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The Challenge of Assessing Treatment Effectiveness in a Real-World Setting
Real-world data derived from observational studies, particularly from administrative health care and insurance claims databases, are increasingly being used to evaluate treatment effectiveness. To control for potential biases, a number of analytical techniques have been developed. However, the procedures used can be far from intuitive, and this along with other methodological issues can make it challenging to assess whether reported results are real or artefactual. This commentary summarizes some of the issues associated with evaluating treatment effectiveness in the real-world setting, at the same time highlighting the important role observational studies can play.
Journal Article
Incurable but treatable: Understanding, uncertainty and impact in chronic blood cancers—A qualitative study from the UK’s Haematological Malignancy Research Network
Most blood cancers are incurable and typically follow unpredictable remitting-relapsing pathways associated with varying need for treatment, which may be distressing for patients. Our objective was to conduct a qualitative study to explore understanding among patients with such malignancies, including the explanations given by HCPs and the impact of uncertain trajectories, to generate evidence that could guide improvements in clinical practice.
The study is set within a population-based patient cohort (the Haematological Malignancy Research Network), in which care is delivered across 14 hospitals according to national guidelines. In-depth interviews were conducted with 35 patients with chronic lymphocytic leukaemia, follicular lymphoma, marginal zone lymphoma or myeloma; and 10 accompanying relatives. Purposive sampling ensured selection of information-rich participants and the data were interrogated using reflective thematic analysis.
Rich data were collected and four themes (11 sub-themes) were identified: 1) Knowledge and understanding of chronic haematological malignancies; 2) Incurable but treatable; 3) Uncertainty about the future; and 4) Treatable (but still incurable): Impact on patients. Patients had rarely heard of blood cancer and many expressed difficulty understanding how an incurable malignancy that could not be removed, was treatable, often for long periods. While some were reassured that their cancer did not pose an immediate survival threat, others were particularly traumatised by the uncertain future it entailed, suffering ongoing emotional distress as a result, which could be more burdensome than any physical symptoms. Nonetheless, most interviewees understood that uncertain pathways were caused by the unpredictability of their disease trajectory, and not information being withheld.
Many participants lacked knowledge about chronic haematological malignancies. HCPs acted to reassure patients about their diagnosis, and while this was appropriate and effective for some, it was less so for others, as the cancer-impact involved struggling to cope with ongoing uncertainty, distress and a shortened life-span.
Journal Article
The effects of dopamine receptor 1 and 2 agonists and antagonists on sexual and aggressive behaviors in male green anoles
The propensity to exhibit social behaviors during interactions with same-sex and opposite-sex conspecifics is modulated by various neurotransmitters, including dopamine. Dopamine is a conserved neurotransmitter among vertebrates and dopaminergic receptors are also highly conserved among taxa. Activation of D1 and D2 dopamine receptor subtypes has been shown to modulate social behaviors, especially in mammalian and avian studies. However, the specific behavioral functions of these receptors vary across taxa. In reptiles there have been few studies examining the relationship between dopaminergic receptors and social behaviors. We therefore examined the effects of D1 and D2 agonists and antagonists on sexual and aggressive behaviors in the male green anole lizard (Anolis carolinensis). Treatment with high doses of both D1 and D2 agonists was found to impair both sexual and aggressive behaviors. However, the D1 agonist treatment was also found to impair motor function, suggesting that those effects were likely nonspecific. Lower doses of both agonists and antagonists failed to affect social behaviors. These findings provide some evidence for D2 receptor regulation of social behaviors, but in contrast with previous research, these effects are all inhibitory and no effects were found for manipulations of D1 receptors. A potential reason for the lack of more widespread effects on social behaviors using moderate or low drug doses is that systemic injection of drugs resulted in effects throughout the whole brain, thus affecting counteracting circuits which negated one another, making measurable changes in behavioral output difficult to detect. Future studies should administer drugs directly into brain regions known to regulate sexual and aggressive behaviors.
Journal Article
Indigenous health part 2: the underlying causes of the health gap
In this Review we delve into the underlying causes of health disparities between Indigenous and non-Indigenous people and provide an Indigenous perspective to understanding these inequalities. We are able to present only a snapshot of the many research publications about Indigenous health. Our aim is to provide clinicians with a framework to better understand such matters. Applying this lens, placed in context for each patient, will promote more culturally appropriate ways to interact with, to assess, and to treat Indigenous peoples. The topics covered include Indigenous notions of health and identity; mental health and addictions; urbanisation and environmental stresses; whole health and healing; and reconciliation.
