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Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we studied a novel drug conjugate, ZHER3-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin-binding domain for in vivo half-life extension. ZHER3-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (KD 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic carcinoma cell line, BxPC-3. The drug conjugate showed a potent cytotoxic effect on BxPC-3 cells with an IC50 value of 7 nM. Evaluation of a radiolabeled version, [99mTc]Tc-ZHER3-ABD-mcDM1, showed a relatively high rate of internalization, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could target BxPC-3 (pancreatic carcinoma) and DU145 (prostate carcinoma) xenografts in mice, with an uptake peaking at 6.3 ± 0.4% IA/g at 6 h post-injection for the BxPC-3 xenografts. The general biodistribution showed uptake in the liver, lung, salivary gland, stomach, and small intestine, organs known to express murine ErbB3 naturally. The results from the study show that ZHER3-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.

Ovarian stimulation is an indispensable part of IVF and is employed to produce multiple ovarian follicles. In women who undergo ovarian stimulation with gonadotropins, supraphysiological levels of estradiol, as well as a premature rise in progesterone levels, can be seen on the day of hCG administration. These alterations in hormone levels are associated with reduced embryo implantation and pregnancy rates in IVF cycles with a fresh embryo transfer. This article aims to improve the reader’s understanding of the effects of elevated progesterone levels on human endometrial receptivity and oocyte/embryo quality. Based on current clinical data, it appears that the premature rise in progesterone levels exerts minimal or no effects on oocyte/embryo quality, while advancing the histological development of the secretory endometrium and displacing the window of implantation. These clinical findings strongly suggest that reduced implantation and pregnancy rates are the result of a negatively affected endometrium rather than poor oocyte/embryo quality. Understanding the potential negative impact of elevated progesterone levels on the endometrium is crucial to improving implantation rates following a fresh embryo transfer. Clinical studies conducted over the past three decades, many of which have been reviewed here, have greatly advanced our knowledge in this important area.

In cases of nuclear and radiological accidents, public health and emergency response need to assess the magnitude of radiation exposure regardless of whether they arise from disaster, negligence, or deliberate act. Here we report the establishment of a national reference dose–response calibration curve (DRCC) for dicentric chromosome (DC), prerequisite to assess radiation doses received in accidental exposures. Peripheral blood samples were collected from 10 volunteers (aged 20–40 years, median = 29 years) of both sexes (three females and seven males). Blood samples, cytogenetic preparation, and analysis followed the International Atomic Energy Agency EPR-Biodosimetry 2011 report. Irradiations were performed using 320 kVp X-rays. Metafer system was used for automated and assisted (elimination of false-positives and inclusion of true-positives) metaphases findings and DC scoring. DC yields were fit to a linear–quadratic model. Results of the assisted DRCC showed some variations among individuals that were not statistically significant (homogeneity test, P = 0.66). There was no effect of age or sex (P > 0.05). To obtain representative national DRCC, data of all volunteers were pooled together and analyzed. The fitted parameters of the radiation-induced DC curve were as follows: Y = 0.0020 (±0.0002) + 0.0369 (±0.0019) *D + 0.0689 (±0.0009) *D2. The high significance of the fitted coefficients (z-test, P < 0.0001), along with the close to 1.0 p-value of the Poisson-based goodness of fit (χ2 = 3.51, degrees of freedom = 7, P = 0.83), indicated excellent fitting with no trend toward lack of fit. The curve was in the middle range of DRCCs published in other populations. The automated DRCC over and under estimated DCs at low (2 Gy) doses, respectively, with a significant lack of goodness of fit (P < 0.0001). In conclusion, we have established the reference DRCC for DCs induced by 320 kVp X-rays. There was no effect of age or sex in this cohort of 10 young adults. Although the calibration curve obtained by the automated (unsupervised) scoring misrepresented dicentric yields at low and high doses, it can potentially be useful for triage mode to segregate between false-positive and near 2-Gy exposures from seriously irradiated individuals who require hospitalization.

Purpose: The study of breast cancer nearly always involves patients close to menopause or older. Therefore, young patients are mostly underrepresented. Our aim in this study was to demonstrate biological differences in breast cancer of young people using as a model available cell lines derived from people with breast cancer younger than 35 years. Methods: Global miRNA expression was analyzed in breast cancer cells from young (HCC1500, HCC1937) and old patients (MCF-7, MDA-MB-231, HCC1806, and MDA-MB-468). In addition, it was compared with same type of results from patients. Results: We observed a differential profile for 155 miRNAs between young and older cell lines. We identified a set of 24 miRNA associated with aggressiveness that were regulating pluripotency of stem cell-related pathways. Combining the miRNA expression data from cell lines and breast cancer patients, 132 miRNAs were differently expressed between young and old samples, most of them previously found in cell lines. MiR-23a-downregulation was also associated with poor survival in young patients. Conclusions: Our results suggest that HCC1500 and HCC1937 cell lines could be suitable cellular models for breast cancer affecting young women. The miR-23a-downregulation could have a potential role as a poor prognosis biomarker in this age group.

ABSTRACT Central metabolism is a topic that has been studied for decades, and yet, this process is still not fully understood in Escherichia coli, perhaps the most amenable and well-studied model organism in biology. To further our understanding, we used a high-throughput method to measure the growth kinetics of each of 3,796 E. coli single-gene deletion mutants in 30 different carbon sources. In total, there were 342 genes (9.01%) encompassing a breadth of biological functions that showed a growth phenotype on at least 1 carbon source, demonstrating that carbon metabolism is closely linked to a large number of processes in the cell. We identified 74 genes that showed low growth in 90% of conditions, defining a set of genes which are essential in nutrient-limited media, regardless of the carbon source. The data are compiled into a Web application, Carbon Phenotype Explorer (CarPE), to facilitate easy visualization of growth curves for each mutant strain in each carbon source. Our experimental data matched closely with the predictions from the EcoCyc metabolic model which uses flux balance analysis to predict growth phenotypes. From our comparisons to the model, we found that, unexpectedly, phosphoenolpyruvate carboxylase (ppc) was required for robust growth in most carbon sources other than most trichloroacetic acid (TCA) cycle intermediates. We also identified 51 poorly annotated genes that showed a low growth phenotype in at least 1 carbon source, which allowed us to form hypotheses about the functions of these genes. From this list, we further characterized the ydhC gene and demonstrated its role in adenosine efflux. IMPORTANCE While there has been much study of bacterial gene dispensability, there is a lack of comprehensive genome-scale examinations of the impact of gene deletion on growth in different carbon sources. In this context, a lot can be learned from such experiments in the model microbe Escherichia coli where much is already understood and there are existing tools for the investigation of carbon metabolism and physiology (1). Gene deletion studies have practical potential in the field of antibiotic drug discovery where there is emerging interest in bacterial central metabolism as a target for new antibiotics (2). Furthermore, some carbon utilization pathways have been shown to be critical for initiating and maintaining infection for certain pathogens and sites of infection (3–5). Here, with the use of high-throughput solid medium phenotyping methods, we have generated kinetic growth measurements for 3,796 genes under 30 different carbon source conditions. This data set provides a foundation for research that will improve our understanding of genes with unknown function, aid in predicting potential antibiotic targets, validate and advance metabolic models, and help to develop our understanding of E. coli metabolism.

