Supporting self-management of low back pain with an internet intervention with and without telephone support in primary care (SupportBack 2): a randomised controlled trial of clinical and cost-effectiveness.

BACKGROUND: Low back pain is prevalent and a leading cause of disability. We aimed to determine the clinical and cost-effectiveness of an accessible, scalable internet intervention for supporting behavioural self-management (SupportBack). METHODS: Participants in UK primary care with low back pain without serious spinal pathology were randomly assigned 1:1:1 using computer algorithms stratified by disability level and telephone-support centre to usual care, usual care and SupportBack, or usual care and SupportBack with physiotherapist telephone-support (three brief calls). The primary outcome was low back pain-related disability (Roland Morris Disability Questionnaire [RMDQ] score) at 6 weeks, 3 months, 6 months, and 12 months using a repeated measures model, analysed by intention to treat using 97·5% CIs. A parallel economic evaluation from a health services perspective was used to estimate cost-effectiveness. People with lived experience of low back pain were involved in this trial from the outset. This completed trial was registered with ISRCTN, ISRCTN14736486. FINDINGS: Between Nov 29, 2018, and Jan 12, 2021, 825 participants were randomly assigned (274 to usual care, 275 to SupportBack only, 276 to SupportBack with telephone-support). Participants had a mean age of 54 (SD 15), 479 (58%) of 821 were women and 342 (42%) were men, and 591 (92%) of 641 were White. Follow-up rates were 687 (83%) at 6 weeks, 598 (73%) at 3 months, 589 (72%) at 6 months, and 652 (79%) at 12 months. For the primary analysis, 736 participants were analysed (249 usual care, 245 SupportBack, and 242 SupportBack with telephone support). At a significance level of 0·025, there was no difference in RMDQ over 12 months with SupportBack versus usual care (adjusted mean difference -0·5 [97·5% CI -1·2 to 0·2]; p=0·085) or SupportBack with telephone-support versus usual care (-0·6 [-1·2 to 0·1]; p=0·048). There were no treatment-related serious adverse events. The economic evaluation showed that the SupportBack group dominated usual care, being both more effective and less costly. Both interventions were likely to be cost-effective at a threshold of £20 000 per quality adjusted life year compared with usual care. INTERPRETATION: The SupportBack internet interventions did not significantly reduce low back pain-related disability over 12 months compared with usual care. They were likely to be cost-effective and safe. Clinical effectiveness, cost-effectiveness, and safety should be considered together when determining whether to apply these interventions in clinical practice. FUNDING: National Institute for Health and Care Research Health Technology Assessment (16/111/78).

Transcription Factor-Mediated Generation of Dopaminergic Neurons from Human iPSCs-A Comparison of Methods.

Dopaminergic neurons are the predominant brain cells affected in Parkinson's disease. With the limited availability of live human brain dopaminergic neurons to study pathological mechanisms of Parkinson's disease, dopaminergic neurons have been generated from human-skin-cell-derived induced pluripotent stem cells. Originally, induced pluripotent stem-cell-derived dopaminergic neurons were generated using small molecules. These neurons took more than two months to mature. However, the transcription-factor-mediated differentiation of induced pluripotent stem cells has revealed quicker and cheaper methods to generate dopaminergic neurons. In this study, we compared and contrasted three protocols to generate induced pluripotent stem-cell-derived dopaminergic neurons using transcription-factor-mediated directed differentiation. We deviated from the established protocols using lentivirus transduction to stably integrate different transcription factors into the AAVS1 safe harbour locus of induced pluripotent stem cells. We used different media compositions to generate more than 90% of neurons in the culture, out of which more than 85% of the neurons were dopaminergic neurons within three weeks. Therefore, from our comparative study, we reveal that a combination of transcription factors along with small molecule treatment may be required to generate a pure population of human dopaminergic neurons.

The experiences of men on active surveillance for prostate cancer and their significant others: A qualitative synthesis.

