 inhibitor for T-ALL cell lines, namely Jurkat, CCRF-CEM, and Loucy. MATERIALS AND METHODS: Loucy is an early T-precursor ALL (ETP-ALL) cell line characterized by an immature phenotype, whereas Jurkat and CCRF-CEM are late T-cell progenitor ALL (LTP-ALL) cell lines. Monotherapy was conducted with venetoclax, cytarabine, bendamustine, or azacytidine, whereas combination therapy was performed with venetoclax plus cytarabine, venetoclax plus bendamustine, or venetoclax plus azacytidine. Cell viability assay was conducted after 48 h using Trypan blue and the 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Statistical analysis for evaluating synergistic interactions between anticancer drugs was performed by using the SynergyFinder Plus and drc R package. RESULTS: Adding venetoclax to cytarabine, bendamustine, or azacitidine achieved an additive effect, with Loewe synergic scores ranging from -10 to 10 in Jurkat and CCRF-CEM. Conversely, the combination of venetoclax and cytarabine displayed an additive effect (Loewe synergic score: 8.45 and 5.82 with MTS and Trypan blue assays, respectively), whereas venetoclax plus bendamustine or azacitidine exhibited a synergistic effect (Loewe synergic score >10 with MTS assay) in Loucy. Remarkably, the Bliss/Loewe score revealed that the combination of venetoclax and bendamustine was the most synergistic, yielding a score of 13.832±0.55. CONCLUSION: The combination of venetoclax and bendamustine demonstrated the greatest synergistic effect in suppressing ETP-ALL cell proliferation. Further studies are warranted to determine the mechanisms for the synergism between venetoclax and bendamustine in high-risk T-ALL.

Combination Treatment with EGFR Inhibitor and Doxorubicin Synergistically Inhibits Proliferation of MCF-7 Cells and MDA-MB-231 Triple-Negative Breast Cancer Cells In Vitro.

The role of the epidermal growth factor receptor (EGFR) in tumor progression and survival is often underplayed. Its expression and/or dysregulation is associated with disease advancement and poor patient outcome as well as drug resistance in breast cancer. EGFR is often overexpressed in breast cancer and particularly triple-negative breast cancer (TNBC), which currently lacks molecular targets. We examined the synergistic potential of an EGFR inhibitor (EGFRi) in combination with doxorubicin (Dox) in estrogen-positive (ER+) MCF-7 and MDA-MB-231 TNBC cell lines. The exposure of MDA-MB-231 and MCF-7 to EGFRi produced an IC50s of 6.03 µM and 3.96 µM, respectively. Dox induced MDA-MB-231 (IC50 9.67 µM) and MCF-7 (IC50 1.4 µM) cytotoxicity. Combinations of EGFRi-Dox significantly reduced the IC50 in MCF-7 (0.46 µM) and MBA-MB 231 (0.01 µM). Synergistic drug interactions in both cell lines were confirmed using the Bliss independence model. Pro-apoptotic Caspase-3/7 activation occurred in MCF-7 at 0.1-10 µM of EGFRi and Dox single treatments, whilst 1 µM Dox yielded a more potent effect on MDA-MB-231. EGFRi and Dox individually and in combination downregulated the EGFR gene expression in MCF-7 and MDA-MB-231 (p < 0.001). This study demonstrates EGFRi's potential for eliciting synergistic interactions with Dox, causing enhanced growth inhibition, apoptosis induction, and downregulation of EGFR in both cell lines.

Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer.

DNA topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention. Human DNA Ligase 1 (hLig I), recognized primarily for its role in DNA replication and repair of DNA breaks, intriguingly exhibits a DNA relaxation activity akin to Topo 1. This raised the hypothesis that hLig I might compensate for Topo 1 inhibition, contributing to resistance against Topo 1 inhibitors. To explore this hypothesis, we assessed the efficacy of hLig I inhibition alone and in combination with Topo 1 in cancer cells. As anticipated, the overexpression of hLig I was observed after Topo 1 inhibition in colorectal cancer cells, affirming our hypothesis. Previously identified as an inhibitor of hLig I's DNA relaxation activity, compound 27 (C 27), when combined with Topotecan, demonstrated a synergistic antiproliferative effect on colorectal cancer cells. Notably, cells with downregulated hLig I (via siRNA, inhibitors, or genetic manipulation) exhibited significantly heightened sensitivity to Topotecan. This observation strongly supports the concept that hLig I contribute to resistance against clinically relevant Topo 1 inhibitors in colorectal cancers. In conclusion, our findings offer evidence for the synergistic impact of combining hLig I inhibitors with Topotecan in the treatment of colorectal cancers, providing a promising strategy to overcome resistance to Topo 1 inhibitors.Communicated by Ramaswamy H. Sarma.

