Identification of candidate IgG biomarkers for Alzheimer's disease via combinatorial library screening.

The adaptive immune system is thought to be a rich source of protein biomarkers, but diagnostically useful antibodies remain unknown for a large number of diseases. This is, in part, because the antigens that trigger an immune response in many diseases remain unknown. We present here a general and unbiased approach to the identification of diagnostically useful antibodies that avoids the requirement for antigen identification. This method involves the comparative screening of combinatorial libraries of unnatural, synthetic molecules against serum samples obtained from cases and controls. Molecules that retain far more IgG antibodies from the case samples than the controls are identified and subsequently tested as capture agents for diagnostically useful antibodies. The utility of this method is demonstrated using a mouse model for multiple sclerosis and via the identification of two candidate IgG biomarkers for Alzheimer's disease.

Epigenetic instability caused by absence of CIZ1 drives transformation during quiescence cycles.

BACKGROUND: Cip1-interacting zinc finger protein 1 (CIZ1) forms RNA-dependent protein assemblies that stabilise epigenetic state, notable at the inactive X chromosome in females. CIZ1 has been linked with a range of human cancers and in mice genetic deletion of CIZ1 manifests as hyperproliferative lymphoid lineages in females. This suggests that its role in maintenance of epigenetic stability is linked with disease. RESULTS: Here, we show that male and female CIZ1-null primary murine fibroblasts have reduced H4K20me1 and that this compromises nuclear condensation on entry to quiescence. Global transcriptional repression remains intact in condensation-deficient CIZ1-null cells; however, a subset of genes linked with chromatin condensation and homology-directed DNA repair are perturbed. Failure to condense is phenotypically mimicked by manipulation of the H4K20me1 methyltransferase, SET8, in WT cells and partially reverted in CIZ1-null cells upon re-expression of CIZ1. Crucially, during exit from quiescence, nuclear decondensation remains active, so that repeated entry and exit cycles give rise to expanded nuclei susceptible to mechanical stress, DNA damage checkpoint activation, and downstream emergence of transformed proliferative colonies. CONCLUSIONS: Our results demonstrate a role for CIZ1 in chromatin condensation on entry to quiescence and explore the consequences of this defect in CIZ1-null cells. Together, the data show that CIZ1's protection of the epigenome guards against genome instability during quiescence cycles. This identifies loss of CIZ1 as a potentially devastating vulnerability in cells that undergo cycles of quiescence entry and exit.

'The solution is we need to have a centre': a study on diabetes in Liberia.

In Liberia, one of the poorest nations in sub-Saharan Africa, the burden of diabetes is a growing concern. The high mortality and morbidity associated with diabetes have significant implications for individuals, families and society at large. The aim of this critical hermeneutic study was to explore what it is like to live with diabetes in Liberia. We recruited 10 participants from Monrovia, Liberia to partake in this study. Photovoice, a well-established participatory data collection approach was used to gather images and stories that represented participants' everyday experiences of living with diabetes. Three major themes were uncovered, highlighting the strengths, challenges and solutions related to living with diabetes in Liberia: strengths-engagement in diabetes self-management practices, focused on participants' commitment to engage in diabetes self-management practices despite the socioeconomic challenges they experienced; challenges-lack of social and economic support, focused on limited access to food, diabetes medications and supplies and diabetes education; and solutions-centre for diabetes education, care and support, focused on participants' recommendations for a community-based diabetes centre, a single point of access for meeting the needs of people with diabetes. A strong commitment to prioritize diabetes on Liberia's national health agenda and increased resources for diabetes care is needed to address the challenges experienced by people living with this chronic disease in Liberia.

Pain-Related Fear in Adults Living With Chronic Pain: Development and Psychometric Validation of a Brief Form of the Tampa Scale of Kinesiophobia.