This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been withdrawn at the request of the editor and publisher.The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error.

Childhood adversity is heterogeneous with potentially distinct dimensions of violence exposure and social deprivation. These dimensions may differentially shape emotion-based neural circuitry, such as amygdala–PFC white matter connectivity. Amygdala–orbitofrontal cortex (OFC) white matter connectivity has been linked to regulation of the amygdala’s response to emotional stimuli. Using a preregistered analysis plan, we prospectively examined the effects of childhood exposure to two dimensions of adversity, violence exposure and social deprivation, on the adolescent amygdala–PFC white matter connectivity. We also reproduced the negative correlation between amygdala–PFC white matter connectivity and amygdala activation to threat faces. 183 15−17-year-olds were recruited from the Fragile Families and Child Wellbeing Study — a longitudinal, birth cohort, sample of predominantly low-income youth. Probabilistic tractography revealed that childhood violence exposure and social deprivation interacted to predict the probability of adolescent right hemisphere amygdala–OFC white matter connectivity. High violence exposure with high social deprivation related to less amygdala–OFC white matter connectivity. Violence exposure was not associated with white matter connectivity when social deprivation was at mean or low levels (i.e., relatively socially supportive contexts). Therefore, social deprivation may exacerbate the effects of childhood violence exposure on the development of white matter connections involved in emotion processing and regulation. Conversely, social support may buffer against them.

Potato (Solanum tuberosum L.) is the third most economically important crop in the world and has a high nutritional value. In this study, the in vitro culture response of four widely grown in Kazakhstan potato cultivars, Astanalyk, Monument Kunaev, Tokhtar, and Aksor, was investigated using stem and leaf explants. Published protocols were evaluated and optimized to develop a more efficient protocol for the regeneration of plants from local potato cultivars in tissue culture, which is a prerequisite to facilitate potato genome modification. The explants were cultured on solid Murashige and Skoog medium supplemented with different concentrations and combinations of zeatin, 6-benzylaminopurine (BAP), gibberellic acid (GA3), 1-naphthaleneacetic acid (NAA) and indole-3-acetic acid (IAA). The maximum regeneration was induced from the stem internodal explants. A significant effect of the explant source on direct regeneration was confirmed with statistical analysis. The number of shoots obtained from the internode was 10.0 from cv. Aksor followed by cvs. Tokhtar and Astanalyk. The medium DRM-VIII with 1 mg/l zeatin, 0.1 mg/l IAA and 7.0 mg/l GA3 was considered the best for direct shoot regeneration and multiple shoot formation from all cultivars. To conclude, we outline a protocol for direct plant regeneration from four potato cultivars. Our findings suggest commercial cultivars Astanalyk and Aksor are good candidates for developing the genome-edited plants through direct shoot regeneration.

Introduction Severe and persistent mental illness (SPMI) can significantly impact a person’s social, personal and professional life. Previous studies have demonstrated pharmacists’ roles in mental healthcare; however, limited studies to date have focused on pharmacists’ roles in providing healthcare services, specifically, to people living with SPMI. The aim of this systematic review is to explore the pharmacists’ roles in providing support to people living with SPMI.Methods and analysis A systematic search will be conducted in Medline, Embase (Ovid), PsycINFO, CINAHL, Web of Science, Scopus, Cochrane Library, International Pharmaceutical Abstracts and ProQuest Dissertations and Theses to identify potentially relevant primary research for inclusion. This will be guided by the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols checklist for systematic reviews. All primary research publications regardless of study design exploring or reporting on pharmacists’ involvement in supporting people living with SPMI will be considered for inclusion. A tabular summary will be completed using data extracted from each included publication. Data synthesis and quality assessment methods will be chosen based on included study designs.Ethics and dissemination The results will be published in a peer-reviewed journal and used to inform the development of a pharmacist-specific training package to support people living with SPMI.PROSPERO registration number CRD42020170711.

Introduction There is a significant life expectancy gap attributable to physical comorbidities for people living with severe and persistent mental illness (SPMI) compared with the general population. Medications are a major treatment for SPMI management and physical illnesses, hence pharmacists are well positioned to support mental healthcare and comorbidities. The randomised controlled trial (RCT) aim is to evaluate effectiveness of an individualised, pharmacist led, support service for people experiencing SPMI focusing on medication adherence and physical comorbidity management, compared with standard care (a medication-management service; MedsCheck).Methods and analysis PharMIbridge is a cluster RCT, whereby community pharmacies in four Australian regions will be randomised (1:1 ratio), to either Intervention Group (IG) or Comparator Group (CG). All IG and CG pharmacy staff will receive Blended-Mental Health First Aid training. Additionally, IG pharmacists will receive further training on medication adherence, goal setting, motivational interviewing, managing physical health concerns and complex issues relating to psychotropic medication. CG pharmacists will not receive additional training, and will provide standard care (MedsCheck). The primary outcome will be change in participants medication adherence for psychotropic medication over 6-months. Using mixed-effects logistic regression model and a cluster size of 48 pharmacies, a total of 190 participants will need to be recruited to each arm to find a statistically significant difference in medication adherence. Secondary outcomes will be changes in factors associated with cardiometabolic risk and quality of life, emphasising physical and psychological well-being; medication-related problems; adherence to other prescribed medication; pharmacists knowledge, confidence and ability to support people experiencing SPMI; and effects on healthcare utilisation. A within RCT-based economic evaluation comparing the intervention with standard care will be undertaken.Ethics and dissemination The protocol and pharmacist training programme received Griffith University Human Research Ethics Committee approval (HREC/2019/473 and HREC/2019/493 respectively). Results will be published in peer-reviewed journals and available at the Sixth Community Pharmacy Agreement website (http://6cpa.com.au/about-6cpa/).Trial registration number ANZCTR12620000577910.

Entry-level occupational therapy doctorate (OTD) students receive education and training to interpret and disseminate evidenced-based literature. However, these students are often missing the clinical experience to identify clinically relevant questions that impact occupational outcomes. Conversely, occupational therapy practitioners have the clinical experience to determine clinically appropriate questions but often encounter time, budget, and setting constraints on researching and learning up-to-date evidence-based practice assessment and intervention techniques. The purpose of this paper is to describe the development and design of an exploratory educational project in which OTD students utilized clinically relevant questions identified by local occupational therapy practitioners to disseminate evidence-based literature in the form of continuing competency in-services to clinicians as it related to their clinical practice setting. Nineteen sites participated and 33 one-hour presentations were presented to clinical sites in the local area and within the occupational therapy student body. Students reflected that this was a positive learning experience and a valuable component of the course.