BACKGROUND: Active surveillance (AS) for prostate cancer (PCa) is a monitoring pathway for men with low-grade, slow growing PCa and aims to delay or avoid active treatment by treating only in the case of disease progression. Experiences of this pathway vary but living with an untreated cancer can have a negative psychological impact on both the patient and their significant other (SO). Literature suggests partners are the primary source of support for men on AS, and therefore it is important to consider SO experiences alongside those of the patient. To the best of our knowledge this is the first UK-based qualitative review looking specifically at experiences of AS for both men with PCa and their SOs. METHODS: MEDLINE (Ovid), EMBASE, PsychINFO, CINAHL and Cochrane Library were searched for literature reporting qualitative experiences of AS for PCa for either men on AS or SOs (or both). 2769 records were identified and screened, with 28 meeting the eligibility criteria. Qualitative data were synthesised and included men on AS (n = 428), and SOs (n = 51). RESULTS: Experiences of the AS pathway vary but reports of uncertainty and anxiety were present in the accounts of both men on AS and SOs. SOs are intertwined throughout every part of the PCa journey, and couples presented as a unit that were on AS together. Both patients and SOs expressed a need for more support, and highly valued peer support. Despite this finding, men expressed a dislike towards 'support groups'. CONCLUSIONS: Increased recognition in clinical practice of SO involvement in AS is needed. Further research is required to explore the specific types of support that would be most acceptable to this population to address the unmet support needs uncovered in this review.

Mothers' and fathers' attitudes toward stuttering in the Middle East compared to Europe and North America.

BACKGROUND: Parents play a central role in the treatment of childhood stuttering. Addressing parental attitudes toward stuttering is helpful therapeutically. The extent to which differences in attitudes toward stuttering exist on the basis of sex, geographical region and parental status (e.g., parent of a stuttering child, parent of a nonstuttering child, nonparent) is unclear. Many studies investigating such factors have used the Public Opinion Survey of Human Attributes-Stuttering (POSHA-S) questionnaire. A large POSHA-S database has collected responses from over 20 000 people from 49 countries. AIMS: The aim of this study was to use the POSHA-S database to examine the extent to which the following variables influence attitudes toward stuttering: (a) parents' sex (mothers vs. fathers), (b) geographic region (Middle East vs. Europe and North America), (c) parents' children (stuttering vs. nonstuttering) and (d) parental status (parents versus nonparents). METHODS & PROCEDURES: Data used in this study were extracted from selected, relevant studies that administered the POSHA-S to respondents. The Overall Stuttering Scores were compared on the basis of sex and parent status (i.e., mothers and fathers; nonparent women and men) and were then compared within and across the two geographical areas. Group comparisons were performed using analysis of variance followed by independent t tests, and Cohen's d was calculated to determine effect sizes. OUTCOMES & RESULTS: Statistically significant differences were observed upon the basis of geographical region. In general, male parents and nonparents tend to have more positive stuttering attitudes among the Middle Eastern samples while female parents and nonparents tend to show more positive attitudes in European and North American samples in the POSHA-S database. Effect sizes were small for all comparisons. CONCLUSIONS & IMPLICATIONS: The effect of geographic region and culture may predict sex-based differences among mothers' and fathers' attitudes toward stuttering; however, the clinical significance is unclear. Additional research is needed to better understand how children who stutter are affected by their parents' attitudes toward stuttering. WHAT THIS PAPER ADDS: What is already known on this subject The research clearly indicates that attitudes toward stuttering vary according to geographical region. Less clear is whether mothers and fathers from geographically diverse backgrounds hold different attitudes toward stuttering and the extent to which parental status (being a parent, parent of a child who stutters or nonparent) affects attitudes toward stuttering. What this study adds This study's findings confirm that geographical differences do influence attitudes toward stuttering. Male parents and nonparents tend to have equal or more positive attitudes toward stuttering in Middle Eastern samples, whereas non-Middle Eastern female parents and nonparents tend to show hold more positive attitudes. What are the clinical implications of this work? In addition to being culturally sensitive when working with parents of children who stutter, clinicians should also consider that mothers and fathers may have some differences in attitudes and behaviours toward their child's stuttering. These differences should be considered when designing treatment plans. It should also be noted that, despite statistical significance, the effect sizes in this study were low, suggesting that further research as well as close collaboration with parents of children who stutter is warranted.

