lbrutinib (lmbruvica™) for Treatment of Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare and moderately aggressive form of non-Hodgkin\u27s lymphoma (NHL) that predominantly presents at an advanced stage in older males. Patients often present with multiple involvement in the lymph nodes, blood, spleen, bone marrow and gastrointestinal tract (GIT). Some patients may be asymptomatic in early stages or present with an incurable, indolent (slow progressing) form, while other patients display rapid growth of more aggressive lymphomas. Overall survival for patients diagnosed with MCL is four to five years and treatment should be initiated in those who are symptomatic. Mantle cell lymphoma responds well to first-line treatment, but recurrent relapses are common, and no regimen has been proven superior for relapsed or refractory MCL. The U.S. Food and Drug Administration (FDA) has recently approved ibrutinib (lmbruvica™) as breakthrough MCL therapy. lbrutinib is a Bruton\u27s tyrosine kinase (BTK) inhibitor that interferes with malignant B-cell proliferation and survival. In a recent clinical study, ibrutinib proved to be a highly active monotherapy with a favorable toxicity profile in 111 patients with relapsed or refractory MCL. As an oral chemotherapy drug, ibrutinib has the potential to improve patient compliance. Additionally, specialty pharmacies dispensing ibrutinib will be able to play an important role in patient counseling and monitoring

Beware Zombies and Unicorns: Toward critical patient and public involvement in health research in a neoliberal context

Patient and Public Involvement (PPI) in UK National Health Service (NHS) research has become an imperative in policy and practice. However, lack of clarity on what PPI is (or might be) has given rise to a poorly monitored, complex field of activity, variously framed by the expectations of policy makers, funders, host organisations, researchers, health professionals, individual recruits, volunteers, activists and third sector organisations. The normative shift towards PPI has taken place within a neoliberal policy context, the implications of which needs to be explicitly considered, particularly after the Brexit referendum which has left policy makers and researchers wondering how to better appeal to a distrustful public subjected to ‘post-truth’ and ‘dog whistle’ politics. This commentary examines the prospects for a more critical approach to PPI which addresses context, is evidence-informed and mindful of persistent inequalities in health outcomes, at a time when models of PPI in NHS health research tend to be conceptually vague, derived from limited clinical and managerial settings, and centred on a construction of the abstract, rational, compliant and self-managing patient or lay-person

Sustained Immune Complex-Mediated Reduction in CD16 Expression after Vaccination Regulates NK Cell Function

Cross-linking of FcγRIII (CD16) by immune complexes induces antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, contributing to control of intracellular pathogens; this pathway can also be targeted for immunotherapy of cancerous or otherwise diseased cells. However, downregulation of CD16 expression on activated NK cells may limit or regulate this response. Here, we report sustained downregulation of CD16 expression on NK cells in vivo after intramuscular (but not intranasal) influenza vaccination. CD16 downregulation persisted for at least 12 weeks after vaccination and was associated with robust enhancement of influenza-specific plasma antibodies after intramuscular (but not intranasal) vaccination. This effect could be emulated in vitro by co-culture of NK cells with influenza antigen and immune serum and, consistent with the sustained effects after vaccination, only very limited recovery of CD16 expression was observed during long-term in vitro culture of immune complex-treated cells. CD16 downregulation was most marked among normally CD16high CD57+ NK cells, irrespective of NKG2C expression, and was strongly positively associated with degranulation (surface CD107a expression). CD16 downregulation was partially reversed by inhibition of ADAM17 matrix metalloprotease, leading to a sustained increase in both CD107a and CD25 (IL-2Rα) expression. Both the degranulation and CD25 responses of CD57+ NK cells were uniquely dependent on trivalent influenza vaccine-specific IgG. These data support a role for CD16 in early activation of NK cells after vaccination and for CD16 downregulation as a means to modulate NK cell responses and maintain immune homeostasis of both antibody and T cell-dependent pathways

The pulsating hot subdwarf Balloon 090100001: results of the 2005 multisite campaign

