Vaccine Mandates and Cultural Safety.

The issues and problems of mandatory vaccination policy and roll out in First Nations communities are unique and do not concern the safety and effectiveness of vaccines. These issues are also independent of more specific arguments of mandatory vaccination of healthcare workers as a condition of employment. As important as these issues are, they do not consider the complex politics of ongoing settler colonialism and First Nations community relations. In this paper, we also set aside the very real problems of disinformation, hesitancy, scientific and health illiteracy, and other concerns that drive vaccine hesitancy and refusal. These affect all communities, including First Nations communities. We, instead describe the dominant arguments in favour of mandatory vaccination and critique them in terms of the disputed legitimacy of Settler-Colonial decision-making as it impacts First Nations communities. We contend cultural responsiveness and safety-not state compulsion-must remain the first principles of any engagement-including vaccination-with First Nations Peoples, families, and communities.

Comorbid mental health issues in patients with pemphigus vulgaris and pemphigus foliaceus.

The term 'pemphigus' refers to chronic autoimmune skin disorders that cause blistering erosions on the skin and oral mucosa. The two major clinical forms are pemphigus vulgaris and pemphigus foliaceus. Although rare, they confer a stark symptomatic burden upon patients that significantly impacts daily life. Comorbid mental health issues are not routinely screened for in patients with pemphigus, and current UK guidance provides no formal provision for the identification and treatment of psychological issues. This review is the first of its kind, to our knowledge, to systematically examine the available evidence on mental health issues in pemphigus. Published work suggests that the incidence of anxiety and depression is much higher in patients with pemphigus compared with both the general population and with patients having other chronic skin disorders. Disease severity appears to be closely linked to mental health, with worsening of pemphigus associated with deteriorations in psychological wellbeing. Corticosteroids, which are associated with depression in chronic use, are the current first-line therapy for pemphigus and have been identified as a potential confounder and independent risk factor for mental health comorbidity in pemphigus. Current evidence is unclear whether a bidirectional relationship exists between mental health and pemphigus severity, and more thorough research is required to develop understanding of this issue. In conclusion, we have identified a high incidence of mental health comorbidity in pemphigus, and recommend routine screening of patients with pemphigus for mental health issues and signposting toward mental health services as an initial measure to address this.

Overriding water table control on managed peatland greenhouse gas emissions.

Global peatlands store more carbon than is naturally present in the atmosphere1,2. However, many peatlands are under pressure from drainage-based agriculture, plantation development and fire, with the equivalent of around 3 per cent of all anthropogenic greenhouse gases emitted from drained peatland3-5. Efforts to curb such emissions are intensifying through the conservation of undrained peatlands and re-wetting of drained systems6. Here we report eddy covariance data for carbon dioxide from 16 locations and static chamber measurements for methane from 41 locations in the UK and Ireland. We combine these with published data from sites across all major peatland biomes. We find that the mean annual effective water table depth (WTDe; that is, the average depth of the aerated peat layer) overrides all other ecosystem- and management-related controls on greenhouse gas fluxes. We estimate that every 10 centimetres of reduction in WTDe could reduce the net warming impact of CO2 and CH4 emissions (100-year global warming potentials) by the equivalent of at least 3 tonnes of CO2 per hectare per year, until WTDe is less than 30 centimetres. Raising water levels further would continue to have a net cooling effect until WTDe is within 10 centimetres of the surface. Our results suggest that greenhouse gas emissions from peatlands drained for agriculture could be greatly reduced without necessarily halting their productive use. Halving WTDe in all drained agricultural peatlands, for example, could reduce emissions by the equivalent of over 1 per cent of global anthropogenic emissions.

Time-of-day and days-on-shift predict increased fatigue over two-week offshore day-shifts.

OBJECTIVES: The purpose of this study was to investigate the accumulation of fatigue over a two-week offshore period. In particular, the effects of (1) time-of-day and days-on-shift as well as (2) acute and chronic sleep loss on the rate at which fatigue accumulates were investigated. METHODS: 42 day-shift offshore workers were examined. Fatigue was measured using pre- and post-shift scores on the Karolinska Sleepiness Scale (KSS). Total sleep time was measured using actigraphy (Motionwatch8, Camntech). Data was analyzed using a linear mixed model analyses. RESULTS: Average sleep loss per night was 92 min (95%CI: 89.6-94.0; p < .001). Mean cumulative sleep loss across the study was 21:20hrs (SD = 08:10hrs) over the 14 days. Chronic sleep loss was significantly related to a modest increase in sleepiness (KSS) across the shift (95%CI: 0.01-0.17; p = .020) and in post-shift scores (95%CI:.07-0.19; p < .001). Time-of-day (95%CI: 0.63 to -0.01; p = .042) and days-on-shift (95%CI: 0.03-0.08; p < .001) as well as their interaction (95%CI: 0.08 to -0.00; p = .027) influenced the rate at which fatigue accumulated over a two-week offshore period. CONCLUSIONS: Pre- and post-shift fatigue accumulate in different ways over the two-week offshore period. The accumulation of post-shift fatigue scores was positively related to successive days-on-shift and chronic sleep loss. Our results suggest that prolonging offshore periods will likely result in elevated fatigue risk. Accumulating fatigue and sleep loss over two-week offshore periods should be considered in fatigue risk management plans and systems.

ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells.

L-selectin on T-cells is best known as an adhesion molecule that supports recruitment of blood-borne naïve and central memory cells into lymph nodes. Proteolytic shedding of the ectodomain is thought to redirect activated T-cells from lymph nodes to sites of infection. However, we have shown that activated T-cells re-express L-selectin before lymph node egress and use L-selectin to locate to virus-infected tissues. Therefore, we considered other roles for L-selectin proteolysis during T cell activation. In this study, we used T cells expressing cleavable or non-cleavable L-selectin and determined the impact of L-selectin proteolysis on T cell activation in virus-infected mice. We confirm an essential and non-redundant role for ADAM17 in TCR-induced proteolysis of L-selectin in mouse and human T cells and show that L-selectin cleavage does not regulate T cell activation measured by CD69 or TCR internalisation. Following virus infection of mice, L-selectin proteolysis promoted early clonal expansion of cytotoxic T cells resulting in an 8-fold increase over T cells unable to cleave L-selectin. T cells unable to cleave L-selectin showed delayed proliferation in vitro which correlated with lower CD25 expression. Based on these results, we propose that ADAM17-dependent proteolysis of L-selectin should be considered a regulator of T-cell activation at sites of immune activity.

Advancing Risk-Informed Decision Making in Managing Defense Nuclear Waste in the United States: Opportunities and Challenges for Risk Analysis.

An omnibus spending bill in 2014 directed the Department of Energy to analyze how effectively Department of Energy (DOE) identifies, programs, and executes its plans to address public health and safety risks that remain as part of DOE's remaining environmental cleanup liabilities. A committee identified two dozen issues and associated recommendations for the DOE, other federal agencies, and the U.S. Congress to consider, as well as other stakeholders such as states and tribal nations. In regard to risk assessment, the committee described a risk review process that uses available data, expert experience, identifies major data gaps, permits input from key stakeholders, and creates an ordered set of risks based on what is known. Probabilistic risk assessments could be a follow-up from these risk reviews. In regard to risk management, the states, in particular, have become major drivers of how resources are driven. States use different laws, different priorities, and challenge DOE's policies in different ways. Land use decisions vary, technology choices are different, and other notable variations are apparent. The cost differences associated with these differences are marked. The net result is that resources do not necessarily go to the most prominent human health and safety risks, as seen from the national level.

Age and Ageing to introduce a new category of paper: healthcare improvement science.

Age and Ageing is now inviting papers on healthcare improvement for older people. In this article we outline the nature and scope of healthcare improvement and reference improvement models and the tools and methods of improvement science. We emphasise the issues of sustainability, including scale and spread; evaluation - including associated ethical consideration and the involvement of patients and the public in healthcare improvement and associated research. Throughout we refer to resources the authors have found useful in their own work, and provide a bibliography of sources and web-links which will provide essential guidance and support for potential contributors to this new category of submission to Age and Ageing.

Utility of 18F sodium fluoride PET/CT imaging in the evaluation of postoperative pain following surgical spine fusion.