Liposomal ozonated oil effectiveness in the signs and symptoms of blepharitis in usual clinical practice.

PURPOSE: To analyze the efficacy of liposomal ozonated oil (Ozonest®) treatment, in patients with blepharitis or blepharoconjunctivitis, in improving the signs and symptoms of the pathology. METHODS: Exploratory, open-label, prospective, single-arm, pre-post comparative pilot study in usual clinical practice, in 20 patients with blepharitis/blepharoconjunctivitis, receiving treatment with liposomal ozonated oil, one drop in each eye, 4 times a day, for 28 days. Main purpose was to assess whether there was a clinically improvement in the blepharitis specific BLISS questionnaire score. Changes in the 12-item OSDI, in eyelid signs of blepharitis assessed by the physicians were also evaluated among other tests, and there was also a subjective evaluation of the treatment by patients. RESULTS: The BLISS score significantly improved from 16.4 before treatment to 11.8 after treatment (p < 0.05). The OSDI score was also significantly improved from 27.5 before treatment to 20.5 after treatment (p < 0.05). All tests conducted before and after treatment showed significant improvement (p < 0.05), except for NIBUT. The treatment received a score of 7 out of 10 by the patients. There were no adverse events in any patient. CONCLUSION: Liposomal ozonated oil treatment showed good efficacy in improving the signs and symptoms of blepharitis/blepharoconjunctivitis, satisfaction of patients, and good safety and tolerability.

Anti-cancer potential of synergistic phytochemical combinations is influenced by the genetic profile of prostate cancer cell lines.

Introduction: Despite strong epidemiological evidence that dietary factors modulate cancer risk, cancer control through dietary intervention has been a largely intractable goal for over sixty years. The effect of tumour genotype on synergy is largely unexplored. Methods: The effect of seven dietary phytochemicals, quercetin (0-100 µM), curcumin (0-80 µM), genistein, indole-3-carbinol (I3C), equol, resveratrol and epigallocatechin gallate (EGCG) (each 0-200 µM), alone and in all paired combinations om cell viability of the androgen-responsive, pTEN-null (LNCaP), androgen-independent, pTEN-null (PC-3) or androgen-independent, pTEN-positive (DU145) prostate cancer (PCa) cell lines was determined using a high throughput alamarBlue® assay. Synergy, additivity and antagonism were modelled using Bliss additivism and highest single agent equations. Patterns of maximum synergy were identified by polygonogram analysis. Network pharmacology approaches were used to identify interactions with known PCa protein targets. Results: Synergy was observed with all combinations. In LNCaP and PC-3 cells, I3C mediated maximum synergy with five phytochemicals, while genistein was maximally synergistic with EGCG. In contrast, DU145 cells showed resveratrol-mediated maximum synergy with equol, EGCG and genistein, with I3C mediating maximum synergy with only quercetin and curcumin. Knockdown of pTEN expression in DU145 cells abrogated the synergistic effect of resveratrol without affecting the synergy profile of I3C and quercetin. Discussion: Our study identifies patterns of synergy that are dependent on tumour cell genotype and are independent of androgen signaling but are dependent on pTEN. Despite evident cell-type specificity in both maximally-synergistic combinations and the pathways that phytochemicals modulate, these combinations interact with similar prostate cancer protein targets. Here, we identify an approach that, when coupled with advanced data analysis methods, may suggest optimal dietary phytochemical combinations for individual consumption based on tumour molecular profile.Graphical abstract.

On the use of historical estimates.