The family environment, with all its complexity and diverse components, plays a critical role in shaping neurodevelopmental outcomes in children. Herein we review several domains of the family environment (family socioeconomic status, family composition and home environment, parenting behaviors and interaction styles, parental mental health and functioning, and parental substance use) and discuss how these domains influence neurodevelopment, with particular emphasis on mental health outcomes. We also highlight a new initiative launched by the National Institutes of Health, the Environmental influences on Child Health Outcomes (ECHO) program. We discuss the role that ECHO will play in advancing our understanding of the impact of the family environment on children’s risk for psychiatric outcomes. Lastly, we conclude with important unanswered questions and controversies in this area of research, highlighting how ECHO will contribute to resolving these gaps in our understanding, clarifying relationships between the family environment and children’s mental health.

Objectives: The incidence and the prevalence of eosinophilic esophagitis (EoE) are increasing, and healthcare utilization among children with EoE is high. This study provides novel insights into the health services and the treatments, including complementary medicines (CMs), used by carers to manage their children's EoE as well as the carers' beliefs and attitudes toward these treatments.Methods: A national cross-sectional online survey was conducted in Australia between September 2018 and February 2019. The survey included questions about health service and treatment utilization, health insurance and government support, health-related quality of life of children with EoE and their carers, views and attitudes toward CM use, and perceived efficacy of treatment.Results: The survey was completed by 181 carers (96.6% of whom were mothers) of EoE children. Most children (91.2%, n = 165) had seen a medical doctor for their EoE, and almost half had consulted with a CM practitioner (40.3%, n = 73). Pharmaceuticals (n = 156, 86.2%) were the most commonly used treatment option, followed by dietary changes (n = 142, 78.5%), CM products (n = 109, 60.2%), and CM therapies (n = 42, 23.2%). Most children received care from numerous practitioners on multiple occasions, indicating a substantial financial and treatment-related burden.Conclusions: A variety of practitioners are involved in the care of children with EoE, and a high rate of CM use warrants further attention to ensure that appropriate treatment is provided. Carer involvement and guidance, combined with individual practitioner expertise, referrals, and collaboration between providers, is essential to successfully navigate this complex disease and provide adequate care for these patients.

The toxigenic conversion of Escherichia coli strains by Shiga toxin-converting (Stx) bacteriophages were prominent and recurring events in the stepwise evolution of enterohemorrhagic E. coli (EHEC) O157:H7 from an enteropathogenic (EPEC) O55:H7 ancestor. Atypical, attenuated isolates have been described for both non-sorbitol fermenting (NSF) O157:H7 and SF O157:NM serotypes, which are distinguished by the absence of Stx, the characteristic virulence hallmark of Stx-producing E. coli (STEC). Such atypical isolates either never acquired Stx-phages or may have secondarily lost stx during the course of infection, isolation, or routine subculture; the latter are commonly referred to as LST (Lost Shiga Toxin)-isolates. In this study we analyzed the genomes of 15 NSF O157:H7 and SF O157:NM strains from North America, Europe, and Asia that are characterized by the absence of stx, the virulence hallmark of STEC. The individual genomic basis of the Stx (−) phenotype has remained largely undetermined as the majority of STEC genomes in public genome repositories were generated using short read technology and are in draft stage, posing a major obstacle for the high-resolution whole genome sequence typing (WGST). The application of LRT (long-read technology) sequencing provided us with closed genomes, which proved critical to put the atypical non-shigatoxigenic NSF O157:H7 and SF O157:NM strains into the phylogenomic context of the stepwise evolutionary model. Availability of closed chromosomes for representative Stx (−) NSF O157:H7 and SF O157:NM strains allowed to describe the genomic basis and individual evolutionary trajectories underlying the absence of Stx at high accuracy and resolution. The ability of LRT to recover and accurately assemble plasmids revealed a strong correlation between the strains’ featured plasmid genotype and chromosomally inferred clade, which suggests the coevolution of the chromosome and accessory plasmids. The identified ancestral traits in the pSFO157 plasmid of NSF O157:H7 strain LSU-61 provided additional evidence for its intermediate status. Taken together, these observations highlight the utility of LRTs for advancing our understanding of EHEC O157:H7/NM pathogenome evolution. Insights into the genomic and phenotypic plasticity of STEC on a lineage- and genome-wide scale are foundational to improve and inform risk assessment, biosurveillance, and prevention strategies.

Background: Thirty-day hospital readmission is receiving growing attention as an indicator of the quality of hospital care. Understanding factors associated with 30-day hospital readmission among HIV patients in Portugal is essential given the high burden cost of HIV hospitalizations in Portugal, a country suffering from financial constrains for almost 10 years.Objectives: We aimed to estimate the 30-day hospital readmission rates among HIV patients in Portugal and to identify its determinants using population-based data for Portuguese public hospitals.Study Design: A multilevel longitudinal population-based study.Methods: Between January 2009 and December 2014, a total of 37,134 registered discharges in the Portuguese National Health Service (NHS) facilities with HIV/AIDS as a main or secondary cause of admission were analyzed. Logistic regression was used to compare 30-day hospital readmission categories by computing odds ratio (OR) and corresponding 95% confidence intervals (95% CIs). A normal random effects model was used to determine unmeasured factors specific to each hospital.Results: A total of 4914 (13.2%, 95% CI: 12.9%−13.6%) hospitalizations had a subsequent 30-day readmission. Hospitalizations that included exit against medical opinion (OR = 1.18, 95% CI: 1.01–1.39), scheduled admissions (OR = 1.71, 95% CI: 1.58–1.85), and tuberculosis infection (OR = 1.20, 95% CI: 1.05–1.38) exhibited a higher risk of hospitalizations with subsequent 30-day readmission. In contrast, hospitalizations that included females (OR = 0.87, 95% CI: 0.81–0.94), a transfer to another facility (OR = 0.78, 95% CI: 0.67–0.91), and having a responsible financial institution (OR = 0.63, 95% CI: 0.55–0.72) exhibited a lower risk of hospitalizations with subsequent 30-day readmission. Hospitalizations associated with higher number of diagnosis, older ages, or hospitalizations during the economic crisis showed an increasing trend of 30-day readmission, whereas an opposite trend was observed for hospitalizations with higher number of procedures. Significant differences exist between hospital quality, adjusting for other factors.Conclusion: This study analyzes the indicators of 30-day hospital readmission among HIV patients in Portugal and provides useful information for enlightening policymakers and health care providers for developing health policies that can reduce costs associated with HIV hospitalizations.