STUDY DESIGN: A retrospective case review of patients who underwent 18F sodium fluoride PET/CT imaging of the spine with postoperative pain following vertebral fusion. OBJECTIVE: To determine the benefit of 18F sodium fluoride PET/CT imaging in the diagnosis of persistent pain in the postoperative spine. The diagnosis of pain generators in the postoperative spine has proven to be a diagnostic challenge. The conventional radiologic evaluation of persistent pain after spine surgery with the use of plain radiographs, MRI, and CT can often fall short of diagnosis in the complex patient. 18F sodium fluoride PET/CT imaging is an alternative tool to accurately identify a patient's source of pain in the difficult patient. METHODS: This retrospective study looked at 25 adult patients who had undergone 18F sodium fluoride PET/CT imaging. All patients had persistent or recurrent back pain over the course of a 15-month period after having undergone spinal fusion surgery. All patients had inconclusive dedicated MRI. The clinical accuracy of PET/CT in identifying the pain generator and contribution to altering the decision making process was compared to the use of CT scan alone. RESULTS: Of the 25 patients studied, 17 patients had increased uptake on the 18F sodium fluoride PET/CT fusion images. There was a high-level correlation of radiotracer uptake to the patients' pain generator. Overall 88% of the studies were considered beneficial with either PET/CT altering the clinical diagnosis and treatment plan of the patient or confirming unnecessary surgery. CONCLUSION: 18F sodium fluoride PET/CT proves to be a useful tool in the diagnosis of complex spine pathology of the postoperative patients. In varied cases, a high correlation of metabolic activity to the source of the patient's pain was observed.

Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.

STUDY QUESTION: What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? SUMMARY ANSWER: UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. WHAT IS KNOWN ALREADY: Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking. STUDY DESIGN SIZE, DURATION: Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9-12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38-52 with fibroids were derived from institutional tissue archives. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. MAIN RESULTS AND THE ROLE OF CHANCE: UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding. STUDY FUNDING/COMPETING INTEREST(S): H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.

Purity of transferred CD8(+) T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP-1.

Adoptive transfer of tumor-specific cytotoxic T cells is a promising advance in cancer therapy. Similarly, checkpoint inhibition has shown striking clinical results in some patients. Here we combine adoptive cell transfer with ablation of the checkpoint protein Src homology 2-domain-containing phosphatase 1 (SHP-1, Ptpn6). Naturally occurring motheaten mice lack SHP-1 and do not survive weaning due to extensive immunopathology. To circumvent this limitation, we created a novel SHP-1(null) mouse that is viable up to 12 weeks of age by knocking out IL1r1. Using this model, we demonstrate that the absence of SHP-1 augments the ability of adoptively transferred CD8(+) T cells to control tumor growth. This therapeutic effect was only observed in situations where T-cell numbers were limited, analogous to clinical settings. However, adoptive transfer of non-CD8(+) SHP-1(null) hematopoietic cells resulted in lethal motheaten-like pathology, indicating that systemic inhibition of SHP-1 could have serious adverse effects. Despite this caveat, our findings support the development of SHP-1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic.

The relationship between general health and lifestyle factors and oral health outcomes.

Aim The primary research question addressed in this paper was 'are lower than average oral health scores observed for those patients who report problems with general health and high-risk lifestyle factors?'Methods A population analysis was conducted on the first 37,330 patients, assessed by 493 dentists in the UK, to receive a Denplan PreViser Patient Assessment (DEPPA) at their dental practice. The Oral Health Score (OHS) was generated using a mixture of patient-reported factors and clinical findings and is an integrated component of DEPPA. Patients' self-reported risk factors included diabetes status, tobacco use and alcohol consumption. Patients' general health was measured by self-report, that is, a yes/no answer to the question 'have you experienced any major health problems in the last year for example a stroke, heart attack or cancer?' Multivariable linear regression analysis was employed to study the association between the OHS and general health and risk factors for patients in the DEPPA cohort.Results The mean age of participants was 54 years (range 17-101; S.D. 16 years) and the mean OHS for the group was 78.4 (range 0-100; S.D. 10). 1,255 (3%) of patients reported experiencing a major health problem in the previous year. In the fully adjusted model, diabetes, tobacco use, excessive alcohol consumption (three or more drinks per day), and poor overall health in the preceding year were all associated with a statistically significant drop in the mean OHS of patients. Having diabetes was associated with a 1.7 point (95% CI 1.3-2.1, P <0.001) drop in OHS, tobacco use was associated with a 2.7 point (95% CI 2.5-2.9, P <0.001) drop in OHS, and excessive alcohol consumption was associated with a 1.8 point (95% CI 1.3-2.4, P <0.001) drop in OHS. The mean OHS in patients who reported a major health problem in the preceding year was 0.7 points (95% CI 0.2-1.2, P = 0.006) lower than that of patients who did not report a major health problem in the preceding year.Conclusion The current study has demonstrated that patient reported general health and risk factors were negatively associated with an overall composite oral health score outcome in a large population of over 37,000 patients examined by 493 dentists. While the clinical significance of some of the reported associations is unknown, the data lend support to the growing body of evidence linking the oral and systemic health of individuals. Therefore, GDPs may be in a unique position to influence the lifestyle and general health of patients as part of their specific remit to attain and maintain optimal oral health.