We present the results of a multisite photometric campaign on the pulsating sdB star Balloon 090100001. The star is one of the two known hybrid hot subdwarfs with both long- and short-period oscillations. The campaign involved eight telescopes with three obtaining UBVR data, four B-band data, and one Stromgren uvby photometry. The campaign covered 48 nights, providing a temporal resolution of 0.36microHz with a detection threshold of about 0.2mmag in B-filter data. Balloon 090100001 has the richest pulsation spectrum of any known pulsating subdwarf B star and our analysis detected 114 frequencies including 97 independent and 17 combination ones. The strongest mode (f_1) in the 2.8mHz region is most likely radial while the remaining ones in this region form two nearly symmetric multiplets: a triplet and quintuplet, attributed to rotationally split \ell=1 and 2 modes, respectively. We find clear increases of splitting in both multiplets between the 2004 and 2005 observing campaigns, amounting to 15% on average. The observed splittings imply that the rotational rate in Bal09 depends on stellar latitude and is the fastest on the equator. We use a small grid of models to constrain the main mode (f_1), which most likely represents the radial fundamental pulsation. The groups of p-mode frequencies appear to lie in the vicinity of consecutive radial overtones, up to the third one. Despite the large number of g-mode frequencies observed, we failed to identify them, most likely because of the disruption of asymptotic behaviour by mode trapping. The observed frequencies were not, however, fully exploited in terms of seismic analysis which should be done in the future with a larger grid of reliable evolutionary models of hot subdwarfs.Comment: accepted for publication in MNRA

Barriers to primary care responsiveness to poverty as a risk factor for health

<p>Abstract</p> <p>Background</p> <p>Poverty is widely recognized as a major determinant of poor health, and this link has been extensively studied and verified. Despite the strong evidentiary link, little work has been done to determine what primary care health providers can do to address their patients' income as a risk to their health. This qualitative study explores the barriers to primary care responsiveness to poverty as a health issue in a well-resourced jurisdiction with near-universal health care insurance coverage.</p> <p>Methods</p> <p>One to one interviews were conducted with twelve experts on poverty and health in primary care in Ontario, Canada. Participants included family physicians, specialist physicians, nurse practitioners, community workers, advocates, policy experts and researchers. The interviews were analysed for anticipated and emergent themes.</p> <p>Results</p> <p>This study reveals provider- and patient-centred structural, attitudinal, and knowledge-based barriers to addressing poverty as a risk to health. While many of its findings reinforce previous work in this area, this study's findings point to a number of areas front line primary care providers could target to address their patients' poverty. These include a lack of provider understanding of the lived reality of poverty, leading to a failure to collect adequate data about patients' social circumstances, and to the development of inappropriate care plans. Participants also pointed to prejudicial attitudes among providers, a failure of primary care disciplines to incorporate approaches to poverty as a standard of care, and a lack of knowledge of concrete steps providers can take to address patients' poverty.</p> <p>Conclusions</p> <p>While this study reinforces, in a well-resourced jurisdiction such as Ontario, the previously reported existence of significant barriers to addressing income as a health issue within primary care, the findings point to the possibility of front line primary care providers taking direct steps to address the health risks posed by poverty. The consistent direction and replicability of these findings point to a refocusing of the research agenda toward an examination of interventions to decrease the health impacts of poverty.</p

Asteroseismology of the Beta Cephei star 12 (DD) Lacertae: photometric observations, pulsational frequency analysis and mode identification

We report a multisite photometric campaign for the Beta Cephei star 12 Lacertae. 750 hours of high-quality differential photoelectric Stromgren, Johnson and Geneva time-series photometry were obtained with 9 telescopes during 190 nights. Our frequency analysis results in the detection of 23 sinusoidal signals in the light curves. Eleven of those correspond to independent pulsation modes, and the remainder are combination frequencies. We find some slow aperiodic variability such as that seemingly present in several Beta Cephei stars. We perform mode identification from our colour photometry, derive the spherical degree l for the five strongest modes unambiguously and provide constraints on l for the weaker modes. We find a mixture of modes of 0 <= l <= 4. In particular, we prove that the previously suspected rotationally split triplet within the modes of 12 Lac consists of modes of different l; their equal frequency splitting must thus be accidental. One of the periodic signals we detected in the light curves is argued to be a linearly stable mode excited to visible amplitude by nonlinear mode coupling via a 2:1 resonance. We also find a low-frequency signal in the light variations whose physical nature is unclear; it could be a parent or daughter mode resonantly coupled. The remaining combination frequencies are consistent with simple light-curve distortions. The range of excited pulsation frequencies of 12 Lac may be sufficiently large that it cannot be reproduced by standard models. We suspect that the star has a larger metal abundance in the pulsational driving zone, a hypothesis also capable of explaining the presence of Beta Cephei stars in the LMC.Comment: 12 pages, 7 figures, MNRAS, in pres