Abstract In plants, the phenylpropanoid pathway is responsible for the synthesis of a diverse array of secondary metabolites that include lignin monomers, flavonoids, and coumarins, many of which are essential for plant structure, biomass recalcitrance, stress defense, and nutritional quality. Our previous studies have demonstrated that Populus trichocarpa PtrEPSP‐TF, an isoform of 5‐enolpyruvylshikimate 3‐phosphate (EPSP) synthase, has transcriptional activity and regulates phenylpropanoid biosynthesis in Populus. In this study, we report the identification of single nucleotide polymorphism (SNP) of PtrEPSP‐TF that defines its functionality. Populus natural variants carrying this SNP were shown to have reduced lignin content. Here, we demonstrated that the SNP‐induced substitution of 142nd amino acid (PtrEPSP‐TFD142E) dramatically impairs the DNA‐binding and transcriptional activity of PtrEPSP‐TF. When introduced to a monocot species rice (Oryza sativa) in which an EPSP synthase isoform with the DNA‐binding helix‐turn‐helix (HTH) motif is absent, the PtrEPSP‐TF, but not PtrEPSP‐TFD142E, activated genes in the phenylpropanoid pathway. More importantly, heterologous expression of PtrEPSP‐TF uncovered five new transcriptional regulators of phenylpropanoid biosynthesis in rice. Collectively, this study identifies the key amino acid required for PtrEPSP‐TF functionality and provides a strategy to uncover new transcriptional regulators in phenylpropanoid biosynthesis.

The bacteriophage population is vast, dynamic, old, and genetically diverse. The genomics of phages that infect bacterial hosts in the phylum Actinobacteria show them to not only be diverse but also pervasively mosaic, and replete with genes of unknown function. To further explore this broad group of bacteriophages, we describe here the isolation and genomic characterization of 116 phages that infect Microbacterium spp. Most of the phages are lytic, and can be grouped into twelve clusters according to their overall relatedness; seven of the phages are singletons with no close relatives. Genome sizes vary from 17.3 kbp to 97.7 kbp, and their G+C% content ranges from 51.4% to 71.4%, compared to ~67% for their Microbacterium hosts. The phages were isolated on five different Microbacterium species, but typically do not efficiently infect strains beyond the one on which they were isolated. These Microbacterium phages contain many novel features, including very large viral genes (13.5 kbp) and unusual fusions of structural proteins, including a fusion of VIP2 toxin and a MuF-like protein into a single gene. These phages and their genetic components such as integration systems, recombineering tools, and phage-mediated delivery systems, will be useful resources for advancing Microbacterium genetics.

Endometrial cancer is the most common gynecological cancer, representing 3.5% of all new cancer cases in the United States. Abnormal stem cell-like cells, referred to as cancer stem cells (CSCs), reside in the endometrium and possess the capacity to self-renew and differentiate into cancer progenitors, leading to tumor progression. Herein we review the role of the endometrial microenvironment and sex hormone signaling in sustaining EC progenitors and potentially promoting dormancy, a cellular state characterized by cell cycle quiescence and resistance to conventional treatments. We offer perspective on mechanisms by which bone marrow-derived cells (BMDCs) within the endometrial microenvironment could promote endometrial CSC (eCSC) survival and/or dormancy. Our perspective relies on the well-established example of another sex hormone-driven cancer, breast cancer, in which the BM microenvironment plays a crucial role in acquisition of CSC phenotype and dormancy. Our previous studies demonstrate that BMDCs migrate to the endometrium and express sex hormone (estrogen and progesterone) receptors. Whether the BM is a source of eCSCs is unknown; alternatively, crosstalk between BMDCs and CSCs within the endometrial microenvironment could be an additional mechanism supporting eCSCs and tumorigenesis. Elucidating these mechanisms will provide avenues to develop novel therapeutic interventions for EC.

This study aimed to evaluate the antioxidant activity and total phenolic content (TPC) and total flavonoid content (TFC) of crude extracts obtained from three Asclepiadaceae species, namely, Calotropis procera L., Peruglaria tomentosa L., and Pentatropis spiralis (Forsk.) Decne. Both butanol and aq. methanol extracts of the three species showed the highest amount of phenol and flavonoid contents, which exhibited the greatest antioxidant activity in the scavenging of 2,2-diphenyl-2-picrylhydrazyl free radical (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical cation (ABTS), ferrous chelating effect (FIC), and hydroxyl radical (HDR) assays. Phytochemical screening of the extracts revealed the presence of alkaloids, tannins, sponins, flavonoids, terpenoids, and glycosides. LC-MS analysis was carried out to identify the major compounds from each crude extract. A total of 12 phenolic compounds in the extracts of the 3 species were identified and quantified, including 9 flavonoids, 2 hydroxybenzoic acids, and 3 hydroxycinnamic acids. The current study also revealed a good correlation between total phenolic contents and the observed antioxidant activity of the crude extracts.

Objectives: This study aimed to examine gynaecological infectious agents observed in conventional and modified Papanicolaou cervical smears (CS) at a tertiary care hospital in Kuwait. Methods: This retrospective study analysed 121,443 satisfactory CS samples collected between 1997–2014 at the Mubarak Al-Kabeer Hospital, Kuwait. Conventional CS samples were obtained between 1997–2005, while modified CS were obtained between 2006–2014 following the introduction of ThinPrep® testing (Hologic Corp., Bedford, Massachusetts, USA). All samples were initially screened by cytoscreeners before being analysed by cytopathologists to determine the presence of specific infectious agents. Results: Overall, 8,836 (7.28%) of the cervical samples had infectious agents; of these, 62.48% were conventional and 37.52% were modified CS samples. The most frequently observed infectious agents were Candida species (76.05%), Trichomonas vaginalis (9.72%), human papillomavirus (HPV; 9.3%), Actinomyces-like organisms (3.23%), Chlamydia trachomatis (1.27%) and the herpes simplex virus (HSV; 0.43%). There were significantly more cases of Candida species, HPV-associated changes, C. trachomatis, T. vaginalis and Actinomyces-like organisms detected in conventional compared to modified CS samples (P

Chromosome 8q24 is known to be a major susceptibility region for prostate cancer risk. Here the authors analyze genetic data across the 8q24 region from 71,535 prostate cancer patients identifying 12 risk loci, three previously unreported, highlighting the contribution of germline variation at this locus.

Abstract Background Postpartum women are at risk for unintended pregnancy. Access to immediate long-acting reversible contraception (LARC) may help decrease this risk, but it is unclear how many providers in the United States routinely offer this to their patients and what obstacles they face. Our primary objective was to determine the proportion of United States obstetric providers that offer immediate postpartum LARC to their obstetric patients. Methods We surveyed practicing Fellows and Junior Fellows of the American College of Obstetricians and Gynecologists (ACOG) about their use of immediate postpartum LARC. These members are demographically representative of ACOG members as a whole and represent all of the ACOG districts. Half of these Fellows were also part of the Collaborative Ambulatory Research Network (CARN), a group of ACOG members who voluntarily participate in research. We asked about their experience with and barriers to immediate placement of intrauterine devices and contraceptive implants after delivery. Results There were a total of 108 out of 600 responses (18%). Participants practiced in a total of 36 states and/or US territories and their median age was 52 years. Only 26.9% of providers surveyed offered their patients immediate postpartum LARC, and of these providers, 60.7% work in a university-based practice. There was a statistically significant association between offering immediate postpartum LARC and practice type, with the majority of providers working at a university-based practice (p