The use of historical, i.e., already existing, estimates in current studies is common in a wide variety of application areas. Nevertheless, despite their routine use, the uncertainty associated with historical estimates is rarely properly accounted for in the analysis. In this communication, we review common practices and then provide a mathematical formulation and a principled frequentist methodology for addressing the problem of drawing inferences in the presence of historical estimates. Three distinct variants are investigated in detail; the corresponding limiting distributions are found and compared. The design of future studies, given historical data, is also explored and relations with a variety of other well-studied statistical problems discussed.

Initial Development and Validation of a Brief Scale to Measure Genuine Happiness in the USA.

Genuine happiness can be described as an unlimited, everlasting inner joy and peace undisturbed by external circumstances. The current study proposes a Genuine Happiness Scale (GHS) with four items. The sample consisted of 678 US young adults, with 432 completing the online surveys twice, approximately six weeks apart. Exploratory and confirmatory factor analysis provided evidence for a unidimensional factor structure of the GHS. Hierarchical regression analysis revealed that, after controlling for genuine happiness at baseline, caring for bliss, mindfulness, and compassion predicted genuine happiness approximately six weeks later. In addition, genuine happiness predicted later well-being after controlling for well-being at baseline.

Synergistic Interaction of Caspofungin Combined with Posaconazole against FKS Wild-Type and Mutant Candida auris Planktonic Cells and Biofilms.

Candida auris is a potential multidrug-resistant pathogen able to cause biofilm-associated outbreaks, where frequently indwelling devices are the source of infections. The number of effective therapies is limited; thus, new, even-combination-based strategies are needed. Therefore, the in vitro efficacy of caspofungin with posaconazole against FKS wild-type and mutant Candida auris isolates was determined. The interactions were assessed utilizing the fractional inhibitory concentration indices (FICIs), the Bliss model, and a LIVE/DEAD assay. Planktonic minimum inhibitory concentrations (pMICs) for the caspofungin-posaconazole combination showed a 4- to 256-fold and a 2- to 512-fold decrease compared to caspofungin and posaconazole alone, respectively. Sessile minimum inhibitory concentrations (sMICs) for caspofungin and posaconazole in combination showed an 8- to 128-fold and a 4- to 512-fold decrease, respectively. The combination showed synergy, especially against biofilms (FICIs were 0.033-0.375 and 0.091-0.5, and Bliss cumulative synergy volumes were 6.96 and 32.39 for echinocandin-susceptible and -resistant isolates, respectively). The caspofungin-exposed (4 mg/L) C. auris biofilms exhibited increased cell death in the presence of posaconazole (0.03 mg/L) compared to untreated, caspofungin-exposed and posaconazole-treated biofilms. Despite the favorable effect of caspofungin with posaconazole, in vivo studies are needed to confirm the therapeutic potential of this combination in C. auris-associated infections.

HIV-1 bispecific antibody iMab-N6 exhibits enhanced breadth but not potency over its parental antibodies iMab and N6.

The recently published AMP trial (HVTN 703/HPTN 081 and HVTN704/HPTN 085) results have validated broad neutralising antibodies (bNAbs) as potential anti-HIV-1 agents. However, single bNAb preparations are unlikely to cope with the onslaught of existing and de novo resistance mutations, thus necessitating the use of bNAb combinations to achieve clinically relevant results. Specifically engineered antibodies incorporating two bNAbs into a single antibody structure have been developed. These bispecific antibodies (bibNAbs) retain the benefits of bNAb combinations, whilst several conformations exhibit improved neutralisation potency over the parental bNAbs. Here we report on the engineering of a bibNAb comprising of an HIV-1 spike targeting bNAb N6 and a host CD4 targeting antibody ibalizumab (iMab). Antibodies were expressed in HEK293T cells and purified by protein-A affinity chromatography followed by size exclusion chromatography to achieve homogenous, monomeric, bibNAb preparations. Antibody purity was confirmed by SDS-PAGE whilst epitope specificity and binding were confirmed by ELISA. Finally, antibody breadth and potency data were generated by HIV-1 neutralisation assay (n = 21, inclusive of the global panel). iMab-N6 exhibited better neutralisation breadth (100% coverage) in comparison to its parental bNAbs iMab (90%) and N6 (95%). This is encouraging as exceptional neutralisation breadth is necessary for HIV-1 treatment or prevention. Unfortunately, iMab-N6 did not exhibit any enhancement in potency over the most potent parental antibody, iMab (p = 0.1674, median IC50 of 0.0475 µg/ml, and 0.0665 µg/ml respectively) or the parental combination, iMab + N6 (p = 0.1964, median IC50: combination 0.0457 µg/ml). This result may point to a lack of dual engagement of the bibNAb Fab moieties necessary for potency enhancement. Against the previously reported bibNAbs; iMab-CAP256, 10E08-iMab, and PG9-iMab; iMab-N6 was the lowest performing bibNAb. The re-engineering of iMab-N6 to enhance its potency, while retaining breadth, is a worthwhile endeavour due to its clinical potential.

