Somatic genomic changes in single Alzheimer's disease neurons.

Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.

Acceptability, values, and preferences of older people for chronic low back pain management; a qualitative evidence synthesis.

BACKGROUND: Chronic primary low back pain (CPLBP) and other musculoskeletal conditions represent a sizable attribution to the global burden of disability, with rates greatest in older age. There are multiple and varied interventions for CPLBP, delivered by a wide range of health and care workers. However, it is not known if these are acceptable to or align with the values and preferences of care recipients. The objective of this synthesis was to understand the key factors influencing the acceptability of, and values and preferences for, interventions/care for CPLBP from the perspective of people over 60 and their caregivers. METHODS: We searched MEDLINE, CINAHL and OpenAlex, for eligible studies from inception until April 2022. We included studies that used qualitative methods for data collection and analysis; explored the perceptions and experiences of older people and their caregivers about interventions to treat CPLBP; from any setting globally. We conducted a best fit framework synthesis using a framework developed specifically for this review. We assessed our certainty in the findings using GRADE-CERQual. RESULTS: All 22 included studies represented older people's experiences and had representation across a range of geographies and economic contexts. No studies were identified on caregivers. Older people living with CPLBP express values and preferences for their care that relate to therapeutic encounters and the importance of therapeutic alliance, irrespective of the type of treatment, choice of intervention, and intervention delivery modalities. Older people with CPLBP value therapeutic encounters that validate, legitimise, and respect their pain experience, consider their context holistically, prioritise their needs and preferences, adopt a person-centred and tailored approach to care, and are supported by interprofessional communication. Older people valued care that provided benefit to them, included interventions beyond analgesic medicines alone and was financially and geographically accessible. CONCLUSIONS: These findings provide critical context to the implementation of clinical guidelines into practice, particularly related to how care providers interact with older people and how components of care are delivered, their location and their cost. Further research is needed focusing on low- and middle-income settings, vulnerable populations, and caregivers.

Automating risk of bias assessment in systematic reviews: a real-time mixed methods comparison of human researchers to a machine learning system.

BACKGROUND: Machine learning and automation are increasingly used to make the evidence synthesis process faster and more responsive to policymakers' needs. In systematic reviews of randomized controlled trials (RCTs), risk of bias assessment is a resource-intensive task that typically requires two trained reviewers. One function of RobotReviewer, an off-the-shelf machine learning system, is an automated risk of bias assessment. METHODS: We assessed the feasibility of adopting RobotReviewer within a national public health institute using a randomized, real-time, user-centered study. The study included 26 RCTs and six reviewers from two projects examining health and social interventions. We randomized these studies to one of two RobotReviewer platforms. We operationalized feasibility as accuracy, time use, and reviewer acceptability. We measured accuracy by the number of corrections made by human reviewers (either to automated assessments or another human reviewer's assessments). We explored acceptability through group discussions and individual email responses after presenting the quantitative results. RESULTS: Reviewers were equally likely to accept judgment by RobotReviewer as each other's judgement during the consensus process when measured dichotomously; risk ratio 1.02 (95% CI 0.92 to 1.13; p = 0.33). We were not able to compare time use. The acceptability of the program by researchers was mixed. Less experienced reviewers were generally more positive, and they saw more benefits and were able to use the tool more flexibly. Reviewers positioned human input and human-to-human interaction as superior to even a semi-automation of this process. CONCLUSION: Despite being presented with evidence of RobotReviewer's equal performance to humans, participating reviewers were not interested in modifying standard procedures to include automation. If further studies confirm equal accuracy and reduced time compared to manual practices, we suggest that the benefits of RobotReviewer may support its future implementation as one of two assessors, despite reviewer ambivalence. Future research should study barriers to adopting automated tools and how highly educated and experienced researchers can adapt to a job market that is increasingly challenged by new technologies.

Leveraging the replication-competent avian-like sarcoma virus/tumor virus receptor-A system for modeling human gliomas.

Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due to diffuse brain invasion, immune evasion, cellular, and molecular heterogeneity, and resistance to treatments resulting in high rates of recurrence. An extensive understanding of the genomic and microenvironmental landscape of gliomas gathered over the past decade has renewed interest in pursuing novel therapeutics, including immune checkpoint inhibitors, glioma-associated macrophage/microglia (GAMs) modulators, and others. In light of this, predictive animal models that closely recreate the conditions and findings found in human gliomas will serve an increasingly important role in identifying new, effective therapeutic strategies. Although numerous syngeneic, xenograft, and transgenic rodent models have been developed, few include the full complement of pathobiological features found in human tumors, and therefore few accurately predict bench-to-bedside success. This review provides an update on how genetically engineered rodent models based on the replication-competent avian-like sarcoma (RCAS) virus/tumor virus receptor-A (tv-a) system have been used to recapitulate key elements of human gliomas in an immunologically intact host microenvironment and highlights new approaches using this model system as a predictive tool for advancing translational glioma research.

Elevated fibroblast growth factor-inducible 14 expression transforms proneural-like gliomas into more aggressive and lethal brain cancer.

High-grade gliomas (HGGs) are aggressive, treatment-resistant, and often fatal human brain cancers. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild-type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication-competent avian sarcoma-leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural-like gliomas led to the development of highly invasive and lethal brain cancer with striking biological features including extensive pseudopalisading necrosis, constitutive canonical and noncanonical NF-κB pathway signaling, and high plasminogen activator inhibitor-1 (PAI-1) expression. Analyses of HGG patient datasets revealed that high human PAI-1 gene (SERPINE1) expression correlates with shorter patient survival, and that the SERPINE1 and Fn14 (TNFRSF12A) genes are frequently co-expressed in bulk tumor tissues, in tumor subregions, and in malignant cells residing in the tumor microenvironment. These findings provide new insights into the potential importance of Fn14 in human HGG pathobiology and designate both the NF-κB signaling node and PAI-1 as potential targets for therapeutic intervention. MAIN POINTS: This work demonstrates that elevated levels of the TWEAK receptor Fn14 in tumor-initiating, neural progenitor cells leads to the transformation of proneural-like gliomas into more aggressive and lethal tumors that exhibit constitutive NF-κB pathway activation and plasminogen activator inhibitor-1 overexpression.

Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas.

PURPOSE: H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation. METHODS: Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX. RESULTS: Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03). CONCLUSIONS: H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.

Purposive sampling in a qualitative evidence synthesis: a worked example from a synthesis on parental perceptions of vaccination communication.

BACKGROUND: In a qualitative evidence synthesis, too much data due to a large number of studies can undermine our ability to perform a thorough analysis. Purposive sampling of primary studies for inclusion in the synthesis is one way of achieving a manageable amount of data. The objective of this article is to describe the development and application of a sampling framework for a qualitative evidence synthesis on vaccination communication. METHODS: We developed and applied a three-step framework to sample studies from among those eligible for inclusion in our synthesis. We aimed to prioritise studies that were from a range of settings, were as relevant as possible to the review, and had rich data. We extracted information from each study about country and study setting, vaccine, data richness, and study objectives and applied the following sampling framework: 1. Studies conducted in low and middle income settings 2. Studies scoring four or more on a 5-point scale of data richness 3. Studies where the study objectives closely matched our synthesis objectives RESULTS: We assessed 79 studies as eligible for inclusion in the synthesis and sampled 38 of these. First, we sampled all nine studies that were from low and middle-income countries. These studies contributed to the least number of findings. We then sampled an additional 24 studies that scored high for data richness. These studies contributed to a larger number of findings. Finally, we sampled an additional five studies that most closely matched our synthesis objectives. These contributed to a large number of findings. CONCLUSIONS: Our approach to purposive sampling helped ensure that we included studies representing a wide geographic spread, rich data and a focus that closely resembled our synthesis objective. It is possible that we may have overlooked primary studies that did not meet our sampling criteria but would have contributed to the synthesis. For example, two studies on migration and access to health services did not meet the sampling criteria but might have contributed to strengthening at least one finding. We need methods to cross-check for under-represented themes.

Clients' perceptions and experiences of targeted digital communication accessible via mobile devices for reproductive, maternal, newborn, child, and adolescent health: a qualitative evidence synthesis.