This study aimed to evaluate the effects of addition of yacon flour on the quality parameters of goat milk yogurt and investigate the metabolic effects of its regular consumption on high fat diet-fed Wistar rats (30 days). The formulation containing 7% (w/v) yacon flour had higher nutritional values, acceptable sensory attributes and higher count (107 cfu/g) of viable probiotic microorganisms, with shelf life of at least 30 days. 7% yacon flour addition improved goat yogurt sugar profile, reducing lactose (0.94%) and increasing prebiotic fructooligosacharides (4.55%) content in the final product. Supplementation of goat yogurt + yacon to a high fat diet resulted in lower body weight, body mass index, fasting glucose levels, HOMA-IR and atherogenic indices of rats, improving the effects of goat yogurt or yacon flour alone (P

Abstract Background Crassulacean acid metabolism (CAM) enhances plant water-use efficiency through an inverse day/night pattern of stomatal closure/opening that facilitates nocturnal CO2 uptake. CAM has evolved independently in over 35 plant lineages, accounting for ~ 6% of all higher plants. Agave species are highly heat- and drought-tolerant, and have been domesticated as model CAM crops for beverage, fiber, and biofuel production in semi-arid and arid regions. However, the genomic basis of evolutionary innovation of CAM in genus Agave is largely unknown. Results Using an approach that integrated genomics, gene co-expression networks, comparative genomics and protein structure analyses, we investigated the molecular evolution of CAM as exemplified in Agave. Comparative genomics analyses among C3, C4 and CAM species revealed that core metabolic components required for CAM have ancient genomic origins traceable to non-vascular plants while regulatory proteins required for diel re-programming of metabolism have a more recent origin shared among C3, C4 and CAM species. We showed that accelerated evolution of key functional domains in proteins responsible for primary metabolism and signaling, together with a diel re-programming of the transcription of genes involved in carbon fixation, carbohydrate processing, redox homeostasis, and circadian control is required for the evolution of CAM in Agave. Furthermore, we highlighted the potential candidates contributing to the adaptation of CAM functional modules. Conclusions This work provides evidence of adaptive evolution of CAM related pathways. We showed that the core metabolic components required for CAM are shared by non-vascular plants, but regulatory proteins involved in re-reprogramming of carbon fixation and metabolite transportation appeared more recently. We propose that the accelerated evolution of key proteins together with a diel re-programming of gene expression were required for CAM evolution from C3 ancestors in Agave.

Whilst estrogen is known to be tumorigenic in some breast cancer, in some contexts it can be protective against invasion and dissemination. Here, the authors show estrogen can promote generation of Suppressive Cortical Actin Bundles that can inhibit motility dynamics through EVL-mediated actin cytoskeletal remodeling.

Abstract Background Compared to higher socioeconomic status (SES) groups, those in lower SES groups are financially strained, experience higher rates of smoking-related morbidity, are in poorer health and have reduced life expectancy. This is especially true for the city of Rotterdam, where a large inequality in health is observed between low and high SES groups. The BeHealthyR study (Dutch: Grip en Gezondheid) is a randomized controlled trial (RCT) which will evaluate the impact of a theory-based multicomponent behavior intervention aiming to reduce stress, smoking, and improve financial health by means of a group-based stress management program combining cognitive and behavioral techniques, and nudges in low-SES residents living in Rotterdam. Methods The BeHealthyR study is a three-arm RCT. Between February 2018 and July 2019, low-SES participants who perceive stress, smoke, are financially strained and reside in Rotterdam (one of the four largest cities in The Netherlands) are recruited. Subsequently, participants are randomly assigned to either a stress management condition (SM), stress management with a buddy condition (SM-B) or a control condition (CC). Participants in the SM and SM-B conditions will attend four weekly group sessions (1.5 h/session) and a follow-up session eight weeks later. The SM condition includes psychoeducation and exercises, and cognitive and behavioral intervention techniques. Demographic data and objective measures will be collected at baseline (T0), four weeks post-baseline (T1), and twelve weeks post-baseline (T2). Primary outcome measures are to reduce stress, smoking and improve financial health. We hypothesize that low-SES participants in the intervention conditions, compared with those in the control condition, will experience less stress, smoke less and have improved financial health. Discussion This study is a group-based intervention which aims to investigate the effects of a theory-based behavioral change intervention employing several components on reducing stress, smoking, and improving financial health in low-SES residents living in Rotterdam. If effective, the findings from the present study will serve to inform future directions of research and clinical practice with regard to behavioral change interventions for low-SES groups. Trial registration ClinicalTrials.gov (ID: NCT03553979). Registered on January 1 2018.

Abstract Background While the US population overall has experienced improvements in oral health over the past 60 years, oral diseases remain among the most common chronic conditions across the life course. Further, lack of access to oral health care contributes to profound and enduring oral health inequities worldwide. Vulnerable and underserved populations who commonly lack access to oral health care include racial/ethnic minority older adults living in urban environments. The aim of this study was to use a systematic approach to explicate cause and effect relationships in creating a causal map, a type of concept map in which the links between nodes represent causality or influence. Methods To improve our mental models of the real world and devise strategies to promote oral health equity, methods including system dynamics, agent-based modeling, geographic information science, and social network simulation have been leveraged by the research team. The practice of systems science modeling is situated amidst an ongoing modeling process of observing the real world, formulating mental models of how it works, setting decision rules to guide behavior, and from these heuristics, making decisions that in turn affect the state of the real world. Qualitative data were obtained from focus groups conducted with community-dwelling older adults who self-identify as African American, Dominican, or Puerto Rican to elicit their lived experiences in accessing oral health care in their northern Manhattan neighborhoods. Results The findings of this study support the multi-dimensional and multi-level perspective of access to oral health care and affirm a theorized discrepancy in fit between available dental providers and patients. The lack of information about oral health at the community level may be compromising the use and quality of oral health care among racial/ethnic minority older adults. Conclusions Well-informed community members may fill critical roles in oral health promotion, as they are viewed as highly credible sources of information and recommendations for dental providers. The next phase of this research will involve incorporating the knowledge gained from this study into simulation models that will be used to explore alternative paths toward improving oral health and health care for racial/ethnic minority older adults.

Abstract Objective Healthy habits during childhood has been of prime importance. We aimed to gather baseline information about health habits from children in kindergarten and first grade (typically ages 5–7). Our objectives were to validate the questionnaire in assessing health habits, as well as the electronic audience response system, iClicker (MPS, Gordonsville, VA), in this age group. Results The questionnaire completed by 75 kindergarteners and 66 first graders. For the first graders, questions involving healthy choices were answered correctly 78% of the time (range 8–94%) and had 84% agreement on repeat testing (range 64–93%). Questions on diabetes were answered correctly 79% of the time (range 65–94%) and had 85% agreement on repeat testing. Crohnbach’s alpha was calculated to determine the reliability of the questionnaire: on the revised kindergarten questionnaire, this ranged from 0.79 to 0.81 on Day 1 and 0.84–0.97 on Day 5; for the first graders, this ranged 0.79–0.81 on Day 1 and 0.84–0.97 on Day 5. Both kindergarteners and first graders answered the simplest of the basic knowledge questions correctly > 80% of the time, with acceptable test–retest agreement. Additionally, these children demonstrated acceptable understanding of the use of the iClicker classroom response system.