OBJECTIVE: To develop and validate a brief version of the Tampa Scale of Kinesiophobia (TSK) while preserving content validity in a mixed chronic pain population. DESIGN: Cross-sectional study. SETTING: Tertiary care interdisciplinary chronic pain clinic. PARTICIPANTS: Adults with chronic pain (N=933; mean age, 53.5±15.7 years; 63% women). INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: TSK-11 measured at intake. Self-reported data from a patient registry were extracted from November 2017 to October 2019. RESULTS: An exploratory factor analysis identified a 2-factor structure from the TSK-11 and item reduction resulted in a 7-item TSK (TSK-7) with 61.2% explained variance and Cronbach's alphas of 0.76 and 0.70 for each of the 2 factors. To maximally reduce the number of items without affecting internal consistency, a 5-item TSK (TSK-5) with 72% explained variance was also explored. Strong correlations were found between the newly developed brief TSK versions and TSK-11 (r>0.93), suggesting good concurrent validity. TSK-11, TSK-7, and TSK-5 had similar convergent validity with moderate correlations for pain catastrophizing (r=0.57, 0.58, 0.54), depression (r=0.45, 0.46, 0.42), pain interference (r=0.43, 0.44, 0.40), and pain acceptance (r=-0.57, -0.59, -0.55). CONCLUSIONS: These 2 brief versions of the TSK may help to simplify questionnaires across chronic pain centers where multiple outcome measures are used for a complete biopsychosocial assessment of patients.

Investigating Specialized Chronic Pain Care Among Emerging Adults.

BACKGROUND: AIMS: To investigate characteristics of emerging adults accessing a specialized chronic non-cancer pain clinic and describe interventions offered and utilized by this group. DESIGN: A retrospective chart review was conducted of emerging adults and middle-aged adults with chronic pain receiving care over a six-month period. SETTING: A chronic pain clinic in Southeastern Ontario. PARTICIPANTS: 82 participants comprised of 41 emerging adults (aged 18-29) and 41 middle-aged adults (aged 30-64) METHODS: Groups were matched on sex and number of pain sites. Demographic and pain characteristics, interventions, referrals, and clinic utilization were examined using bivariate and multivariate analysis. RESULTS: Emerging adults reported lower pain severity scores (t(80) = -2.15, p = .035), were more likely to receive referrals for additional consultation and/or diagnostic investigations (X2(1, n = 82) = 4.97, p = .026) and to have at least one psychology visit (X2 = 7.29, p = .007). Moreover, emerging adults with higher depression scores were more likely to see a psychologist (OR 1.23, 95% CI 1.014-1.492). CONCLUSIONS: Pain presentation and care patterns differed between emerging adults and middle-aged adults. Increased use of non-pharmacologic interventions in emerging adults may reflect differences in pain presentations as well as clinician's sensitivity to emerging adult's particular developmental needs but further research is needed. Further research is needed to contribute to nurses' understanding of the quality and efficacy of pain management approaches.

Healthcare Simulation Use to Support Guidelines Implementation: An Integrative Review.

INTRODUCTION: Simulation-based education is a useful teaching and learning strategy that can help to implement guidelines into healthcare settings. Therefore, the purpose of this paper is to collate, synthesize, and analyze the literature focusing on the use of simulation as an educational strategy to support guidelines implementation among healthcare providers (HCPs). MATERIALS AND METHODS: Integrative literature review using the methodology proposed by Ganong. RESULTS/DISCUSSION: Twenty-three articles were selected, the majority (n=19, 82%) used simulation in practice settings and pre- and post-test measurement (n=16, 69%). All studies that assessed simulation effects highlighted that the use of simulation improved the measured outcomes related to guideline implementation. Simulation-based education can be an effective strategy to support guidelines implementation among HCPs, but aspects such as cost involved, time constraints, training of educators, and the HCPs' learning needs can affect its applicability. Future research should focus on more transparent reports related to the guidelines for simulation content, virtual learning, costs of simulation, and measurement of the long-term effects of simulation-based education.