BACKGROUND: Governments and health systems are increasingly using mobile devices to communicate with patients and the public. Targeted digital client communication is when the health system transmits information to particular individuals or groups of people, based on their health or demographic status. Common types of targeted client communication are text messages that remind people to go to appointments or take their medicines. Other types include phone calls, interactive voice response, or multimedia messages that offer healthcare information, advice, monitoring, and support. OBJECTIVES: To explore clients' perceptions and experiences of targeted digital communication via mobile devices on topics related to reproductive, maternal, newborn, child, or adolescent health (RMNCAH). SEARCH METHODS: We searched MEDLINE (OvidSP), MEDLINE In-Process & Other Non-Indexed Citations (OvidSP), Embase (Ovid), World Health Organization Global Health Library, and POPLINE databases for eligible studies from inception to 3-6 July 2017 dependant on the database (See appendix 2). SELECTION CRITERIA: We included studies that used qualitative methods for data collection and analysis; that explored clinets' perceptions and experiences of targeted digital communication via mobile device in the areas of RMNCAH; and were from any setting globally. DATA COLLECTION AND ANALYSIS: We used maximum variation purposive sampling for data synthesis, employing a three-step sampling frame. We conducted a framework thematic analysis using the Supporting the Use of Research Evidence (SURE) framework as our starting point. We assessed our confidence in the findings using the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach. We used a matrix approach to explore whether potential implementation barriers identified in our synthesis had been addressed in the trials included in the related Cochrane Reviews of effectiveness. MAIN RESULTS: We included 35 studies, from a wide range of countries on six continents. Nineteen studies were conducted in low- and middle-income settings and sixteen in high-income settings. Some of the studies explored the views of people who had experienced the interventions, whereas others were hypothetical in nature, asking what people felt they would like from a digital health intervention. The studies covered a range of digital targeted client communication, for example medication or appointment reminders, prenatal health information, support for smoking cessation while pregnant, or general sexual health information.Our synthesis showed that clients' experiences of these types of programmes were mixed. Some felt that these programmes provided them with feelings of support and connectedness, as they felt that someone was taking the time to send them messages (moderate confidence in the evidence). They also described sharing the messages with their friends and family (moderate confidence).However, clients also pointed to problems when using these programmes. Some clients had poor access to cell networks and to the internet (high confidence). Others had no phone, had lost or broken their phone, could not afford airtime, or had changed their phone number (moderate confidence). Some clients, particularly women and teenagers, had their access to phones controlled by others (moderate confidence). The cost of messages could also be a problem, and many thought that messages should be free of charge (high confidence). Language issues as well as skills in reading, writing, and using mobile phones could also be a problem (moderate confidence).Clients dealing with stigmatised or personal health conditions such as HIV, family planning, or abortion care were also concerned about privacy and confidentiality (high confidence). Some clients suggested strategies to deal with these issues, such as using neutral language and tailoring the content, timing, and frequency of messages (high confidence).Clients wanted messages at a time and frequency that was convenient for them (moderate confidence). They had preferences for different delivery channels (e.g. short message service (SMS) or interactive voice response) (moderate confidence). They also had preferences about message content, including new knowledge, reminders, solutions, and suggestions about health issues (moderate confidence). Clients' views about who sent the digital health communication could influence their views of the programme (moderate confidence).For an overview of the findings and our confidence in the evidence, please see the 'Summary of qualitative findings' tables.Our matrix shows that many of the trials assessing these types of programmes did not try to address the problems we identified, although this may have been a reporting issue. AUTHORS' CONCLUSIONS: Our synthesis identified several factors that can influence the successful implementation of targeted client communication programmes using mobile devices. These include barriers to use that have equity implications. Programme planners should take these factors into account when designing and implementing programmes. Future trial authors also need to actively address these factors and to report their efforts in their trial publications.

Leveraging Surface Plasmon Resonance to Dissect the Interfacial Properties of Nanoparticles: Implications for Tissue Binding and Tumor Penetration.

Therapeutic efficacy of nanoparticle-drug formulations for cancer applications is significantly impacted by the extent of intra-tumoral accumulation and tumor tissue penetration. We advanced the application of surface plasmon resonance to examine interfacial properties of various clinical and emerging nanoparticles related to tumor tissue penetration. We observed that amine-terminated or positively-charged dendrimers and liposomes bound strongly to tumor extracellular matrix (ECM) proteins, whereas hydroxyl/carboxyl-terminated dendrimers and PEGylated/neutrally-charged liposomes did not bind. In addition, poly(lactic-co-glycolic acid) (PLGA) nanoparticles formulated with cholic acid or F127 surfactants bound strongly to tumor ECM proteins, whereas nanoparticles formulated with poly(vinyl alcohol) did not bind. Unexpectedly, following blood serum incubation, this binding increased and particle transport in ex vivo tumor tissues reduced markedly. Finally, we characterized the protein corona on PLGA nanoparticles using quantitative proteomics. Through these studies, we identified valuable criteria for particle surface characteristics that are likely to mediate their tissue binding and tumor penetration.