Journal Article
IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth
Vessel loss precipitates many diseases. In particular, vessel loss resulting in hypoxia induces retinal neovascularization in diabetic retinopathy and in retinopathy of prematurity (ROP), major causes of blindness. Here we define insulin-like growth factor binding protein-3 (IGFBP3) as a new modulator of vascular survival and regrowth in oxygen-induced retinopathy. In IGFBP3-deficient mice, there was a dose-dependent increase in oxygen-induced retinal vessel loss. Subsequent to oxygen-induced retinal vessel loss, Igfbp3⁻/⁻ mice had a 31% decrease in retinal vessel regrowth versus controls after returning to room air. No difference in serum insulin-like growth factor 1 (IGF1) levels was observed among groups. Wild-type mice treated with exogenous IGFBP3 had a significant increase in vessel regrowth. This correlated with a 30% increase in endothelial progenitor cells in the retina at postnatal day 15, indicating that IGFBP3 could be serving as a progenitor cell chemoattractant. In a prospective clinical study, we measured IGFBP3 (and IGF1) plasma levels weekly and examined retinas in all premature infants born at gestational ages <32 weeks at high risk for ROP. The mean level of IGFBP3 at 30-35 weeks postmenstrual age (PMA) for infants with proliferative ROP (ROP stages 3>, n = 13) was 802 μg/liter, and for infants with no ROP (ROP stage 0, n = 38) the mean level was 974 μg/liter (P < 0.03). These results suggest that IGFBP3, acting independently of IGF1, helps to prevent oxygen-induced vessel loss and to promote vascular regrowth after vascular destruction in vivo in a dose-dependent manner, resulting in less retinal neovascularization.
Journal Article
“You Have to be Resilient”: A Qualitative Study Exploring Advice Newcomer Youth Have for Other Newcomer Youth
Research infrequently includes the perspectives of vulnerable and marginalized youth. As the population of newcomer youth in Canada continues to grow, it is imperative that attention is devoted not only to challenges they experience, but also to resilience factors they perceive to support their adjustment and well-being. To address this gap, this qualitative research explored newcomer youths’ experiences and advice for other newcomer youth who have recently arrived in Canada. Thirty-seven newcomer youth from two medium-sized cities in Ontario participated in focus groups. Participants ranged from 14 to 22 in age and identified mostly as female refugees from the Middle East. Through thematic analysis, five overarching themes were found across groups: (1) moving to a new country is hard, (2) maintain a healthy mindset, (3) take an active role in the adjustment process, (4) stay true to who you are, (5) and you are not alone. Youth described hardships that make moving to a new country difficult including lack of belonging due to racism and bullying, insufficient orientation to new systems, language barriers, and high levels of stress. Findings demonstrated youths’ resilience, coping skills, and strategies to lead meaningful lives. Youth discussed resilience strategies such as maintaining a connection with home culture and religion, reframing thinking to be positive, receiving emotional support, accessing community support at newcomer agencies, and building language proficiency. Findings provide implications for professionals working with newcomer youth and reflect the importance of addressing structural barriers and racism. The opportunity for newcomer youth to share experiences as experts in research may also help to promote resilience.
Journal Article
Myeloma: Patient accounts of their pathways to diagnosis
Pathways to myeloma diagnosis can be prolonged, and are often preceded by multiple GP consultations and emergency presentation. This is the first qualitative study to examine events leading to diagnosis by asking patients about their experiences during this time.
Set within a UK population-based cohort, semi-structured interviews were conducted with 20 myeloma patients with varying characteristics and pathways, 12 of whom invited their relatives to take part. Interviews were audio-recorded and qualitative analysis undertaken.
Pre-diagnostic awareness of myeloma was minimal. Disease onset was typically described as gradual, and health changes vague but progressive, with increasing loss of function. A wide range of symptoms was reported, with the similarity of these to self-limiting conditions failing to raise suspicion of myeloma among patients and GPs. Patients tended to normalise symptoms at first, although all eventually sought GP advice. GPs often initially suggested benign diagnoses, which were sometimes only revised after multiple consultations with persistent/worsening symptoms. Referrals were made to various hospital specialities, and haematology if associated with abnormal blood tests suggestive of myeloma. Once in secondary care, progress towards diagnosis was generally rapid.
Accounts confirmed that pathways to diagnosis could be difficult, largely due to the way myeloma presents, and how symptoms are interpreted and managed by patients and GPs. Recognition of 'normal' health and consultation patterns for the individual could promote appropriate help-seeking and timely referral when changes occur, and may be more effective than raising awareness about the myriad of potential symptoms associated with this disease.
Journal Article
Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice
Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krev1 interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Krit1. PDCD10 bound to germinal center kinase III (GCKIII) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcd10 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity.
Journal Article
Nucleoporin TPR is an integral component of the TREX-2 mRNA export pathway
Nuclear pore complexes (NPCs) are important for cellular functions beyond nucleocytoplasmic trafficking, including genome organization and gene expression. This multi-faceted nature and the slow turnover of NPC components complicates investigations of how individual nucleoporins act in these diverse processes. To address this question, we apply an
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uxin-
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nduced
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egron (AID) system to distinguish roles of basket nucleoporins NUP153, NUP50 and TPR. Acute depletion of TPR causes rapid and pronounced changes in transcriptomic profiles. These changes are dissimilar to shifts observed after loss of NUP153 or NUP50, but closely related to changes caused by depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. Moreover, TPR depletion disrupts association of TREX-2 subunits (GANP, PCID2, ENY2) to NPCs and results in abnormal RNA transcription and export. Our findings demonstrate a unique and pivotal role of TPR in gene expression through TREX-2- and/or NXF1-dependent mRNA turnover.
mRNAs export from the nucleus is thought to be regulated in part by three nucleoporins that comprise the nuclear basket, but whether and how distinct basket nucleoporins interact with the RNA export machinery is unclear. Here, the authors use rapid auxin-mediated degradation of basket nucleoporins Nup153, Nup50, and Tpr, and see that Tpr interacts with the TREX-2 mRNA export complex.
Journal Article