Neuroproteomic Analysis after SARS-CoV-2 Infection Reveals Overrepresented Neurodegeneration Pathways and Disrupted Metabolic Pathways.

Besides respiratory illness, SARS-CoV-2, the causative agent of COVID-19, leads to neurological symptoms. The molecular mechanisms leading to neuropathology after SARS-CoV-2 infection are sparsely explored. SARS-CoV-2 enters human cells via different receptors, including ACE-2, TMPRSS2, and TMEM106B. In this study, we used a human-induced pluripotent stem cell-derived neuronal model, which expresses ACE-2, TMPRSS2, TMEM106B, and other possible SARS-CoV-2 receptors, to evaluate its susceptibility to SARS-CoV-2 infection. The neurons were exposed to SARS-CoV-2, followed by RT-qPCR, immunocytochemistry, and proteomic analyses of the infected neurons. Our findings showed that SARS-CoV-2 infects neurons at a lower rate than other human cells; however, the virus could not replicate or produce infectious virions in this neuronal model. Despite the aborted SARS-CoV-2 replication, the infected neuronal nuclei showed irregular morphology compared to other human cells. Since cytokine storm is a significant effect of SARS-CoV-2 infection in COVID-19 patients, in addition to the direct neuronal infection, the neurons were treated with pre-conditioned media from SARS-CoV-2-infected lung cells, and the neuroproteomic changes were investigated. The limited SARS-CoV-2 infection in the neurons and the neurons treated with the pre-conditioned media showed changes in the neuroproteomic profile, particularly affecting mitochondrial proteins and apoptotic and metabolic pathways, which may lead to the development of neurological complications. The findings from our study uncover a possible mechanism behind SARS-CoV-2-mediated neuropathology that might contribute to the lingering effects of the virus on the human brain.

Maternal varicella antibodies in children aged less than one year: Assessment of antibody decay.

OBJECTIVES: To investigate maternal antibody levels to varicella in infants <12 months of age in Ontario, Canada. STUDY DESIGN: In this study, we included specimens from infants <12 months of age, born at ≥37 weeks gestational age, who had sera collected at The Hospital for Sick Children (Toronto, Canada) between 2014-2016. We tested sera using a glycoprotein-based enzyme-linked immunosorbent assay (gpELISA). We measured varicella susceptibility (antibody concentration <150mIU/mL) and mean varicella antibody concentration, and assessed the probability of susceptibility and concentration between one and 11 months of age using multivariable logistic regression and Poisson regression. RESULTS: We found that 32% of 196 included specimens represented infants susceptible to varicella at one month of age, increasing to nearly 80% at three months of age. At six months of age, all infants were susceptible to varicella and the predicted mean varicella antibody concentration declined to 62 mIU/mL (95% confidence interval 40, 84), well below the threshold of protection. CONCLUSIONS: We found that varicella maternal antibody levels wane rapidly in infants, leaving most infants susceptible by four months of age. Our findings have implications for the timing of first dose of varicella-containing vaccine, infection control measures, and infant post-exposure prophylaxis recommendations.

Patient perceptions of empathy in primary care telephone consultations: A mixed methods study.