Differential neuronal susceptibility and apoptosis in congenital Zika virus infection.

To characterize the mechanism of Zika virus (ZIKV)-associated microcephaly, we performed immunolabeling on brain tissue from a 20-week fetus with intrauterine ZIKV infection. Although ZIKV demonstrated a wide range of neuronal and non-neuronal tropism, the infection rate was highest in intermediate progenitor cells and immature neurons. Apoptosis was observed in both infected and uninfected bystander cortical neurons, suggesting a role for paracrine factors in induction of neuronal apoptosis. Our results highlight differential neuronal susceptibility and neuronal apoptosis as potential mechanisms in the development of ZIKV-associated microcephaly, and may provide insights into the design and best timing of future therapy. Ann Neurol 2017;82:121-127.

MicroRNA profiling of low-grade glial and glioneuronal tumors shows an independent role for cluster 14q32.31 member miR-487b.

Low-grade (WHO I-II) gliomas and glioneuronal tumors represent the most frequent primary tumors of the central nervous system in children. They often have a good prognosis following total resection, however they can create many neurological complications due to mass effect, and may be difficult to resect depending on anatomic location. MicroRNAs have been identified as molecular regulators of protein expression/translation that can repress multiple mRNAs concurrently through base pairing, and have an important role in cancer, including brain tumors. Using the NanoString digital counting system, we analyzed the expression levels of 800 microRNAs in nine low-grade glial and glioneuronal tumor types (n=45). A set of 61 of these microRNAs were differentially expressed in tumors compared with the brain, and several showed levels varying by tumor type. The expression differences were more accentuated in subependymal giant cell astrocytoma, compared with other groups, and demonstrated the highest degree of microRNA repression validated by RT-PCR, including miR-129-2-3p, miR-219-5p, miR-338-3p, miR-487b, miR-885-5p, and miR-323a-3p. Conversely, miR-4488 and miR-1246 were overexpressed in dysembryoplastic neuroepithelial tumors compared with the brain and other tumors. The cluster 14q32.31 member miR-487b was variably under-expressed in pediatric glioma lines compared with human neural stem cells. Overexpression of miR-487b in a pediatric glioma cell line (KNS42) using lentiviral vectors led to a decrease in colony formation in soft agar (30%) (P<0.05), and decreased expression of known predicted targets PROM1 and Nestin (but not WNT5A). miR-487b overexpression had no significant effect on cell growth, proliferation, sensitivity to temozolomide, migration, or invasion. In summary, microRNA regulation appears to have a role in the biology of glial and glioneuronal tumor subtypes, a finding that deserves further investigation.

Parents' and informal caregivers' views and experiences of communication about routine childhood vaccination: a synthesis of qualitative evidence.