Rif1 acts through Protein Phosphatase 1 but independent of replication timing to suppress telomere extension in budding yeast.

The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast Saccharomyces cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore, we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant defective for PP1 interaction causes a long-telomere phenotype, similar to that of rif1Δ cells. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control. Ablating Rif1-PP1 interaction is known to cause precocious activation of telomere-proximal replication origins and aberrantly early telomere replication. However, we find that Rif1 still limits telomere length even if late replication is forced through deletion of nearby replication origins, indicating that Rif1 can control telomere length independent of replication timing. Moreover we find that, even at a de novo telomere created after DNA synthesis during a mitotic block, Rif1-PP1 interaction is required to suppress telomere lengthening and prevent inappropriate recruitment of Tel1 kinase. Overall, our results show that Rif1 controls telomere length by recruiting PP1 to directly suppress telomerase-mediated TG repeat lengthening.

Clinical and genetic differences between pustular psoriasis subtypes.

BACKGROUND: The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, can have an acute systemic (generalized pustular psoriasis [GPP]) or chronic localized (palmoplantar pustulosis [PPP] and acrodermatitis continua of Hallopeau [ACH]) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations. OBJECTIVE: We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort. METHODS: We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases. RESULTS: Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10-5). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10-15). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10-14 and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003). CONCLUSIONS: The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.

Predatory publications in evidence syntheses.

OBJECTIVES: The number of predatory journals is increasing in the scholarly communication realm. These journals use questionable business practices, minimal or no peer review, or limited editorial oversight and, thus, publish articles below a minimally accepted standard of quality. These publications have the potential to alter the results of knowledge syntheses. The objective of this study was to determine the degree to which articles published by a major predatory publisher in the health and biomedical sciences are cited in systematic reviews. METHODS: The authors downloaded citations of articles published by a known predatory publisher. Using forward reference searching in Google Scholar, we examined whether these publications were cited in systematic reviews. RESULTS: The selected predatory publisher published 459 journals in the health and biomedical sciences. Sixty-two of these journal titles had published a total of 120 articles that were cited by at least 1 systematic review, with a total of 157 systematic reviews citing an article from 1 of these predatory journals. DISCUSSION: Systematic review authors should be vigilant for predatory journals that can appear to be legitimate. To reduce the risk of including articles from predatory journals in knowledge syntheses, systematic reviewers should use a checklist to ensure a measure of quality control for included papers and be aware that Google Scholar and PubMed do not provide the same level of quality control as other bibliographic databases.

Fostering positive spaces in public health using a cultural humility approach.

Culturally competent frameworks used within health care systems are contributing to the discrimination and marginalization of sexually and/or gender diverse persons. In this discursive paper, we argue that cultural humility ought to be implemented as the best practice approach for fostering sexually and gender diverse positive spaces in public health settings. A paradigm shift away from cultural competence frameworks toward cultural humility is necessary. This shift can be achieved by enhancing educational opportunities for public health nursing students and professionals and by recruiting organizational leaders to be champions for systemic change. In order to achieve this, we must establish effective educational programs that espouse cultural humility practices and develop valid measurement tools for assessing the provision of culturally humble care. This would equip educators, students, practitioners, and organizational leaders with the necessary tools to guide and assess their performance. Integrating a culturally humble approach will ultimately enhance self-reported cultural safety in public health spaces and reduce health inequities experienced by sexually and/or gender diverse clients and staff members.

The central question and the scope of nursing research.

As nursing continues to develop as a professional discipline, it is important for nurses to have a central question to guide their research. Since the 1800s, nursing practice and research have covered a wide scope in cooperation with other disciplines. This wide area of nursing practice and research has led to the proposal that the central question be: How can the well-being of a person, family, community, or population be improved? The proposed question must remain flexible and open to revision because nurses will continue to adapt to the changing needs of their patients and populations and to their complex and evolving work environments.