Reorganization of Synaptic Connections and Perineuronal Nets in the Deep Cerebellar Nuclei of Purkinje Cell Degeneration Mutant Mice.

The perineuronal net (PN) is a subtype of extracellular matrix appearing as a net-like structure around distinct neurons throughout the whole CNS. PNs surround the soma, proximal dendrites, and the axonal initial segment embedding synaptic terminals on the neuronal surface. Different functions of the PNs are suggested which include support of synaptic stabilization, inhibition of axonal sprouting, and control of neuronal plasticity. A number of studies provide evidence that removing PNs or PN-components results in renewed neurite growth and synaptogenesis. In a mouse model for Purkinje cell degeneration, we examined the effect of deafferentation on synaptic remodeling and modulation of PNs in the deep cerebellar nuclei. We found reduced GABAergic, enhanced glutamatergic innervations at PN-associated neurons, and altered expression of the PN-components brevican and hapln4. These data refer to a direct interaction between ECM and synapses. The altered brevican expression induced by activated astrocytes could be required for an adequate regeneration by promoting neurite growth and synaptogenesis.

Long-term validity and reliability of a patient survey instrument designed for general dental practice.

AIM: To consider the extent to which the validity and reliability of the Denplan Excel Patient Survey (DEPS) has been confirmed during its development and by its use in general dental practice and to explore methods by which any survey instrument used in general dental practice might be validated and tested for reliability. METHODS: DEPS seeks to measure perceived practice performance on those issues considered to be of greatest importance to patients. Content validity was developed by a literature review and tested in a pilot study. Criterion validity was tested by comparing patient retention in a payment plan for practices achieving the highest DEPS scores with those attaining the lowest scores over a two year period (surveys completed between 2010 and 2012). Reliability was assessed using the test/re-test method for 23 practices with approximately a three year time interval between tests. Internal consistency was tested by comparing Net Promoter Scores (NPS - which is measured in DEPS) attained by practices with their Patient Perception Index (PPI) as measured by the ten core questions in DEPS. RESULTS: Practices in the pilot study strongly endorsed the content validity of DEPS. The 12 practices with the highest scores in the DEPS slightly increased their number of patients registered in Denplan payment plans during a two year period. The 12 lowest scoring practices saw 7% of their patients de-register during the same period. The 23 practices selected for the test/re-test study averaged more than 250 responses for both the test and re-test phases. The magnitude and pattern of their results were similar in both phases, while, on average, a modest improvement in results was observed. Internal consistency was confirmed as NPS results in DEPS closely mapped PPI results. The higher the measurement of perceived quality (PPI) the more likely patients were to recommend the practice (NPS). CONCLUSION: Both through its development and use over the last four years The DEPS has demonstrated good validity and reliability. The authors conclude that this level of validity and reliability is adequate for the clinical/general care audit purpose of DEPS and that it is therefore likely to reliably inform practices where further development are indicated. It is important and quite straightforward to both validate and check the reliability of patient surveys used in general dental practice so that dental teams can be confident in the instrument they are using.

Is any particular aspect of perceived quality associated with patients tending to promote a dental practice to their friends and colleagues?

AIMS: To investigate the relationship between perceived quality and patients' tendencies to recommend a practice to friends and colleagues. METHODS: Data from 64 practices using the Denplan Excel Patient Survey (DEPS) were analysed. The Net Promoter Score (NPS max score 100), developed by Reichheld, is reported to each practice using DEPS. It is claimed that the NPS measures the likelihood that patients will recommend the practice to friends and colleagues. A Patient Perception Index (PPI max score 100) is also reported to practices. The PPI is calculated from the responses to the ten core questions of DEPS on perceived quality. The 64 practices were placed into three groups for data analysis according to their NPS result: group one practices receiving an NPS of less than 80, group two practices receiving an NPS of 80-89 and group three practices receiving an NPS of greater than 89. These groups represented practices scoring statistically significantly (to 90% confidence) below the mean NPS (group one), practices close to the mean NPS (group two) and practices statistically significantly (to 90% confidence) above the mean NPS. RESULTS: Group one practices scored a mean PPI of 73, group two scored a mean PPI of 76 and group three a mean PPI of 80. These differences in values of PPI between the groups are statistically significant (to 90% confidence). Of the ten constituent issues which contribute to PPI, the greatest difference in scoring between group one and group three was found to be around perceived value for money. CONCLUSION: The probability of patients recommending a dental practice seems to rise in direct proportion to favourable perceptions of quality. A perception of 'ideal' value for money is the most highly correlated aspect with a high NPS.