BACKGROUND: Childhood vaccination is an effective way to prevent serious childhood illnesses, but many children do not receive all the recommended vaccines. There are various reasons for this; some parents lack access because of poor quality health services, long distances or lack of money. Other parents may not trust vaccines or the healthcare workers who provide them, or they may not see the need for vaccination due to a lack of information or misinformation about how vaccinations work and the diseases they can prevent.Communication with parents about childhood vaccinations is one way of addressing these issues. Communication can take place at healthcare facilities, at home or in the community. Communication can be two-way, for example face-to-face discussions between parents and healthcare providers, or one-way, for instance via text messages, posters or radio programmes. Some types of communication enable parents to actively discuss vaccines and their benefits and harms, as well as diseases they can prevent. Other communication types simply give information about vaccination issues or when and where vaccines are available. People involved in vaccine programmes need to understand how parents experience different types of communication about vaccination and how this influences their decision to vaccinate. OBJECTIVES: The specific objectives of the review were to identify, appraise and synthesise qualitative studies exploring: parents' and informal caregivers' views and experiences regarding communication about childhood vaccinations and the manner in which it is communicated; and the influence that vaccination communication has on parents' and informal caregivers' decisions regarding childhood vaccination. SEARCH METHODS: We searched MEDLINE (OvidSP), MEDLINE In-process and Other Non-Index Citations (Ovid SP), Embase (Ovid), CINAHL (EbscoHOST), and Anthropology Plus (EbscoHost) databases for eligible studies from inception to 30 August 2016. We developed search strategies for each database, using guidelines developed by the Cochrane Qualitative Research Methods Group for searching for qualitative evidence as well as modified versions of the search developed for three related reviews of effectiveness. There were no date or geographic restrictions for the search. SELECTION CRITERIA: We included studies that utilised qualitative methods for data collection and analysis; focused on the views and experiences of parents and informal caregivers regarding information about vaccination for children aged up to six years; and were from any setting globally where information about childhood vaccinations was communicated or distributed. DATA COLLECTION AND ANALYSIS: We used maximum variation purposive sampling for data synthesis, using a three-step sampling frame. We conducted a thematic analysis using a constant comparison strategy for data extraction and synthesis. We assessed our confidence in the findings using the GRADE-CERQual approach. High confidence suggests that it is highly likely that the review finding is a reasonable representation of the phenomenon of interest, while very low confidence indicates that it is not clear whether the review finding is a reasonable representation of it. Using a matrix model, we then integrated our findings with those from other Cochrane reviews that assessed the effects of different communication strategies on parents' knowledge, attitudes and behaviour about childhood vaccination. MAIN RESULTS: We included 38 studies, mostly from high-income countries, many of which explored mothers' perceptions of vaccine communication. Some focused on the MMR (measles, mumps, rubella) vaccine.In general, parents wanted more information than they were getting (high confidence in the evidence). Lack of information led to worry and regret about vaccination decisions among some parents (moderate confidence).Parents wanted balanced information about vaccination benefits and harms (high confidence), presented clearly and simply (moderate confidence) and tailored to their situation (low confidence in the evidence). Parents wanted vaccination information to be available at a wider variety of locations, including outside health services (low confidence) and in good time before each vaccination appointment (moderate confidence).Parents viewed health workers as an important source of information and had specific expectations of their interactions with them (high confidence). Poor communication and negative relationships with health workers sometimes impacted on vaccination decisions (moderate confidence).Parents generally found it difficult to know which vaccination information source to trust and challenging to find information they felt was unbiased and balanced (high confidence).The amount of information parents wanted and the sources they felt could be trusted appeared to be linked to acceptance of vaccination, with parents who were more hesitant wanting more information (low to moderate confidence).Our synthesis and comparison of the qualitative evidence shows that most of the trial interventions addressed at least one or two key aspects of communication, including the provision of information prior to the vaccination appointment and tailoring information to parents' needs. None of the interventions appeared to respond to negative media stories or address parental perceptions of health worker motives. AUTHORS' CONCLUSIONS: We have high or moderate confidence in the evidence contributing to several review findings. Further research, especially in rural and low- to middle-income country settings, could strengthen evidence for the findings where we had low or very low confidence. Planners should consider the timing for making vaccination information available to parents, the settings where information is available, the provision of impartial and clear information tailored to parental needs, and parents' perceptions of health workers and the information provided.

The comprehensive 'Communicate to Vaccinate' taxonomy of communication interventions for childhood vaccination in routine and campaign contexts.

BACKGROUND: Communication can be used to generate demand for vaccination or address vaccine hesitancy, and is crucial to successful childhood vaccination programmes. Research efforts have primarily focused on communication for routine vaccination. However, vaccination campaigns, particularly in low- or middle-income countries (LMICs), also use communication in diverse ways. Without a comprehensive framework integrating communication interventions from routine and campaign contexts, it is not possible to conceptualise the full range of possible vaccination communication interventions. Therefore, vaccine programme managers may be unaware of potential communication options and researchers may not focus on building evidence for interventions used in practice. In this paper, we broaden the scope of our existing taxonomy of communication interventions for routine vaccination to include communication used in campaigns, and integrate these into a comprehensive taxonomy of vaccination communication interventions. METHODS: Building on our taxonomy of communication for routine vaccination, we identified communication interventions used in vaccination campaigns through a targeted literature search; observation of vaccination activities in Cameroon, Mozambique and Nigeria; and stakeholder consultations. We added these interventions to descriptions of routine vaccination communication and categorised the interventions according to their intended purposes, building from an earlier taxonomy of communication related to routine vaccination. RESULTS: The comprehensive taxonomy groups communication used in campaigns and routine childhood vaccination into seven purpose categories: 'Inform or Educate'; 'Remind or Recall'; 'Enhance Community Ownership'; 'Teach Skills'; 'Provide Support'; 'Facilitate Decision Making' and 'Enable Communication'. Consultations with LMIC stakeholders and experts informed the taxonomy's definitions and structure and established its potential uses. CONCLUSIONS: This taxonomy provides a standardised way to think and speak about vaccination communication. It is categorised by purpose to help conceptualise communication interventions as potential solutions to address needs or problems. It can be utilised by programme planners, implementers, researchers and funders to see the range of communication interventions used in practice, facilitate evidence synthesis and identify evidence gaps.