OBJECTIVE: Clinical empathy can enhance patient outcomes. This study examined patients' perceptions of empathy in primary care consultations delivered by telephone. METHODS: A mixed methods study was nested in a larger feasibility study conducted May-October 2020. Adults reporting a UK primary care consultation in the previous 2 weeks completed an online survey. A sample of survey respondents participated in a semi-structured qualitative interview. Interviews were analysed thematically. RESULTS: Survey respondents (n = 359) rated practitioners as between 'good' and 'very good' at established patient-reported indicators of clinical empathy. Telephone consultations were rated slightly lower than face-to-face or other consultations. 30 survey respondents were interviewed. Three qualitative themes identified how telephone consultations can shape clinical empathy: setting for an empathic encounter; feeling connected; being acknowledged. CONCLUSION: Primary care patients typically perceive good levels of clinical empathy in telephone consultations; specific features of telephone consultations may facilitate and/or hinder clinical empathy. PRACTICE IMPLICATIONS: To ensure patients feel listened to, acknowledged and understood, practitioners may need to increase their empathic verbalisations in telephone consultations. By using verbal responses to demonstrate active listening and by clearly describing and/or implementing next steps in management, practitioners may be able to enhance clinical empathy in telephone consultations.

Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes.

Secreted amyloid precursor protein alpha (sAPPα), processed from a parent mammalian brain protein, amyloid precursor protein, can modulate learning and memory. Recently it has been shown to modulate the transcriptome and proteome of human neurons, including proteins with neurological functions. Here, we analysed whether the acute administration of sAPPα facilitated changes in the proteome and secretome of mouse primary astrocytes in culture. Astrocytes contribute to the neuronal processes of neurogenesis, synaptogenesis and synaptic plasticity. Cortical mouse astrocytes in culture were exposed to 1 nM sAPPα, and changes in both the whole-cell proteome (2 h) and the secretome (6 h) were identified with Sequential Window Acquisition of All Theoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS). Differentially regulated proteins were identified in both the cellular proteome and secretome that are involved with neurologically related functions of the normal physiology of the brain and central nervous system. Groups of proteins have a relationship to APP and have roles in the modulation of cell morphology, vesicle dynamics and the myelin sheath. Some are related to pathways containing proteins whose genes have been previously implicated in Alzheimer's disease (AD). The secretome is also enriched in proteins related to Insulin Growth Factor 2 (IGF2) signaling and the extracellular matrix (ECM). There is the promise that a more specific investigation of these proteins will help to understand the mechanisms of how sAPPα signaling affects memory formation.

Assessing Disparities in Medicaid Home- and Community-Based Services: A Systematic Review.

In recent years, expansion of home and community-based services (HCBS) for older adults and persons with disabilities has become a national priority in the U.S. In addition, lawmakers and health-care providers are pursuing opportunities to minimize disparities in healthcare service delivery. Marrying these priorities will require policymakers to identify existing Medicaid HCBS disparities toward development of new, more equitable policies. This study provides a systematic literature review using an adapted theoretical framework to describe disparities in Medicaid HCBS. Key findings are organized into four domains: availability, accessibility, accommodation, and acceptability. We found a lack of concerted research effort targeting Medicaid HCBS disparities in the context of all four domains, with an especially notable dearth of content related to acceptability. We also identified very few articles that focused on specific marginalized groups, suggesting a need for more research into whether Medicaid HCBS are available, accessible, accommodating, and acceptable for a variety of diverse populations. Our findings underscore the need for researchers and policymakers to conceptualize and evaluate existing Medicaid HCBS policy toward development of a more equitable Medicaid HCBS program design in the future.

Planning and developing a web-based intervention for active surveillance in prostate cancer: an integrated self-care programme for managing psychological distress.