Summary: Of the ∼4,400 genes that constitute Escherichia coli's genome, ∼300 genes are indispensable for its growth in nutrient-rich conditions. These encode housekeeping functions, including cell wall, DNA, RNA, and protein syntheses. Under conditions in which nutrients are limited to a carbon source, nitrogen source, essential phosphates, and salts, more than 100 additional genes become essential. These largely code for the synthesis of amino acids, vitamins, and nucleobases. Although much is known about this collection of ∼400 genes, their interactions under nutrient stress are uncharted. Using a chemical biology approach, we focused on 45 chemical probes targeting encoded proteins in this collection and mapped their interactions under nutrient-limited conditions. Encompassing 990 unique pairwise chemical combinations, we revealed a highly connected network of 186 interactions, of which 81 were synergistic and 105 were antagonistic. The network revealed signature interactions for each probe and highlighted new connectivity between housekeeping functions and those essential in nutrient stress. : Biochemistry; Chemical-Chemical Combinations; Cellular Network; Nutrient Stress; Antibiotic Combinations; Synergistic Interactions; Antagonistic Interactions Subject Areas: Biochemistry, Chemical-Chemical Combinations, Cellular Network, Nutrient Stress, Antibiotic Combinations, Synergistic Interactions, Antagonistic Interactions

Magnetic fields are thought to have been influential in the formation of our solar system. Here, the authors observe thermomagnetically stable, non-uniformly magnetized kamacite grains within chondritic meteorites, and calculate the grains to retain recordings of these magnetic fields.

Introduction: Portuguese adults have a long lifespan, but it is unclear whether they live a healthy life in their final years. We aimed to determine the prevalence of multimorbidity and characterize lifestyle and other health outcomes among older Portuguese adults. Material and Methods: We performed a cross-sectional evaluation of 2393 adults, aged 65 and older, during the second wave of follow-up of the EpiDoC cohort, a population-based study involving long-term follow-up of a representative sample of the Portuguese population. Subjects completed a structured questionnaire during a telephone interview. Socioeconomic, demographic, lifestyle behaviours, chronic diseases, and health resources consumption were assessed. Cluster analysis was done to identify dietary patterns. Descriptive and analytic analysis was performed to estimate multimorbidity prevalence and its associated factors. Results: Multimorbidity prevalence among older adults was 78.3%, increased with age strata (72.8% for 65 – 69 years to 83.4% for ≥ 80 years), and was highest in Azores (84.9%) and Alentejo (83.6%). The most common chronic diseases were hypertension (57.3%), rheumatic disease (51.9%), hypercholesterolemia (49.4%), and diabetes (22.7%). Depression symptoms were frequent (11.8%) and highest in the oldest strata. The mean health-related quality of life (EQ-5D-3L) score was 0.59 ± 0.38. Hospitalization in the previous 12 months was reported by 25.8% of individuals. Overall, 66.6% of older adults were physically inactive. ‘Fruit and vegetables dietary pattern’ was followed by 85.4% of individuals; however, regional inequalities were found (69% in Azores). Obesity prevalence was 22.3% overall and was highest among Azoreans (33%). Conclusion: The high prevalence of multimorbidity, combined with unhealthy lifestyle behaviours, suggests that the elderly population constitutes a vulnerable group warranting dedicated intervention.

Improving the accuracy of fire behavior prediction requires better understanding of live fuel, the dominant component of tree crowns, which dictates the consumption and energy release of the crown fire flame-front. Live fuel flammability is not well represented by existing evaluation methods. High-flammability live fuel, e.g., in conifers, may maintain or increase the energy release of the advancing crown fire flame-front, while low-flammability live fuel, e.g., in boreal deciduous stands, may reduce or eventually suppress flame-front energy release. To better characterize these fuel–flame-front interactions, we propose a method for quantifying flammability as the fuel’s net effect on (contribution to) the frontal flame energy release, in which the frontal flame is simulated using a methane diffusion flame. The fuel’s energy release contribution to the methane flame was measured using oxygen consumption calorimetry as the difference in energy release between the methane flame interacting with live fuel and the methane flame alone. In-flame testing resulted in fuel ignition and consumption comparable to those in wildfires. The energy release contribution of live fuel was significantly lower than its energy content measured using standard methods, suggesting better sensitivity of the proposed metric to water content- and oxygen deficiency-associated energy release reductions within the combustion zone.

A large body of research has established a relation between maternal education and children's neurocognitive functions, such as executive function and language. However, most studies have focused on early childhood and relatively few studies have examined associations with changes in maternal education over time. Consequently, it remains unclear if early maternal education is longitudinally related to neurocognitive functions in children, adolescents, and young adults. In addition, the associations between changes in maternal education across development and more broadly defined neurocognitive outcomes remain relatively untested. The current study leveraged a large multicohort sample to examine the longitudinal relations between perinatal maternal education and changes in maternal education during development with children's, adolescents', and young adults' neurocognitive functions (N = 2,688; M[subscript age] = 10.32 years; SD[subscript age] = 4.26; range = 3-20 years). Moreover, we examined the differential effects of perinatal maternal education and changes in maternal education across development on executive function and language performance. Perinatal maternal education was positively associated with children's later overall neurocognitive function. This longitudinal relation was stronger for language than executive function. In addition, increases in maternal education were related to improved language performance but were not associated with executive functioning performance. Our findings support perinatal maternal education as an important predictor of neurocognitive outcomes later in development. Moreover, our results suggest that examining how maternal education changes across development can provide important insights that can help inform policies and interventions designed to foster neurocognitive development. [This paper was written on behalf of program collaborators for Environmental Influences on Child Health Outcomes.]

This study assessed whether self-perceived grit is malleable and, if so, how it evolved during the educational journey of students at a four-year military college. By design, the military learning environment tests students' perseverance and determination while teaching lessons in goal commitment and development of purpose, both empirically documented predictors of grit (Hwang and Nam in Multidisciplinary perspectives on grit, Springer, pp 77-92, 2021). Utilizing longitudinal survey data collected over four years, we examined how self-perceived grit changed over time. Results indicate that perceptions of grit dropped during the first year, which is designed to be grueling and challenging and to deconstruct students' perceptions of perseverance and then build them up in the context of the collective. However, as students go through their four-year training, their self-perceptions of grit strengthen and become more robust. These empirical results provide support for the hypothesis that well-designed educational interventions and learning environments may help to foster grit.

The increasing availability of data, which becomes a continually increasing trend in multiple fields of application, has given machine learning approaches a renewed interest in recent years. Accordingly, manufacturing processes and sheet metal forming follow such directions, having in mind the efficiency and control of the many parameters involved, in processing and material characterization. In this article, two applications are considered to explore the capability of machine learning modeling through shallow artificial neural networks (ANN). One consists of developing an ANN to identify the constitutive model parameters of a material using the force–displacement curves obtained with a standard bending test. The second one concentrates on the springback problem in sheet metal press-brake air bending, with the objective of predicting the punch displacement required to attain a desired bending angle, including additional information of the springback angle. The required data for designing the ANN solutions are collected from numerical simulation using finite element methodology (FEM), which in turn was validated by experiments.