Using Simulation to Enhance Education Regarding Epidural Analgesia for Registered Nurses.

BACKGROUND: Registered nurses (RNs) receive didactic training regarding caring for patients receiving epidural analgesia. Although RNs are tested on their knowledge after this training, their ability to critically think through adverse events has not been assessed at our institution. AIM: The aim of this study was to examine the feasibility and effectiveness of simulation education for RNs regarding the assessment and management of patients receiving epidural analgesia. METHOD: The study included an education intervention, which consisted of a 4-hour workshop. After obtaining informed consent, RNs completed a preworkshop evaluation of skill performance where they completed an Objective Structured Clinical Examination (OSCE) in which they demonstrated an epidural assessment of a standardized patient. RNs then completed a demographic and knowledge questionnaire followed by a lecture regarding care, management, and assessment of patients who are receiving epidural analgesia. After the lecture, RNs practiced epidural assessments within small groups. A postworkshop OSCE, questionnaire, and debriefing were completed before the end of the workshop. RESULTS: Thirty-seven RNs completed the workshop. The mean age of participants was 43 years. For the pre- and postworkshop knowledge questionnaire, there was significant improvement in answers related to epidural pharmacology and assessment of blockade questions. For the pre- and postworkshop OSCE, there was a significant increase in the number of correct procedures performed in all categories, with the exception of assessment of equipment. There was also a significant change in the proportion of RNs who stated that they felt confident in their assessment of a patient receiving epidural analgesia.

Cyclin-A-CDK2-mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication.

CIZ1 is a nuclear matrix protein that cooperates with cyclin A2 (encoded by CCNA2) and CDK2 to promote mammalian DNA replication. We show here that cyclin-A-CDK2 also negatively regulates CIZ1 activity by phosphorylation at threonines 144, 192 and 293. Phosphomimetic mutants do not promote DNA replication in cell-free and cell-based assays, and also have a dominant-negative effect on replisome formation at the level of PCNA recruitment. Phosphorylation blocks direct interaction with cyclin-A-CDK2 and recruitment of endogenous cyclin A to the nuclear matrix. In contrast, phosphomimetic CIZ1 retains the ability to bind to the nuclear matrix, and its interaction with CDC6 is not affected. Phospho-T192-specific antibodies confirm that CIZ1 is phosphorylated during S phase and G2, and show that phosphorylation at this site occurs at post-initiation concentrations of cyclin-A-CDK2. Taken together, the data suggest that CIZ1 is a kinase sensor that promotes initiation of DNA replication at low kinase levels, when in a hypophosphorylated state that is permissive for cyclin-A-CDK2 interaction and delivery to licensed origins, but blocks delivery at higher kinase levels when it is phosphorylated.

Development of a Guided Internet-based Psycho-education Intervention Using Cognitive Behavioral Therapy and Self-Management for Individuals with Chronic Pain.

Evidence-based chronic pain treatment includes nonpharmacologic therapies. When addressing barriers to treatment, there is a need to deliver these therapies in a way that is accessible to all individuals who may benefit. To develop a guided Internet-based intervention for individuals with chronic pain, program content and sequence of evidence-based treatments for chronic pain, traditionally delivered via in-person sessions, were identified to be adapted for Internet delivery. With consideration to historical barriers to treatment, and through use of a concept map, therapeutic components and educational material were situated, in an ordered sequence, into six modules. An Internet-based chronic pain intervention was constructed to improve access to evidence-based chronic pain therapies. Research using this intervention, in the form of a pilot study for intervention refinement, was conducted, and a large-scale study to assess effectiveness is necessary prior to implementation. As clients may face barriers to multimodal treatment for chronic pain, nurses could introduce components of education, cognitive behavioral therapy and self-management to clients and prepare them for the "work" of managing chronic pain, through use of this Internet-based intervention.