Developing a model of mental health self-care support for children and young people through an integrated evaluation of available types of provision involving systematic review, meta-analysis and case study

Background The mental health of children and young people (CYP) is a major UK public health concern. Recent policy reviews have identified that service provision for CYP with mental health needs is not as effective, responsive, accessible or child-centred as it could be. Following on from a previous National Institute for Health Research (NIHR) study into self-care support for CYP with long-term physical health needs, this study explored self-care support’s potential in CYP’s mental health. Objectives To identify and evaluate the types of mental health self-care support used by, and available to, CYP and their parents, and to establish how such support interfaces with statutory and non-statutory service provision. Design Two inter-related systematic literature reviews (an effectiveness review with meta-analysis and a perceptions review), together with a service mapping exercise and case study. Setting Global (systematic reviews); England and Wales (mapping exercise and case study). Participants (case study) Fifty-two individuals (17 CYP, 16 family members and 19 staff) were interviewed across six sites. Main outcome measures (meta-analysis) A measure of CYP’s mental health symptomatology. Data sources (literature reviews) MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, All Evidence-Based Medicine (EBM) Reviews, Applied Social Sciences Index and Abstracts (ASSIA) and Education Resources Information Center (ERIC). Review methods Titles and abstracts of papers were screened for relevance then grouped into studies. Two independent reviewers extracted data from studies meeting the inclusion criteria. A descriptive analysis and meta-analysis were conducted for the effectiveness review; descriptive analyses were conducted for the perceptions review. These analyses were integrated to elicit a mixed-methods review. Results Sixty-five of 71 included studies were meta-analysable. These 65 studies elicited 71 comparisons which, when meta-analysed, suggested that self-care support interventions were effective at 6-month [standardised mean difference (SMD) = −0.20; 95% confidence interval (CI) −0.28 to −0.11] and 12-month (SMD = −0.12; 95% CI −0.17 to −0.06) follow-ups. However, judged against Cochrane criteria, the studies were mostly low quality. Key elements of self-care support identified in the perceptions review were the acquisition of knowledge and skills, peer support and the relationship with the self-care support agent; CYP also had different perceptions from adults about what is important in self-care support. The mapping exercise identified 27 providers of 33 self-care support services. According to the case study data, effective self-care support services are predicated on flexibility; straightforward access; non-judgemental, welcoming organisations and staff; the provision of time and attention; opportunities to learn and practise skills relevant to self-care; and systems of peer support. Conclusions Mental health self-care support interventions for CYP are modestly effective in the short to medium term. Self-care support can be conceptualised as a process which has overlap with ‘recovery’. CYP and their families want choice and flexibility in the provision of such interventions and a continued relationship with services after the nominal therapy period. Those delivering self-care support need to have specific child-centred attributes. Future work Future work should focus on under-represented conditions (e.g. psychosis, eating disorders, self-harm); the role of technology, leadership and readiness in self-care support; satisfaction in self-care support; the conceptualisation of self-care support in CYP’s mental health; and efficacy and cost-effectiveness

HIV research in Australia: linking basic research findings with clinical and public health outcomes

Despite a population of only 20 million and sustained low prevalence of HIV infection in Australia, Australian researchers have provided many substantial original findings to the fields of HIV pathogenesis, treatment and prevention. More recently, Australian clinicians and scientists have turned their attention to assisting other countries in developing effective responses, particularly within the Asia-Pacific region. It is therefore fitting that the 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention will be held in Sydney in July 2007. The meeting is expected to attract over 5000 participants and will have a dynamic and innovative programme within the three major themes of HIV basic science, clinical research and biomedical prevention