Multicenter Collaborative Study of the Interaction of Antifungal Combinations against Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis.

Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5−4, indicating no significant pharmacodynamic interactions for all of the strain−combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p < 0.0001). Using a narrower additivity range of 1−2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found.

Complementary Feeding Caregivers' Practices and Growth, Risk of Overweight/Obesity, and Other Non-Communicable Diseases: A Systematic Review and Meta-Analysis.

Several institutions propose responsive feeding (RF) as the caregivers' relational standard when nurturing a child, from breast/formula feeding onwards. Previous systematic reviews (SRs) on caregivers' feeding practices (CFPs) have included studies on populations from countries with different cultures, rates of malnutrition, and incomes, whereas this SR compares different CFPs only in healthy children (4-24 months) from industrialized countries. Clinical questions were about the influence of different CFPs on several important outcomes, namely growth, overweight/obesity, risk of choking, dental caries, type 2 diabetes (DM2), and hypertension. The literature review does not support any Baby Led Weaning's or Baby-Led Introduction to SolidS' (BLISS) positive influence on children's weight-length gain, nor their preventive effect on future overweight/obesity. RF-CFPs can result in adequate weight gain and a lower incidence of overweight/obesity during the first two years of life, whereas restrictive styles and coercive styles, two kinds of non-RF in CF, can have a negative effect, favoring excess weight and lower weight, respectively. Choking risk: failure to supervise a child's meals by an adult represents the most important risk factor; no cause-effect relation between BLW/BLISS/RF/NRCF and choking could be found. Risks of DM2, hypertension, and caries: different CFPs cannot be considered as a risky or preventive factor for developing these conditions later in life.

Evaluation of synergism in drug combinations and reference models for future orientations in oncology.

Current cancer therapy includes a variety of strategies that can comprise only one type of treatment or a combination of multiple treatments. Chemotherapy is still the gold standard for cancer therapy, though sometimes associated with undesired side effects and the development of drug resistance. For this reason, drug combination is an approach that has been proposed to overcome the problems related to monotherapy and several studies have already demonstrated the superiority of combined therapies compared to monotherapy. The main goal when designing and evaluating drug combinations is to achieve synergistic effects by demonstrating that the combined effects are greatly superior to the expected from the additive effects of the single drugs, allowing for dosage reduction and therefore decreasing toxicity. Nevertheless, synergism quantification is not a simple task due to the different definitions of additivity and over the years several reference models have been proposed based on different assumptions and with different mathematical frameworks. In this review, we begin to cover the available treatment options for cancer therapy, with emphasis on the importance of drug combinations in cancer therapy. We next describe the classical reference models that have been proposed for synergism evaluation, usually classified as effect-based and dose-effect based methods, with a brief analysis of the current limitations of these models. We also describe here the novel methods for the accurate quantification of drug interactions in combined treatments. At the end of this manuscript, we covered some of the most recent preclinical and clinical combination studies that reflect the importance of the appropriate, accurate and precise application of the concepts and methodologies here described for the evaluation of synergism.

Psychometric validity and measurement invariance of the caring for Bliss Scale in the Philippines and the United States.