Guided Internet-based Psycho-educational Intervention Using Cognitive Behavioral Therapy and Self-management for Individuals with Chronic Pain: A Feasibility Study.

When considering barriers to chronic pain treatment, there is a need to deliver nonpharmacological therapies in a way that is accessible to all individuals who may benefit. To conduct feasibility testing using a guided, Internet-based intervention for individuals with chronic pain, a novel, Internet-based, chronic pain intervention (ICPI) was developed, using concepts proven effective in face-to-face interventions. This study was designed to assess usability of the ICPI and feasibility of conducting larger-scale research, and to collect preliminary data on effectiveness of the intervention. Data were collected at baseline, after each of the six intervention modules, and 12 weeks after intervention completion. Forty-one participants completed baseline questionnaires, and 15 completed the 12-week postintervention questionnaires. At baseline, all participants reported satisfaction with the structure of the intervention and ease of use. Internet-based platforms such as Facebook aided in accrual of participants, making further large-scale study of the ICPI feasible. There is preliminary evidence suggesting that the ICPI improves emotional function but not physical function, with a small but significant decrease in pain intensity and pain interference. Most participants felt they benefited at least minimally as a result of using the ICPI. The ICPI was well received by participants and demonstrated positive outcomes in this preliminary study. Further research with more participants is feasible and necessary to fully assess the effect of this intervention.

Exploration of pressure ulcer and related skin problems across the spectrum of health care settings in Ontario using administrative data.

This is a prospective cohort study using population-level administrative data to describe the scope of pressure ulcers in terms of its prevalence, incidence risk, associating factors and the extent to which best practices were applied across a spectrum of health care settings. The data for this study includes the information of Ontario residents who were admitted to acute care, home care, long term care or continuing care and whose health care data is contained in the resident assessment instrument-minimum data set (RAI-MDS) and the health outcomes for better information and care (HOBIC) database from 2010 to 2013. The analysis included 203 035 unique patients. The overall prevalence of pressure ulcers was approximately 13% and highest in the complex continuing care setting. Over 25% of pressure ulcers in long-term care developed one week after discharge from acute care hospitalisation. Individuals with cardiovascular disease, dementia, bed mobility problems, bowel incontinence, end-stage diseases, daily pain, weight loss and shortness of breath were more likely to develop pressure ulcers. While there were a number of evidence-based interventions implemented to treat pressure ulcers, only half of the patients received nutritional interventions.

Relationship between DNA replication and the nuclear matrix.

There is an extensive list of primary published work related to the nuclear matrix (NM). Here we review the aspects that are required to understand its relationship with DNA replication, while highlighting some of the difficulties in studying such a structure, and possible differences that arise from the choice of model system. We consider NM attachment regions of DNA and discuss their characteristics and potential function before reviewing data that deal specifically with functional interaction with DNA replication factors. Data have long existed indicating that newly synthesized DNA is associated with a nuclease-resistant NM, allowing the conclusion that the elongation step of DNA synthesis is immobilized within the nucleus. We review in more detail the emerging data that suggest that prereplication complex proteins and origins of replication are transiently recruited to the NM during late G1 and early S-phase. Collectively, these data suggest that the initiation step of the DNA replication process is also immobilized by attachment to the NM. We outline models that discuss the possible spatial relationships and highlight the emerging evidence that suggests there may be important differences between cell types.

Brief review: Adoption of electronic medical records to enhance acute pain management.

