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Differential negative reinforcement of alternative behavior is a technique in which students can escape a portion of a task they perceive to be unpleasant by reaching a predetermined criterion. In this article, we define the negative reinforcement trap and review research on differential negative reinforcement of alternative behavior. We then describe procedural steps for teachers to effectively prevent students from escaping tasks or activities they find unpleasant as well as increase work accuracy and productivity.

Objectives To determine the need for recovery (NFR) among emergency physicians and to identify demographic and occupational characteristics associated with higher NFR scores.Design Cross-sectional electronic survey.Setting Emergency departments (EDs) (n=112) in the UK and Ireland.Participants Emergency physicians, defined as any registered physician working principally within the ED, responding between June and July 2019.Main outcome measure NFR Scale, an 11-item self-administered questionnaire that assesses how work demands affect intershift recovery.Results The median NFR Score for all 4247 eligible, consented participants with a valid NFR Score was 70.0 (95% CI: 65.5 to 74.5), with an IQR of 45.5–90.0. A linear regression model indicated statistically significant associations between gender, health conditions, type of ED, clinical grade, access to annual and study leave, and time spent working out-of-hours. Groups including male physicians, consultants, general practitioners (GPs) within the ED, those working in paediatric EDs and those with no long-term health condition or disability had a lower NFR Score. After adjusting for these characteristics, the NFR Score increased by 3.7 (95% CI: 0.3 to 7.1) and 6.43 (95% CI: 2.0 to 10.8) for those with difficulty accessing annual and study leave, respectively. Increased percentage of out-of-hours work increased NFR Score almost linearly: 26%–50% out-of-hours work=5.7 (95% CI: 3.1 to 8.4); 51%–75% out-of-hours work=10.3 (95% CI: 7.6 to 13.0); 76%–100% out-of-hours work=14.5 (95% CI: 11.0 to 17.9).Conclusion Higher NFR scores were observed among emergency physicians than reported in any other profession or population to date. While out-of-hours working is unavoidable, the linear relationship observed suggests that any reduction may result in NFR improvement. Evidence-based strategies to improve well-being such as proportional out-of-hours working and improved access to annual and study leave should be carefully considered and implemented where feasible.

This systematic literature review summarises the research into interventions intended to improve the wellbeing of educators in the early childhood to secondary sectors. A search of articles published between 2000 and 2020 yielded 23 articles that met our inclusion criteria. Studies were included if they collected quantitative or qualitative data about educator wellbeing pre-intervention and post-intervention from the same group(s) of educators. We classified articles into five categories based on their content: multi-foci (several content areas included in a program), mindfulness, gratitude, professional development (classroom practice oriented), and physical environment. The articles revealed wide variations in: wellbeing theories underpinning interventions, the phenomena measured, and the effectiveness of the interventions. In some studies wellbeing was conceptualised as the absence of negative states (such as stress), in other studies to the presence of positive states (such as satisfaction), and in a few studies as the combination of both these approaches. Some of the gaps noted across the research include the lack of attention to the role of the school climate in determining the success of an intervention, and the lack of analysis to explore whether interventions work better for some individuals than others (for example, a lack of reporting of the characteristics of participants who drop out of the interventions). Overall, the multi-foci interventions show the most promise for improving educator wellbeing.

Increasing diversity in science, technology, engineering, and math (STEM) and STEM-related degrees and professions is a national priority. Research on students' pathways in STEM may contribute to our understanding of how to change institutions to achieve diversity; however, until recently, the dominant narrative invoked a "pipeline" metaphor. In this work, we challenge the pipeline metaphor by interrogating what is meant by a "STEM" pathway, measuring constructs not typically measured in STEM pipeline research, endeavoring to make our measures intersectional, and imagining alternative outcomes in addition to "staying in STEM." We have been following students who completed an out-of-school mentored science research program since 2017. Three hundred fifty-eight participants responded to an alumni survey designed to collect data about their location along their pathway, constructs related to the pursuit of a pathway, and demographic information. Here, we describe the characteristics of this sample and initial findings about the new constructs we measured. By measuring constructs not typically measured in pathways research and designing items and scales using an intersectional approach, we challenge the problematic pipeline metaphor that dominates the STEM persistence literature.