The Caring for Bliss Scale (CBS) is a new measure that assesses an individuals' capacity to cultivate inner joy and happiness. Developed in the United States, its generalizability remains unknown in non-Western contexts. This research explored the scale's cross-national invariance among college students in the Philippines (n = 546) and the United States (n = 643). A multi-group confirmatory factor analysis using maximum likelihood estimation showed that the unidimensional model of caring for bliss exhibited configural, metric, scalar, and residual invariance across the Filipino and the U.S. samples. This scale also had good internal consistency estimates in both settings. In both contexts, caring for bliss was positively correlated with well-being and negatively correlated with different negative quality of life indicators (i.e., stress, anxiety, and depression). This study offered preliminary evidence regarding the cross-national applicability of the CBS in different cultural settings during the COVID-19 pandemic.

Whole-Genome Sequence and Interaction Analysis in the Production of Six Enzymes From the Three Bacillus Strains Present in a Commercial Direct-Fed Microbial (Norum™) Using a Bliss Independence Test.

The three Bacillus strains present in Norum™ were initially selected by their excellent to good relative enzyme activity (REA) production score for amylase, protease, lipase, phytase, cellulase, ß-glucanase, and xylanase. Further studies confirmed that the three isolates also showed an antibacterial activity, Gram-positive and Gram-negative poultry pathogens. Norum™ (Eco-Bio/Euxxis Bioscience LLC) is a Bacillus spore direct-fed microbial (DFM). The Bacillus isolates were screened and selected based on in vitro enzyme production profiles. Moreover, in chickens fed high non-starch polysaccharides, this DFM demonstrated to reduce digesta viscosity, bacterial translocation, increase performance, bone mineralization, and balance the intestinal microbiota. In the present study, we present the whole-genome sequence of each of the three isolates in Norum™, as well as the synergistic, additive, or antagonistic effects on the enzyme production behavior of the three Bacillus strains and their combinations when grown together vs. when grown individually. The whole-genome sequence identified isolate AM1002 as Bacillus subtilis (isolate 1), isolate AM0938 as Bacillus amyloliquefaciens (isolate 2), and isolate JD17 as Bacillus licheniformis (isolate 3). The three Bacillus isolates used in the present study produce different enzymes (xylanase, cellulase, phytase, lipase, protease, and ß-glucanase). However, this production was modified when two or more Bacillus strains were combined, suggesting possible synergistic, antagonistic, or additive interactions. The Bliss analysis suggested (p < 0.05) that the combination of Bacillus strains 1-2 and 1-2-3 had intermediate effects and predicted that the combination of Bacillus strains 2-3 could have better effects than the combination of all the three Bacillus strains. In summary, the current study demonstrated the need of selecting Bacillus strains based on quantitative enzyme determination and data analysis to assess the impacts of combinations to avoid antagonistic interactions that could limit treatment efficacy. These results suggest that using Bacillus strains 2-3 together could lead to a new generation of DFMs with effects superior to those already examined in Bacillus strains 1-2-3 and, therefore, a potential alternative to growth-promoting antibiotics. More research utilizing poultry models is being considered to confirm and expand the existing findings.

Exploring synergy and its role in antimicrobial peptide biology.

Antimicrobial peptides will be an essential component in combating the escalating issue of antibiotic resistance. Identifying synergistic combinations of two or more substances will increase the value of these peptides further. Several potential pitfalls in conducting synergy testing with peptides are discussed in detail. As case studies, we describe observations of AMP synergy with peptides, antibiotics, and metal ions as well as some of the mechanistic details that have been uncovered. The Bliss and Loewe models for synergy are presented prior to recommending protocols for conducting checkerboard, minimal inhibitory concentration, and time-kill assays. Establishing mechanisms of action and exploring the potential for resistance will be crucial to translate these studies into the clinic.

Recommendations on Complementary Feeding as a Tool for Prevention of Non-Communicable Diseases (NCDs)-Paper Co-Drafted by the SIPPS, FIMP, SIDOHaD, and SINUPE Joint Working Group.