Factors affecting the implementation of childhood vaccination communication strategies in Nigeria: a qualitative study.

BACKGROUND: The role of health communication in vaccination programmes cannot be overemphasized: it has contributed significantly to creating and sustaining demand for vaccination services and improving vaccination coverage. In Nigeria, numerous communication approaches have been deployed but these interventions are not without challenges. We therefore aimed to explore factors affecting the delivery of vaccination communication in Nigeria. METHODS: We used a qualitative approach and conducted the study in two states: Bauchi and Cross River States in northern and southern Nigeria respectively. We identified factors affecting the implementation of communication interventions through interviews with relevant stakeholders involved in vaccination communication in the health services. We also reviewed relevant documents. Data generated were transcribed verbatim and analysed using thematic analysis. RESULTS: We used the SURE framework to organise the identified factors (barriers and facilitators) affecting vaccination communication delivery. We then grouped these into health systems and community level factors. Some of the commonly reported health system barriers amongst stakeholders interviewed included: funding constraints, human resource factors (health worker shortages, training deficiencies, poor attitude of health workers and vaccination teams), inadequate infrastructure and equipment and weak political will. Community level factors included the attitudes of community stakeholders and of parents and caregivers. We also identified factors that appeared to facilitate communication activities. These included political support, engagement of traditional and religious institutions and the use of organised communication committees. CONCLUSIONS: Communication activities are a crucial element of immunization programmes. It is therefore important for policy makers and programme managers to understand the barriers and facilitators affecting the delivery of vaccination communication so as to be able to implement communication interventions more effectively.

Mapping how information about childhood vaccination is communicated in two regions of Cameroon: What is done and where are the gaps?

BACKGROUND: The 'Communicate to vaccinate' (COMMVAC) project builds research evidence for improving communication with parents and communities about childhood vaccinations in low- and middle-income countries. Understanding and mapping the range of vaccination communication strategies used in different settings is an important component of this work. In this part of the COMMVAC project, our objectives were: (1) to identify the vaccination communication interventions used in two regions of Cameroon; (2) to apply the COMMVAC taxonomy, a global taxonomy of vaccination communication interventions, to these communication interventions to help us classify these interventions, including their purposes and target audiences; and identify whether gaps in purpose or target audiences exist; (3) to assess the COMMVAC taxonomy as a research tool for data collection and analysis. METHODS: We used the following qualitative methods to identify communication strategies in the Central and North West Regions of Cameroon in the first half of 2014: interviews with program managers, non-governmental organizations, vaccinators, parents and community members; observations and informal conversations during routine immunization clinics and three rounds of the National Polio Immunization Campaign; and document analysis of reports and mass media communications about vaccination. A survey of parents and caregivers was also done. We organised the strategies using the COMMVAC taxonomy and produced a map of Cameroon-specific interventions, which we presented to local stakeholders for feedback. RESULTS: Our map of the interventions used in Cameroon suggests that most childhood vaccination communication interventions focus on national campaigns against polio rather than routine immunisation. The map also indicates that most communication interventions target communities more broadly, rather than parents, and that very few interventions target health workers. The majority of the communication interventions aimed to inform or educate or remind or recall members of the community about vaccination. The COMMVAC taxonomy provided a useful framework for quickly and simply mapping existing vaccination communication strategies. CONCLUSIONS: By identifying the interventions used in Cameroon and developing an intervention map, we allowed stakeholders to see where they were concentrating their communication efforts and where gaps exist, allowing them to reflect on whether changes are needed to the communication strategies they are using.

Tools for assessing the methodological limitations of a QES-a short note.