PURPOSE: The purpose of this paper is to examine physician barriers to adopting electronic medical records (EMRs) as well as anesthesiologists' experiences with the EMRs used by the acute pain management service at two tertiary care centres in Canada. SOURCE: We first review the recent literature to determine if physician barriers to adoption are changing given the exponential growth of information technology and the evolving healthcare environment. We next report on institutional experience from two academic health sciences centres regarding the challenges they encountered over the past ten years in developing and implementing an electronic medical record system for acute pain management. PRINCIPAL FINDINGS: The key identified barriers to adoption of EMRs are financial, technological, and time constraints. These barriers are identical to those reported in a systematic review performed prior to 2009 and remain significant factors challenging implementation. These challenges were encountered during our institution's process of adopting EMRs specific to acute pain management. In addition, our findings emphasize the importance of physician participation in the development and implementation stages of EMRs in order to incorporate their feedback and ensure the EMR system is in keeping with their workflow. CONCLUSIONS: Use of EMRs will inevitably become the standard of care; however, many barriers persist to impede their implementation and adoption. These challenges to implementation can be facilitated by a corporate strategy for change that acknowledges the barriers and provides the resources for implementation. Adoption will facilitate benefits in communication, patient management, research, and improved patient safety.

The feasibility of a social media-based foot self-management education and support program for adults with diabetes: A partially randomized preference trial.

Aim: To assess the feasibility of Diabetic Foot Care Group (DFCG), a social media-based self-management education and support intervention, for people with diabetes (PWD) empowerment in diabetes-related foot ulceration prevention. Methods: A partially randomized preference trial was conducted among 32 PWD. DFCG was implemented through Facebook. Participants in the intervention group joined the DFCG in addition to their usual care, while the control group received usual care. Data were collected online using questionnaires on participants' DFCG acceptance, engagement and preliminary efficacy on nine diabetes foot care-related outcomes at baseline, one, and three months post-intervention. Results: The participants' study intervention acceptability and engagement rates were 84.2% and 55.2%, respectively. DFCG efficacy rate compared to usual care was 88.9% to 22.2%. Three diabetes foot care-related outcomes increased significantly in the intervention group three-month post-intervention: foot self-care adherence (p = 0.001, ηp 2 = 0.35), preventive foot self-care practice (p = 0.002, ηp 2 = 0.33), and physical health status (p < 0.02, ηp 2 = 0.23). Conclusion: DFCG is feasible and could effectively improve diabetes foot care-related outcomes. Innovation: Social media is an innovative approach healthcare professionals could utilize to virtually support PWD in ongoing learning and engagement in optimal foot self-care activities. Trial registration: ClinicalTrials.gov, Identifier: NCT04395521.

Empowered management for pelvic pain: The experiences of women with persistent pelvic pain participating in an online self-directed self-management program while they wait for interprofessional care.

BACKGROUND: Persistent pelvic pain is pain sensed in or around the pelvis and is often associated with negative cognitive, behavioral, sexual, and emotional consequences. The lack of interprofessional persistent pelvic pain management programs that address the complex interplay of biopsychosocial factors result in lengthy wait times and negative health outcomes. Limited access to evidence informed self-management educational resources contributes to poor coping strategies. Evidence shows that self-management education and strategies support patients while they wait for care. However, very few studies explore the patient's lived experience of participating in an online educational program designed for persistent pelvic pain. OBJECTIVES: This study aims to understand the experience of women with persistent pelvic pain participating in an online, self-management education program ("Pelvic Pain Empowered Management" program) while awaiting care at an interprofessional pelvic pain clinic. DESIGN: A descriptive qualitative approach was used to explore the experiences of women participating in an online educational program designed for cis women with persistent pelvic pain. METHODS: We conducted semi-structured interviews with 11 women, transcribed the data verbatim using NVivo software (NVivo 12, QSR International Pty Ltd.), and analyzed inductively using previously established methods. RESULTS: We identified four main themes relevant to women's experiences of the program: (1) the program shaped expectations around upcoming pelvic pain appointments, (2) the program content is relevant and resonates with people with lived experience of persistent pelvic pain, (3) the program enhanced understanding of persistent pelvic pain, and (4) the program empowered people with skills and strategies to better manage their persistent pelvic pain. CONCLUSION: Our findings highlight how self-directed online patient education can be leveraged while persistent pelvic pain patients wait for care to support them in setting expectations around care and in engaging in pain self-management.