Abstract Despite their efficacy, the currently available polio vaccines, oral polio vaccine (OPV) and inactivated polio vaccine (IPV), possess inherent flaws posing significant challenges in the global eradication of polio. OPV, which uses live Sabin attenuated strains, carries the risk of reversion to pathogenic forms and causing vaccine-associated paralytic poliomyelitis (VAPP) and vaccine-derived polio disease (VDPD) in incompletely vaccinated or immune-compromised individuals. Conventional IPVs, which are non-replicative, are more expensive to manufacture and introduce biohazard and biosecurity risks due to the use of neuropathogenic strains in production. These types of limitations have led to a call by the Global Polio Eradication Initiative and others for the development of updated polio vaccines. We are developing a novel Ultraviolet-C radiation (UVC) inactivation method that preserves immunogenicity and is compatible with attenuated strains of polio. The method incorporates an antioxidant complex, manganese-decapeptide-phosphate (MDP), derived from the radioresistant bacterium Deinococcus radiodurans. The inclusion of MDP protects the immunogenic neutralizing epitopes from damage during UVC inactivation. The novel vaccine candidate, ultraIPVTM, produced using these methods demonstrates three crucial attributes: complete inactivation, which precludes the risk of vaccine-associated disease; use of non-pathogenic strains to reduce production risks; and significantly enhanced yield of doses per milligram of input virus, which could increase vaccine supply while reducing costs. Additionally, ultraIPVTM retains antigenicity post-freeze–thaw cycles, a testament to its robustness.

Abstract Chlamydia trachomatis infections are the most common bacterial STIs globally and can lead to serious morbidity if untreated. Development of a killed, whole-cell vaccine has been stymied by coincident epitope destruction during inactivation. Here, we present a prototype Chlamydia vaccine composed of elementary bodies (EBs) from the related mouse pathogen, Chlamydia muridarum (Cm). EBs inactivated by gamma rays (Ir-Cm) in the presence of the antioxidant Mn2+-Decapeptide (DEHGTAVMLK) Phosphate (MDP) are protected from epitope damage but not DNA damage. Cm EBs gamma-inactivated with MDP retain their structure and provide significant protection in a murine genital tract infection model. Mice vaccinated with Ir-Cm (+MDP) exhibited elevated levels of Cm-specific IgG and IgA antibodies, reduced bacterial burdens, accelerated clearance, and distinctive cytokine responses compared to unvaccinated controls and animals vaccinated with EBs irradiated without MDP. Preserving EB epitopes with MDP during gamma inactivation offers the potential for a polyvalent, whole-cell vaccine against C. trachomatis.

ABSTRACT The bacterium responsible for Lyme disease, Borrelia burgdorferi, accumulates high levels of manganese without iron and possesses a polyploid genome, characteristics suggesting potential extreme resistance to radiation. Contrary to expectations, we report that wild-type B. burgdorferi B31 cells are radiosensitive, with a gamma-radiation survival limit for 106 wild-type cells of

BackgroundDifficult facemask ventilation is perilous in children whose tracheas are difficult to intubate. We hypothesised that certain physical characteristics and anaesthetic factors are associated with difficult mask ventilation in paediatric patients who also had difficult tracheal intubation.MethodsWe queried a multicentre registry for children who experienced "difficult" or "impossible" facemask ventilation. Patient and case factors known before mask ventilation attempt were included for consideration in this regularised multivariable regression analysis. Incidence of complications, and frequency and efficacy of rescue placement of a supraglottic airway device were also tabulated. Changes in quality of mask ventilation after injection of a neuromuscular blocking agent were assessed.ResultsThe incidence of difficult mask ventilation was 9% (483 of 5453 patients). Infants and patients having increased weight, being less than 5th percentile in weight for age, or having Treacher-Collins syndrome, glossoptosis, or limited mouth opening were more likely to have difficult mask ventilation. Anaesthetic induction using facemask and opioids was associated with decreased risk of difficult mask ventilation. The incidence of complications was significantly higher in patients with "difficult" mask ventilation than in patients without. Rescue placement of a supraglottic airway improved ventilation in 71% (96 of 135) of cases. Administration of neuromuscular blocking agents was more frequently associated with improvement or no change in quality of ventilation than with worsening.ConclusionsCertain abnormalities on physical examination should increase suspicion of possible difficult facemask ventilation. Rescue use of a supraglottic airway device in children with difficult or impossible mask ventilation should be strongly considered.

Abstract PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate the molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3. Our findings rationalize why the dimerization of PEAK proteins has a crucial function in signal transduction and provide biophysical and structural data to unravel binding specificity within the PEAK interactome. We identify a conserved high affinity 14-3-3 motif on PEAK3 and demonstrate its role as a molecular switch to regulate CrkII binding and signaling via Grb2. Together, our studies provide a detailed structural snapshot of PEAK interaction networks and further elucidate how PEAK proteins, especially PEAK3, act as dynamic scaffolds that exploit adapter proteins to control signal transduction in cell growth/motility and cancer.