Abstract Background Domain of Unknown Function 231-containing proteins (DUF231) are plant specific and their function is largely unknown. Studies in the model plants Arabidopsis and rice suggested that some DUF231 proteins act in the process of O-acetyl substitution of hemicellulose and esterification of pectin. However, little is known about the function of DUF231 proteins in woody plant species. Results This study provides evidence supporting that one member of DUF231 family proteins in the woody perennial plant Populus deltoides (genotype WV94), PdDUF231A, has a role in the acetylation of xylan and affects cellulose biosynthesis. A total of 52 DUF231-containing proteins were identified in the Populus genome. In P. deltoides transgenic lines overexpressing PdDUF231A (OXPdDUF231A), glucose and cellulose contents were increased. Consistent with these results, the transcript levels of cellulose biosynthesis-related genes were increased in the OXPdDUF231A transgenic lines. Furthermore, the relative content of total acetylated xylan was increased in the OXPdDUF231A transgenic lines. Enzymatic saccharification assays revealed that the rate of glucose release increased in OXPdDUF231A transgenic lines. Plant biomass productivity was also increased in OXPdDUF231A transgenic lines. Conclusions These results suggest that PdDUF231A affects cellulose biosynthesis and plays a role in the acetylation of xylan. PdDUF231A is a promising target for genetic modification for biofuel production because biomass productivity and compositional quality can be simultaneously improved through overexpression.

Abstract Background As part of a long-standing line of research regarding how peer density affects health, researchers have sought to understand the multifaceted ways that the density of contemporaries living and interacting in proximity to one another influence social networks and knowledge diffusion, and subsequently health and well-being. This study examined peer density effects on oral health for racial/ethnic minority older adults living in northern Manhattan and the Bronx, New York, NY. Methods Peer age-group density was estimated by smoothing US Census data with 4 kernel bandwidths ranging from 0.25 to 1.50 mile. Logistic regression models were developed using these spatial measures and data from the ElderSmile oral and general health screening program that serves predominantly racial/ethnic minority older adults at community centers in northern Manhattan and the Bronx. The oral health outcomes modeled as dependent variables were ordinal dentition status and binary self-rated oral health. After construction of kernel density surfaces and multiple imputation of missing data, logistic regression analyses were performed to estimate the effects of peer density and other sociodemographic characteristics on the oral health outcomes of dentition status and self-rated oral health. Results Overall, higher peer density was associated with better oral health for older adults when estimated using smaller bandwidths (0.25 and 0.50 mile). That is, statistically significant relationships (p

Abstract Background Although there has been growing research on the burden of treatment, the current state of evidence on measuring this concept is unknown. This scoping review aimed to provide an overview of the current state of knowledge as well as clear recommendations for future research, within the context of chronic disease. Methods Four health-based databases, Scopus, CINAHL, Medline, and PsychInfo, were comprehensively searched for peer-reviewed articles published between the periods of 2000–2016. Titles and abstracts were independently read by two authors. All discrepancies between the authors were resolved by a third author. Data was extracted using a standardized proforma and a comparison analysis was used in order to explore the key treatment burden measures and categorize them into three groups. Results Database searching identified 1458 potential papers. After removal of duplications, and irrelevant articles by title, 1102 abstracts remained. An additional 22 papers were added via snowball searching. In the end, 101 full papers were included in the review. A large number of the studies involved quantitative measures and conceptualizations of treatment burden (n = 64; 63.4%), and were conducted in North America (n = 49; 48.5%). There was significant variation in how the treatment burden experienced by those with chronic disease was operationalized and measured. Conclusion Despite significant work, there is still much ground to cover to comprehensively measure treatment burden for chronic disease. Greater qualitative focus, more research with cultural and minority populations, a larger emphasis on longitudinal studies and the consideration of the potential effects of “identity” on treatment burden, should be considered.

Objective: The transcription factors (TF) Foxa2 and Pdx1 are key regulators of beta-cell (β-cell) development and function. Mutations of these TFs or their respective cis-regulatory consensus binding sites have been linked to maturity diabetes of the young (MODY), pancreas agenesis, or diabetes susceptibility in human. Although Foxa2 has been shown to directly regulate Pdx1 expression during mouse embryonic development, the impact of this gene regulatory interaction on postnatal β-cell maturation remains obscure. Methods: In order to easily monitor the expression domains of Foxa2 and Pdx1 and analyze their functional interconnection, we generated a novel double knock-in homozygous (FVFPBFDHom) fluorescent reporter mouse model by crossing the previously described Foxa2-Venus fusion (FVF) with the newly generated Pdx1-BFP (blue fluorescent protein) fusion (PBF) mice. Results: Although adult PBF homozygous animals exhibited a reduction in expression levels of Pdx1, they are normoglycemic. On the contrary, despite normal pancreas and endocrine development, the FVFPBFDHom reporter male animals developed hyperglycemia at weaning age and displayed a reduction in Pdx1 levels in islets, which coincided with alterations in β-cell number and islet architecture. The failure to establish mature β-cells resulted in loss of β-cell identity and trans-differentiation towards other endocrine cell fates. Further analysis suggested that Foxa2 and Pdx1 genetically and functionally cooperate to regulate maturation of adult β-cells. Conclusions: Our data show that the maturation of pancreatic β-cells requires the cooperative function of Foxa2 and Pdx1. Understanding the postnatal gene regulatory network of β-cell maturation will help to decipher pathomechanisms of diabetes and identify triggers to regenerate dedifferentiated β-cell mass. Keywords: Foxa2, Pdx1, β-Cell maturation, β-Cell identity, Trans-differentiation

Abstract Background Despite a body of evidence on racial/ethnic minority enrollment and retention in research, literature specifically focused on recruiting racially/ethnically diverse older adults for social science studies is limited. There is a need for more rigorous research on methodological issues and the efficacy of recruitment methods. Cultural obstacles to recruitment of racial/ethnic minority older adults include language barriers, lack of cultural sensitivity of target communities on the part of researchers, and culturally inappropriate assessment tools. Methods Guided by the Consolidated Framework for Implementation Research (CFIR), this study critically appraised the recruitment of racial/ethnic minority older adults for focus groups. The initial approach involved using the physical and social infrastructure of the ElderSmile network, a community-based initiative to promote oral and general health and conduct health screenings in places where older adults gather, to recruit racial/ethnic minority adults for a social science component of an interdisciplinary initiative. The process involved planning a recruitment strategy, engaging the individuals involved in its implementation (opinion leaders in senior centers, program staff as implementation leaders, senior community-based colleagues as champions, and motivated center directors as change agents), executing the recruitment plan, and reflecting on the process of implementation. Results While the recruitment phase of the study was delayed by 6 months to allow for ongoing recruitment and filling of focus group slots, the flexibility of the recruitment plan, the expertise of the research team members, the perseverance of the recruitment staff, and the cultivation of change agents ultimately resulted in meeting the study targets for enrollment in terms of both numbers of focus group discussions (n = 24) and numbers of participants (n = 194). Conclusions This study adds to the literature in two important ways. First, we leveraged the social and physical infrastructure of an existing program to recruit participants through community sites where older adults gather. Second, we used the CFIR to guide the appraisal of the recruitment process, which underscored important considerations for both reaching and engaging this underserved population. This was especially true in terms of understanding the disparate roles of the individuals involved in implementing and facilitating the recruitment plan.