OBJECTIVES: To outline the planning, development and optimisation of a psycho-educational behavioural intervention for patients on active surveillance for prostate cancer. The intervention aimed to support men manage active surveillance-related psychological distress. METHODS: The person-based approach (PBA) was used as the overarching guiding methodological framework for intervention development. Evidence-based methods were incorporated to improve robustness. The process commenced with data gathering activities comprising the following four components: • A systematic review and meta-analysis of depression and anxiety in prostate cancer • A cross-sectional survey on depression and anxiety in active surveillance • A review of existing interventions in the field • A qualitative study with the target audience The purpose of this paper is to bring these components together and describe how they facilitated the establishment of key guiding principles and a logic model, which underpinned the first draft of the intervention. RESULTS: The prototype intervention, named PROACTIVE, consists of six Internet-based sessions run concurrently with three group support sessions. The sessions cover the following topics: lifestyle (diet and exercise), relaxation and resilience techniques, talking to friends and family, thoughts and feelings, daily life (money and work) and information about prostate cancer and active surveillance. The resulting intervention has been trialled in a feasibility study, the results of which are published elsewhere. CONCLUSIONS: The planning and development process is key to successful delivery of an appropriate, accessible and acceptable intervention. The PBA strengthened the intervention by drawing on target-user experiences to maximise acceptability and user engagement. This meticulous description in a clinical setting using this rigorous but flexible method is a useful demonstration for others developing similar interventions. TRIAL REGISTRATION AND ETHICAL APPROVAL: ISRCTN registered: ISRCTN38893965 . NRES Committee South Central - Oxford A. REC reference: 11/SC/0355.

Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures.

Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1-/-) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1-/- mice compared to normal animals. Cln1-/- mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency.

Secreted Amyloid Precursor Protein Alpha, a Neuroprotective Protein in the Brain Has Widespread Effects on the Transcriptome and Proteome of Human Inducible Pluripotent Stem Cell-Derived Glutamatergic Neurons Related to Memory Mechanisms.

Secreted amyloid precursor protein alpha (sAPPα) processed from a parent human brain protein, APP, can modulate learning and memory. It has potential for development as a therapy preventing, delaying, or even reversing Alzheimer's disease. In this study a comprehensive analysis to understand how it affects the transcriptome and proteome of the human neuron was undertaken. Human inducible pluripotent stem cell (iPSC)-derived glutamatergic neurons in culture were exposed to 1 nM sAPPα over a time course and changes in the transcriptome and proteome were identified with RNA sequencing and Sequential Window Acquisition of All THeoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS), respectively. A large subset (∼30%) of differentially expressed transcripts and proteins were functionally involved with the molecular biology of learning and memory, consistent with reported links of sAPPα to memory enhancement, as well as neurogenic, neurotrophic, and neuroprotective phenotypes in previous studies. Differentially regulated proteins included those encoded in previously identified Alzheimer's risk genes, APP processing related proteins, proteins involved in synaptogenesis, neurotransmitters, receptors, synaptic vesicle proteins, cytoskeletal proteins, proteins involved in protein and organelle trafficking, and proteins important for cell signalling, transcriptional splicing, and functions of the proteasome and lysosome. We have identified a complex set of genes affected by sAPPα, which may aid further investigation into the mechanism of how this neuroprotective protein affects memory formation and how it might be used as an Alzheimer's disease therapy.

Clinician views on optimism and empathy in primary care consultations: a qualitative interview study.

BACKGROUND: Practitioner expressions of optimism and empathy may improve treatment engagement, adherence, and patient satisfaction but are not delivered consistently amid the challenges of everyday clinical practice. AIM: To explore primary care practitioner (PCP) views about optimistic and empathic communication in consultations; and to identify behavioural, attitudinal, and/or contextual issues likely to encourage or deter PCPs from practising such communication. DESIGN & SETTING: Qualitative interview study with 20 PCPs (GPs, practice nurses, and primary care physiotherapists). METHOD: Semi-structured telephone interviews with 20 PCPs. Data were analysed thematically. RESULTS: A conceptual mismatch between optimism and patient expectations became apparent; when asked how PCPs communicate about the likely effects of a treatment, answers were focussed around managing patient expectations. When prompted, it became clear PCPs were open to communicating optimistically with patients, but emphasised the need for realism. Concerns arose that patients may not be receptive to optimistic messages, especially when holding negative expectations. PCPs felt that expressing empathy is fundamental to all clinical consultations, noting that it can be challenging. Some PCPs worried that increasing expressions of empathy might increase their risk of clinician burnout and felt guilty about (appropriately) communicating empathy while maintaining some emotional distance. CONCLUSION: PCPs agreed expressing realistic optimism during consultations could aid communication and would constitute a novel change to practice. PCPs strive for clinical empathy but can struggle to manage emotional self-protection. Specific training to help PCPs express realistic optimism and empathy, and better utilise efficient non-verbal skills could help these issues.