Abstract Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Reciprocal interactions between prostate cancer cells and carcinoma‐associated fibroblasts (CAFs) mediate cancer development and progression; however, our understanding of the signalling pathways mediating these cellular interactions remains incomplete. To address this, we defined secretome changes upon co‐culture of prostate epithelial or cancer cells with fibroblasts that mimic bi‐directional communication in tumours. Using antibody arrays, we profiled conditioned media from mono‐ and co‐cultures of prostate fibroblasts, epithelial and cancer cells, identifying secreted proteins that are upregulated in co‐culture compared to mono‐culture. Six of these (CXCL10, CXCL16, CXCL6, FST, PDGFAA, IL‐17B) were functionally screened by siRNA knockdown in prostate cancer cell/fibroblast co‐cultures, revealing a key role for follistatin (FST), a secreted glycoprotein that binds and bioneutralises specific members of the TGF‐β superfamily, including activin A. Expression of FST by both cell types was required for the fibroblasts to enhance prostate cancer cell proliferation and migration, whereas FST knockdown in co‐culture grafts decreased tumour growth in mouse xenografts. This study highlights the complexity of prostate cancer cell–fibroblast communication, demonstrates that co‐culture secretomes cannot be predicted from individual cultures, and identifies FST as a tumour‐microenvironment‐derived secreted factor that represents a candidate therapeutic target.

Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.

Abstract Specific members of the Nima-Related Kinase (NEK) family have been linked to cancer development and progression, and a role for NEK5, one of the least studied members, in breast cancer has recently been proposed. However, while NEK5 is known to regulate centrosome separation and mitotic spindle assembly, NEK5 signalling mechanisms and function in this malignancy require further characterization. To this end, we established a model system featuring overexpression of NEK5 in the immortalized breast epithelial cell line MCF-10A. MCF-10A cells overexpressing NEK5 exhibited an increase in clonogenicity under monolayer conditions and enhanced acinar size and abnormal morphology in 3D Matrigel culture. Interestingly, they also exhibited a marked reduction in Src activation and downstream signalling. To interrogate NEK5 signalling and function in an unbiased manner, we applied a variety of MS-based proteomic approaches. Determination of the NEK5 interactome by Bio-ID identified a variety of protein classes including the kinesins KIF2C and KIF22, the mitochondrial proteins TFAM, TFB2M and MFN2, RhoH effectors and the negative regulator of Src, CSK. Characterization of proteins and phosphosites modulated upon NEK5 overexpression by global MS-based (phospho)proteomic profiling revealed impact on the cell cycle, DNA synthesis and repair, Rho GTPase signalling, the microtubule cytoskeleton and hemidesmosome assembly. Overall, the study indicates that NEK5 impacts diverse pathways and processes in breast epithelial cells, and likely plays a multifaceted role in breast cancer development and progression. Video Abstract

Summary: Crohn's disease (CD) and ulcerative colitis (UC) are two etiologically related yet distinctive subtypes of the inflammatory bowel diseases (IBD). Differentiating CD from UC can be challenging using conventional clinical approaches in a subset of patients. We designed and evaluated a novel molecular-based prediction model aggregating genetics, serum biomarkers, and tobacco smoking information to assist the diagnosis of CD and UC in over 30,000 samples. A joint model combining genetics, serum biomarkers and smoking explains 46% (42–50%, 95% CI) of phenotypic variation. Despite modest overlaps with serum biomarkers, genetics makes unique contributions to distinguishing IBD subtypes. Smoking status only explains 1% (0–6%, 95% CI) of the phenotypic variance suggesting it may not be an effective biomarker. This study reveals that molecular-based models combining genetics, serum biomarkers, and smoking information could complement current diagnostic strategies and help classify patients based on biologic state rather than imperfect clinical parameters.