Abstract Background Antipsychotics are recognised as a critical intervention for schizophrenia and bipolar disorder. Guidelines globally endorse the routine practice of antipsychotic monotherapy, at the minimum effective dose. Even in treatment-resistant schizophrenia, clozapine use is endorsed before combining antipsychotics. This aim of this study was to review antipsychotic polytherapy alone, high-dose therapy alone, polytherapy and high-dose prescribing patterns in adults discharged from an inpatient mental health unit at two time-points, and the alignment of this prescribing with clinical guideline recommendations. Additionally, associations with polytherapy and high-dose antipsychotic prescribing, including patient and clinical characteristics, were explored. Methods A retrospective clinical audit of 400 adults (200 patients at two different time-points) discharged with at least one antipsychotic. Preliminary findings and education sessions were provided to physicians between Cohorts. Outcomes (polytherapy alone, high-dose therapy alone, polytherapy and high-dose therapy) were compared between study Cohorts using chi-squared and rank-sum tests. Associations between outcomes and covariates were assessed using multivariable logistic regression. Results Most patients (62.5%) were discharged on a single antipsychotic within the recommended dose range. There was a clear preference for prescribing second generation antipsychotics, and in this respect, prescribing is aligned with current evidence-based guidelines. However, sub-optimal prescribing practices were identified for both Cohorts in relation to polytherapy and high-dose antipsychotic rates. Involuntary treatment, frequent hospitalisations and previous clozapine use significantly increased the risk of all three prescribing outcomes at discharge. Conclusions In a significant minority, antipsychotic prescribing did not align with clinical guidelines despite increased training, indicating that the education program alone was ineffective at positively influencing antipsychotic prescribing practices. Further consideration should be given when prescribing antipsychotics for involuntary patients, people with frequent hospitalisations, and those who have previously trialled clozapine.

Background Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, although serious adverse effects such as agranulocytosis and cardiomyopathy limit its use. In July 2015, Australian regulations changed to allow community-based prescribing and supply of clozapine for maintenance therapy. However, there is currently no information on the rate of clozapine services available in Australian community pharmacies, or the factors that influence a pharmacist’s decision to provide, or not provide, a clozapine service, particularly from the perspective of those pharmacists who do not offer this service. This study investigated Australian community pharmacies providing a clozapine supply service and the barriers to, and facilitators of, implementing this service. Methods This mixed method exploratory study was conducted in two stages: (1) a brief online survey of community pharmacists Australia-wide; and (2) semi-structured telephone interviews. The survey was conducted between November 2017—January 2018; results were analysed via descriptive statistics. Survey respondents who did not provide a clozapine service were eligible to participate in a telephone interview exploring barriers and facilitators. Interviews were undertaken between December 2017—January 2018 and data analysed thematically. Results A total of 265 pharmacists completed the survey; 51.3% (n = 136) provided a clozapine service. Consumer demand was a key facilitator (n = 18/247; 66.1%) and the main barrier to implementing a clozapine service was a perceived lack of need (n = 70/122; 57.4%). Twelve survey respondents were interviewed; while most participants acknowledged that supplying clozapine in community pharmacies would benefit consumers due to convenience, the lack of training and support led to difficulties in service implementation. Conclusions Although regulatory changes aimed to improve access to clozapine, it is unclear if they have been successful, or to what degree. Community pharmacists were positive about supplying clozapine in the community but identified a need for training and support to raise awareness of the service so that eligible clozapine consumers can be transitioned to community-based care. Further research is needed about the perceptions of clozapine consumers to determine whether the regulatory changes have resulted in positive outcomes for their independence and quality of life.

Alzheimer's disease (AD), including its mild cognitive impairment (MCI) phase that may or may not progress into the AD, is the most ordinary form of dementia. It is extremely important to correctly identify patients during the MCI stage because this is the phase where AD may or may not develop. Thus, it is crucial to predict outcomes during this phase. Thus far, many researchers have worked on only using a single modality of a biomarker for the diagnosis of AD or MCI. Although recent studies show that a combination of one or more different biomarkers may provide complementary information for the diagnosis, it also increases the classification accuracy distinguishing between different groups. In this paper, we propose a novel machine learning-based framework to discriminate subjects with AD or MCI utilizing a combination of four different biomarkers: fluorodeoxyglucose positron emission tomography (FDG-PET), structural magnetic resonance imaging (sMRI), cerebrospinal fluid (CSF) protein levels, and Apolipoprotein-E (APOE) genotype. The Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset was used in this study. In total, there were 158 subjects for whom all four modalities of biomarker were available. Of the 158 subjects, 38 subjects were in the AD group, 82 subjects were in MCI groups (including 46 in MCIc [MCI converted; conversion to AD within 24 months of time period], and 36 in MCIs [MCI stable; no conversion to AD within 24 months of time period]), and the remaining 38 subjects were in the healthy control (HC) group. For each image, we extracted 246 regions of interest (as features) using the Brainnetome template image and NiftyReg toolbox, and later we combined these features with three CSF and two APOE genotype features obtained from the ADNI website for each subject using early fusion technique. Here, a different kernel-based multiclass support vector machine (SVM) classifier with a grid-search method was applied. Before passing the obtained features to the classifier, we have used truncated singular value decomposition (Truncated SVD) dimensionality reduction technique to reduce high dimensional features into a lower-dimensional feature. As a result, our combined method achieved an area under the receiver operating characteristic (AU-ROC) curve of 98.33, 93.59, 96.83, 94.64, 96.43, and 95.24% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIc, and HC vs. MCIs subjects which are high relative to single modality results and other state-of-the-art approaches. Moreover, combined multimodal methods have improved the classification performance over the unimodal classification.

Midget retinal ganglion cells (RGCs) make up the majority of foveal RGCs in the primate retina. The receptive fields of midget RGCs exhibit both spectral and spatial opponency and are implicated in both color and achromatic form vision, yet the exact mechanisms linking their responses to visual perception remain unclear. Efforts to develop color vision models that accurately predict all the features of human color and form vision based on midget RGCs provide a case study connecting experimental and theoretical neuroscience, drawing on diverse research areas such as anatomy, physiology, psychophysics, and computer vision. Recent technological advances have allowed researchers to test some predictions of color vision models in new and precise ways, producing results that challenge traditional views. Here, we review the progress in developing models of color-coding receptive fields that are consistent with human psychophysics, the biology of the primate visual system and the response properties of midget RGCs.