In Elimination Settings, Measles Antibodies Wane After Vaccination but Not After Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: We conducted a systematic review to assess whether measles humoral immunity wanes in previously infected or vaccinated populations in measles elimination settings. METHODS: After screening 16 822 citations, we identified 9 articles from populations exposed to wild-type measles and 16 articles from vaccinated populations that met our inclusion criteria. RESULTS: Using linear regression, we found that geometric mean titers (GMTs) decreased significantly in individuals who received 2 doses of measles-containing vaccine (MCV) by 121.8 mIU/mL (95% confidence interval [CI], -212.4 to -31.1) per year since vaccination over 1 to 5 years, 53.7 mIU/mL (95% CI, -95.3 to -12.2) 5 to 10 years, 33.2 mIU/mL (95% CI, -62.6 to -3.9), 10 to 15 years, and 24.1 mIU/mL (95% CI, -51.5 to 3.3) 15 to 20 years since vaccination. Decreases in GMT over time were not significant after 1 dose of MCV or after infection. Decreases in the proportion of seropositive individuals over time were not significant after 1 or 2 doses of MCV or after infection. CONCLUSIONS: Measles antibody waning in vaccinated populations should be considered in planning for measles elimination.

Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer's disease.

INTRODUCTION: Neutrophil accumulation is a well-established feature of Alzheimer's disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain. MATERIALS AND METHODS: We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD. RESULTS: There was an increase in neutrophils in AD brains as well as in the murine APP/PS1 model of AD. Indeed, MPO expression was almost exclusively confined to S100A8-positive neutrophils in both human AD and murine APP/PS1 brains. The vascular localisation of neutrophils in both human AD and mouse models of AD was striking and driven by enhanced neutrophil adhesion to small vessels. We also observed rare infiltrating neutrophils and deposits of MPO around plaques. Citrullinated histone H3, a marker of neutrophil extracellular traps (NETs), was also detected in human AD cases at these sites, indicating the presence of extracellular MPO in the vasculature. Finally, there was a reduction in the endothelial glycocalyx in AD that may be responsible for non-productive neutrophil adhesion to the vasculature. CONCLUSION: Our report indicates that vascular changes may drive neutrophil adhesion and NETosis, and that neutrophil-derived MPO may lead to vascular oxidative stress and be a relevant therapeutic target in AD.

Patient and practitioner priorities and concerns about primary healthcare interactions for osteoarthritis: A meta-ethnography.

OBJECTIVE: To explore primary care practitioners' (PCPs) and patients' priorities and concerns for healthcare interactions for osteoarthritis (OA) in primary care. METHODS: We searched Embase, CINAHL, Medline, PsychInfo (1990 to present) for primary qualitative and mixed methods studies with findings concerning healthcare interactions for OA symptoms. Patient and PCP perceptions were analysed separately then inter-related using a 'line of argument' synthesis. RESULTS: Twenty-six studies reporting qualitative data from 557 patients and 199 PCPs were synthesised. Our findings suggest that therapeutic interactions for OA can be based on discordant priorities and concerns; some patients perceive that PCPs hold negative attitudes about OA and feel their concerns about impact are not appreciated; some PCPs feel patients have misconceptions about prognosis, and hold pessimistic views about outcomes; and both tend to de-prioritise OA within consultations. CONCLUSION: Greater working in partnership could build mutual trust, facilitate tailored provision of information, and foster a shared understanding of OA upon which to build realistic goals for management. PRACTICE IMPLICATIONS: Developing a better shared understanding of OA has the potential to improve the quality of healthcare interactions for both patients and PCPs. The significant impact of OA on everyday life means it should be given higher priority in primary care consultations.