Adequate and balanced nutrition is essential to promote optimal child growth and a long and healthy life. After breastfeeding, the second step is the introduction of complementary feeding (CF), a process that typically covers the period from 6 to 24 months of age. This process is, however, still highly controversial, as it is heavily influenced by socio-cultural choices, as well as by the availability of specific local foods, by family traditions, and pediatrician beliefs. The Società Italiana di Pediatria Preventiva e Sociale (SIPPS) together with the Federazione Italiana Medici Pediatri (FIMP), the Società Italiana per lo Sviluppo e le Origine della Salute e delle Malattie (SIDOHaD), and the Società Italiana di Nutrizione Pediatrica (SINUPE) have developed evidence-based recommendations for CF, given the importance of nutrition in the first 1000 days of life in influencing even long-term health outcomes. This paper includes 38 recommendations, all of them strictly evidence-based and overall addressed to developed countries. The recommendations in question cover several topics such as the appropriate age for the introduction of CF, the most appropriate quantitative and qualitative modalities to be chosen, and the relationship between CF and the development of Non-Communicable Diseases (NCDs) later in life.

The interplay between mindfulness and caring for bliss on later student burnout.

Objectives: While there are good reasons to assume that mindfulness protects against burnout in students, nothing is known about the role of caring for bliss. This study examined whether caring for bliss moderated the relationship between mindfulness at baseline and aspects of burnout approximately 12 weeks later. Participants: Students (n = 92) from a university in the United States. Methods: Online surveys were administered in 2018. Results: Moderated regression analyses, controlling for depressive symptoms and burnout at baseline, revealed that caring for bliss moderated the relationship between earlier mindfulness and two aspects of later student burnout, namely emotional exhaustion and cynicism. Specifically, exhaustion and cynicism were low when students reported either low or high scores on both mindfulness and caring for bliss. No moderating effect was found for academic efficacy. Conclusions: Mindfulness and caring for bliss appear to work synergistically to reduce aspects of student burnout over time.

Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among Klebsiella pneumoniae by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System.

In over eighty years, despite successive antibiotics discoveries, the rapid advent of multidrug resistance among bacterial pathogens has jolted our misapprehension of success over them. Resistance is spreading faster than the discovery of new antibiotics/antimicrobials. Therefore, the search for better antimicrobials/additives becomes prudent. A water-soluble curcumin derivative (Curaq) was synthesised, employing a Cu (I) catalysed 1, 3-cyclo addition reaction; it has been evaluated as a potential treatment for multidrug-resistant isolates and as an antibiotic adjuvant for meropenem against hypervirulent multidrug-resistant Klebsiella pneumoniae isolates. We also investigated its solubility and effect over carbapenemase activity. Additionally, we investigated its impact on the AcrAB-TolC system. We found that Curaq inhibited bacterial growth at a minimal concentration of 16 µg/mL; at a 32 µg/mL concentration, it killed bacterial growth completely. Only nine (9.4%) Klebsiella isolates were sensitive to meropenem; however, after synergising with Curaq (8 µg/mL), 85 (88.54%) hvKP isolates became sensitive to the drug. The Curaq also inhibited the AcrAB-TolC efflux system at 1 µg/mL concentration by disrupting the membrane potential and causing depolarisation. The kinetic parameters obtained also indicated its promise as a carbapenemase inhibitor. These results suggest that Curaq can be an excellent drug candidate as a broad-spectrum antibacterial and anti-efflux agent.

Genome-Wide CRISPR Off-Target DNA Break Detection by the BLISS Method.

Clustered regularly interspaced palindromic repeat (CRISPR) systems are revolutionizing many areas of biology and medicine, where they are increasingly utilized as therapeutic tools for correcting disease-causing mutations. From a clinical perspective, unintended off-target (OT) DNA double-strand break (DSB) induction by CRISPR nucleases represents a major concern. Therefore, in recent years considerable effort has been dedicated to developing methods for assessing the OT activity of CRISPR nucleases, which in turn can be used to guide engineering of nucleases with minimal OT activity. Here we describe a detailed protocol for quantifying OT DSBs genome-wide in cultured cells transfected with CRISPR enzymes, based on the breaks labeling in situ and sequencing (BLISS) method that we have previously developed. CRISPR-BLISS is versatile and scalable, and allows assessment of multiple guide RNAs in different cell types and time points following cell transfection or transduction.