Abstract Over the past decade, immune checkpoint inhibitor (ICI) therapy has been established as the standard of care for many types of cancer, but the strategies employed have continued to evolve. Recently, much clinical focus has been on combining targeted therapies with ICI for the purpose of manipulating the immune setpoint. The latter concept describes the equilibrium between factors that promote and those that suppress anti-cancer immunity. Besides tumor mutational load and other cancer cell-intrinsic determinants, the immune setpoint is also governed by the cells of the tumor microenvironment and how they are coerced by cancer cells to support the survival and growth of the tumor. These regulatory mechanisms provide therapeutic opportunities to intervene and reduce immune suppression via application of small molecule inhibitors and antibody-based therapies against (receptor) tyrosine kinases and thereby improve the response to ICIs. This article reviews how tyrosine kinase signaling in the tumor microenvironment can promote immune suppression and highlights how therapeutic strategies directed against specific tyrosine kinases can be used to lower the immune setpoint and elicit more effective anti-tumor immunity.

Abstract. Background. Male genital form and function may be rendered abnormal by a number of disease processes, with profound associated psychological and functional consequences. The aim of the study is to review our reconstructive experience with cases of genital loss or distortion due to nonmalignant diseases processes and atypical neoplasia. Materials and methods. A retrospective review of a prospectively maintained database was performed to identify reconstructive cases performed from 2018 to 2020 under the care of a single surgeon. Male patients 18 years or older with a disease diagnosis other than squamous cell carcinoma affecting genital form were included. Disease processes, patient factors, surgical techniques, and both functional and cosmetic outcomes were reviewed. Results. Fourteen cases were identified. The patients had a mean age of 52.2 years (range, 21–72 years). Acquired buried penis was present in 8 patients. Etiology of genital abnormality included balanitis xerotica obliterans (n = 6), excess skin loss at circumcision (n = 2), self-injection of petroleum jelly to penile shaft (n = 1), Fournier gangrene (n = 1), hidradenitis suppurativa (n = 1), extramammary Paget disease (n = 1), idiopathic lymphoedema (n = 1), and penoscrotal webbing (n = 1). Reconstructive techniques performed included penile debridement/shaft skin release, scrotectomy, suprapubic apronectomy, and division of penoscrotal webbing, in combination with split-thickness skin grafting where required. A penile implant was inserted in one patient. Reconstructive planning, techniques, and outcomes are described. Conclusions. A variety of reconstructive techniques in andrology can be used to improve the aesthetic and functional outcomes of multiple disease processes affecting the male external genitalia.

ObjectiveWe tested Goal Management Training (GMT), which has been recommended as an executive training protocol that may improve the deficits in the complex tasks inherent in life role participation experienced by those with chronic mild traumatic brain injury and post-traumatic stress disease (mTBI/PTSD). We assessed, not only cognitive function, but also life role participation (quality of life).MethodsWe enrolled and treated 14 individuals and administered 10 GMT sessions in-person and provided the use of the Veterans Task Manager (VTM), a Smartphone App, which was designed to serve as a “practice-buddy” device to ensure translation of in-person learning to independent home and community practice of complex tasks. Pre-/post-treatment primary measure was the NIH Examiner, Unstructured Task. Secondary measures were as follows: Tower of London time to complete (cTOL), Community Reintegration of Service Members (CRIS) three subdomains [Extent of Participation; Limitations; Satisfaction of Life Role Participation (Satisfaction)]. We analyzed pre-post-treatment, t-test models to explore change, and generated descriptive statistics to inspect given individual patterns of change across measures.ResultsThere was statistically significant improvement for the NIH EXAMINER Unstructured Task (p

A genome-wide association study identifies MFGE8 as protective against coronary atherosclerosis in European and East Asian populations.

Here the authors combine multi-omics approaches to uncover a role for ubiquitination and the ubiquitin ligase NEDD4 in targeting the actin binding protein Profilin 1 to regulate actin polymerisation in neural crest cells.

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Summary: Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.

Precision medicine has emerged as an important paradigm in oncology, driven by the significant heterogeneity of individual patients’ tumour. A key prerequisite for effective implementation of precision oncology is the development of companion biomarkers that can predict response to anti-cancer therapies and guide patient selection for clinical trials and/or treatment. However, reliable predictive biomarkers are currently lacking for many anti-cancer therapies, hampering their clinical application. Here, we developed a novel machine learning-based framework to derive predictive multi-gene biomarker panels and associated expression signatures that accurately predict cancer drug sensitivity. We demonstrated the power of the approach by applying it to identify response biomarker panels for an Hsp90-based therapy in prostate cancer, using proteomic data profiled from prostate cancer patient-derived explants. Our approach employs a rational feature section strategy to maximise model performance, and innovatively utilizes Boolean algebra methods to derive specific expression signatures of the marker proteins. Given suitable data for model training, the approach is also applicable to other cancer drug agents in different tumour settings.