Effect of soluble amyloid precursor protein-alpha on adult hippocampal neurogenesis in a mouse model of Alzheimer's disease.

Soluble amyloid precursor protein-alpha (sAPPα) is a regulator of neuronal and memory mechanisms, while also having neurogenic and neuroprotective effects in the brain. As adult hippocampal neurogenesis is impaired in Alzheimer's disease, we tested the hypothesis that sAPPα delivery would rescue adult hippocampal neurogenesis in an APP/PS1 mouse model of Alzheimer's disease. An adeno-associated virus-9 (AAV9) encoding murine sAPPα was injected into the hippocampus of 8-month-old wild-type and APP/PS1 mice, and later two different thymidine analogues (XdU) were systemically injected to label adult-born cells at different time points after viral transduction. The proliferation of adult-born cells, cell survival after eight weeks, and cell differentiation into either neurons or astrocytes was studied. Proliferation was impaired in APP/PS1 mice but was restored to wild-type levels by viral expression of sAPPα. In contrast, sAPPα overexpression failed to rescue the survival of XdU+-labelled cells that was impaired in APP/PS1 mice, although it did cause a significant increase in the area density of astrocytes in the granule cell layer across both genotypes. Finally, viral expression of sAPPα reduced amyloid-beta plaque load in APP/PS1 mice in the dentate gyrus and somatosensory cortex. These data add further evidence that increased levels of sAPPα could be therapeutic for the cognitive decline in AD, in part through restoration of the proliferation of neural progenitor cells in adults.

Exploring the reasons for low pertussis vaccine effectiveness in Ontario, Canada, 2006-2008: a Canadian Immunization Research Network study.

OBJECTIVES: Although pertussis vaccines have been widely used for many decades, a burden of illness persists. Resurgences in Ontario, Canada, have not been substantial in the past decade, but an outbreak of pertussis occurred in Toronto between 1 October 2005 and 31 March 2006. Previous Ontario studies found high vaccine effectiveness (VE) in the initial years post-immunization. In order to explore the impact of outbreaks and external factors on VE, we investigated pertussis VE during the period 2006-2008. METHODS: We assessed pertussis VE using a frequency-matched case-control study for the period 1 March 2006 to 31 December 2008. We used logistic regression to estimate VE by age, time since last vaccination, and vaccination status according to the Ontario recommended schedule. We compared analyses including and excluding cases from Toronto, and to two recent Ontario pertussis VE studies. RESULTS: We included 1797 confirmed cases and 7188 matched controls. Most cases were under 4 years of age during the study period. Pertussis VE was 3.8% (95% CI: - 21.0, 24.0) in the period 15-364 days following the last pertussis vaccine dose, and increased with increasing time since vaccination. Pertussis VE in the first 15-364 days excluding Toronto increased to 57.1% (95% CI: 26.0, 75.1), but the trend of increasing VE with time since vaccination persisted. Although VE was higher in older (6-11 years) than younger (0-5 years) children, it was lower at 12-13 years than after 14 years. CONCLUSION: VE was lower in comparison with other studies conducted in Ontario, particularly in younger children. Various factors occurring during the study period may have influenced the results, including clinical testing of asymptomatic contacts, laboratory testing and methods and reporting practice, and a sensitive case definition. Further studies are needed to optimize methods for measuring VE to inform pertussis vaccine policy.