The increasing prevalence and application of qualitative evidence syntheses (QES) in decision-making processes underscore the need for robust tools to assess the methodological limitations of a completed QES. This commentary discusses the limitations of three existing tools and presents the authors' efforts to address this gap. Through a simple comparative analysis, the three tools are examined in terms of their coverage of essential topic areas. The examination finds that existing assessment tools lack comprehensive coverage, clarity, and grounding in qualitative research principles. The authors advocate for the development of a new collaboratively developed evidence-based tool rooted in qualitative methodology and best practice methods. The conclusion emphasizes the necessity of a tool that can provide a comprehensive judgement on the methodological limitations of a QES, addressing the needs of end-users, and ultimately enhancing the trustworthiness of QES findings in decision-making processes.

The effect of machine learning tools for evidence synthesis on resource use and time-to-completion: protocol for a retrospective pilot study.

BACKGROUND: Machine learning (ML) tools exist that can reduce or replace human activities in repetitive or complex tasks. Yet, ML is underutilized within evidence synthesis, despite the steadily growing rate of primary study publication and the need to periodically update reviews to reflect new evidence. Underutilization may be partially explained by a paucity of evidence on how ML tools can reduce resource use and time-to-completion of reviews. METHODS: This protocol describes how we will answer two research questions using a retrospective study design: Is there a difference in resources used to produce reviews using recommended ML versus not using ML, and is there a difference in time-to-completion? We will also compare recommended ML use to non-recommended ML use that merely adds ML use to existing procedures. We will retrospectively include all reviews conducted at our institute from 1 August 2020, corresponding to the commission of the first review in our institute that used ML. CONCLUSION: The results of this study will allow us to quantitatively estimate the effect of ML adoption on resource use and time-to-completion, providing our organization and others with better information to make high-level organizational decisions about ML.

Machine learning in systematic reviews: Comparing automated text clustering with Lingo3G and human researcher categorization in a rapid review.

Systematic reviews are resource-intensive. The machine learning tools being developed mostly focus on the study identification process, but tools to assist in analysis and categorization are also needed. One possibility is to use unsupervised automatic text clustering, in which each study is automatically assigned to one or more meaningful clusters. Our main aim was to assess the usefulness of an automated clustering method, Lingo3G, in categorizing studies in a simplified rapid review, then compare performance (precision and recall) of this method compared to manual categorization. We randomly assigned all 128 studies in a review to be coded by a human researcher blinded to cluster assignment (mimicking two independent researchers) or by a human researcher non-blinded to cluster assignment (mimicking one researcher checking another's work). We compared time use, precision and recall of manual categorization versus automated clustering. Automated clustering and manual categorization organized studies by population and intervention/context. Automated clustering failed to identify two manually identified categories but identified one additional category not identified by the human researcher. We estimate that automated clustering has similar precision to both blinded and non-blinded researchers (e.g., 88% vs. 89%), but higher recall (e.g., 89% vs. 84%). Manual categorization required 49% more time than automated clustering. Using a specific clustering algorithm, automated clustering can be helpful with categorization of and identifying patterns across studies in simpler systematic reviews. We found that the clustering was sensitive enough to group studies according to linguistic differences that often corresponded to the manual categories.

DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts.

Glioma stem cells (GSCs) promote tumor progression and therapeutic resistance and exhibit remarkable bioenergetic and metabolic plasticity, a phenomenon that has been linked to their ability to escape standard and targeted therapies. However, specific mechanisms that promote therapeutic resistance have been somewhat elusive. We hypothesized that because GSCs proliferate continuously, they may require the salvage and de novo nucleotide synthesis pathways to satisfy their bioenergetic needs. Here, we demonstrate that GSCs lacking EGFR (or EGFRvIII) amplification are exquisitely sensitive to de novo pyrimidine synthesis perturbations, while GSCs that amplify EGFR are utterly resistant. Furthermore, we show that EGFRvIII promotes BAY2402234 resistance in otherwise BAY2402234 responsive GSCs. Remarkably, a novel, orally bioavailable, blood-brain-barrier penetrating, dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 was found to abrogate GSC proliferation, block cell-cycle progression, and induce DNA damage and apoptosis. When dosed daily by oral gavage, BAY2402234 significantly impaired the growth of two different intracranial human glioblastoma xenograft models in mice. Given this observed efficacy and the previously established safety profiles in preclinical animal models and human clinical trials, the clinical testing of BAY2402234 in patients with primary glioblastoma that lacks EGFR amplification is warranted.