RéSUMé: OBJECTIFS: Bien que les vaccins anticoquelucheux soient couramment utilisés depuis des dizaines d'années, la charge de morbidité de la coqueluche persiste. Sa réapparition en Ontario, au Canada, a été modérée au cours des 10 dernières années, mais une éclosion de coqueluche s'est produite à Toronto entre le 1er octobre 2005 et le 31 mars 2006. Des études antérieures menées en Ontario ont fait état d'une efficacité vaccinale (EV) élevée dans les premières années qui suivent l'immunisation. Pour explorer l'impact des éclosions et des facteurs externes sur l'EV, nous avons étudié l'efficacité des vaccins anticoquelucheux pour la période 2006-2008. MéTHODE: Nous avons évalué l'efficacité des vaccins anticoquelucheux à l'aide d'une étude cas-témoins assortie par fréquence pour la période du 1er mars 2006 au 31 décembre 2008. Nous avons procédé par régression logistique pour estimer l'EV selon l'âge, le temps écoulé depuis la dernière vaccination et le statut vaccinal d'après le calendrier recommandé en Ontario. Nous avons comparé les analyses en incluant et en excluant les cas de Toronto et par rapport à deux récentes études ontariennes sur l'efficacité des vaccins anticoquelucheux. RéSULTATS: Nous avons inclus 1 797 cas confirmés et 7 188 témoins assortis. La plupart des cas avaient moins de 4 ans durant la période de l'étude. L'efficacité des vaccins anticoquelucheux était de 3,8 % (IC de 95 % : -21,0, 24,0) au cours des 15 à 364 jours suivant la dernière dose de vaccin anticoquelucheux et augmentait avec le temps après la vaccination. En excluant Toronto, l'efficacité des vaccins anticoquelucheux au cours des 15 à 364 premiers jours passait à 57,1 % (IC de 95 % : 26,0, 75,1), mais la tendance d'augmentation de l'EV avec le temps après la vaccination était toujours présente. Bien que l'EV ait été supérieure chez les enfants plus vieux (6 à 11 ans) que chez les plus jeunes (0 à 5 ans), elle était plus faible chez les 12-13 ans qu'après 14 ans. CONCLUSION: Nous avons observé une EV plus faible que dans d'autres études menées en Ontario, surtout chez les jeunes enfants. Divers facteurs survenus durant la période de l'étude pourraient en avoir influencé les résultats, dont les tests cliniques menés sur les contacts asymptomatiques, les épreuves et les méthodes de laboratoire, les pratiques de déclaration et l'usage d'une définition de cas sensible. D'autres études sont nécessaires pour optimiser la méthode de mesure de l'EV afin d'éclairer la politique vaccinale contre la coqueluche.

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.

BACKGROUND: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. METHODS: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per µL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. FINDINGS: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. INTERPRETATION: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. FUNDING: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Epidemiology of norovirus and viral gastroenteritis in Ontario, Canada, 2009-2014.

BACKGROUND: Norovirus is the most common cause of acute gastroenteritis in Canada. The illness causes great morbidity and high societal costs. The objective of this article is to describe the epidemiology of norovirus in the province of Ontario, Canada from 2009 to 2014. METHODS: To assess activity of norovirus and viral gastroenteritis (VGE) in Ontario, three datasets were acquired from the provincial government: two traditional surveillance datasets (outbreak and laboratory) and syndromic surveillance data (telehealth), all spanning 2009-2014. All outbreaks, laboratory submissions and telehealth calls were first assessed for total VGE. Norovirus and norovirus-like illness totals were calculated as a proportion of VGE to estimate agent-specific activity levels. Affected institution types, sexes and age groups were also analyzed. RESULTS: Between 2009 and 2014, 41.5% of VGE outbreaks, 63.4% of VGE laboratory submissions and 36.6% of all acute gastroenteritis-related (not restricted to viral causes) telehealth calls were attributed to norovirus and norovirus-like illness in Ontario. The most commonly affected institution type was long-term care homes and the most commonly affected age groups were younger (younger than five years) and older (older than 65 years) individuals. Females were slightly more frequently affected than males. CONCLUSION: Norovirus and norovirus-like illnesses were the leading cause of VGE in Ontario between 2009 and 2014. They comprised the greatest percentage of VGE when compared with all other VGE-associated viruses. Additional work is needed to determine all component costs and necessary public health actions to reduce the burden of disease.