Structural violence and necropolitics among Indigenous Peoples living with HIV who use substances in the Prairie provinces during COVID-19.

BACKGROUND: Within Manitoba and Saskatchewan, pre-existing health inequities amongst Indigenous groups were intensified during the COVID-19 pandemic. Service disruptions in the health and social service sector-combined with the effects of intersectional stigma-disproportionately impacted Indigenous peoples living with HIV (IPLH). IPLH experience structural violence and necropolitical exclusion through systemic forms of stigma situated within Canada's expansive colonial history. Utilizing the theoretical foundations of structural violence and necropolitics, this qualitative study examines how the COVID-19 pandemic amplified preceding states of inequity for IPLH. METHODS: Semi-structured interviews were conducted with 60 participants. The sample comprised of those with lived experience (n = 45) as well as those who provided services for IPLH (n = 15). Indigenous Storywork guided the data collection and analysis process. Topics explored within each interview included access to health and social services, harm reduction, substance use, and experiences in providing services during COVID-19 pandemic. Thematic analysis was used to identify common themes throughout each story. RESULTS: Our results indicate that the COVID-19 pandemic exposed and amplified pre-existing forms of structural violence and necropolitical logics for IPLH within Manitoba and Saskatchewan. Specifically, we describe how structural violence and necropolitics are manifested via three main avenues- (i) restrictions and removal of care, (ii) bureaucracy and institutional care politics, and (iii) discrimination and systemic racism within the Canadian healthcare system. CONCLUSION: The COVID-19 pandemic within Manitoba and Saskatchewan sparked massive changes in service provision within settler-colonial and neoliberal institutions of care. For those services that remained open to IPLH, masking requirements, questionnaire requirements, scheduling requirements, and a lack of in-person services acted as only some of the barriers described by community members as detrimental to care access. Increased experiences of discrimination in health care on the basis of substance use or HIV status further limited access to needed services.

A phenome-wide approach to identify causal risk factors for deep vein thrombosis.

Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index-BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.

"The thing I'm missing the most is just being around other queer people": critical analysis of the impacts of the COVID-19 pandemic on mental health of two-spirit, gay, bisexual, and queer men's communities in Manitoba, Canada.

BACKGROUND: The purpose of this community-based study was to create and advance knowledge on the social impacts of COVID-19 on mental health of Two-Spirit, gay, bisexual, and queer (2SGBQ+) cisgender and transgender men in Manitoba, Canada. METHODS: Participants (n = 20) from 2SGBQ + men's communities were recruited across Manitoba using printed flyers and social media. Individual interviews explored questions relating to the impacts of the COVID-19 pandemic on mental health, social isolation, and service access. Data were critically examined using thematic analysis and the social theory of biopolitics. RESULTS: Key themes focused on COVID-19 pandemic's negative impacts on 2SGBQ + men's mental health, loss of safe queer public spaces, and exacerbated inequities. During the COVID-19 pandemic in Manitoba, 2SGBQ + men experienced a profound loss of social connections, community spaces, and social networks which are specific to their socio-sexual identities, thereby intensifying pre-existing mental health disparities. These findings show how COVID-19 restrictions have come to reinforce the value of close personal communities, families of choice, and social networks among 2SGBQ + men in Manitoba, Canada. CONCLUSIONS: This study supports the line of research on minority stress, biosociality, and place by highlighting some potential links between 2SGBQ + men's mental health and their social and physical environments. This research points to important role of safe community spaces, events, and community organizations that support 2SGBQ + men's mental health.

High prevalence of vaccine-preventable anal human papillomavirus infections is associated with HIV infection among gay, bisexual, and men who have sex with men in Nairobi, Kenya.

BACKGROUND: Human papillomavirus (HPV) infection is associated with anal cancers and is more prevalent in gay, bisexual, and men who have sex with men (gbMSM), partly due to their vulnerability to HIV infection. Baseline HPV genotype distributions and risk factors can inform the design of next-generation HPV vaccines to prevent anal cancer. METHODS: A cross-sectional study was conducted among gbMSM receiving care at a HIV/STI clinic in Nairobi, Kenya. Anal swabs were genotyped using a Luminex microsphere array. Multiple logistic regression methods were used to identify risk factors for four HPV outcomes (any HPV, any HR-HPV, and 4- and 9-valent vaccine-preventable HPVs). RESULTS: Among 115 gbMSM, 51 (44.3%) were HIV-infected. Overall HPV prevalence was 51.3%; 84.3% among gbMSM living with HIV and 24.6% among gbMSM without HIV (p < 0.001). One-third (32.2%) had HR-HPV and the most prevalent vaccine-preventable HR-HPV genotypes were 16, 35, 45, and 58. HPV-18 was uncommon (n = 2). The 9-valent Gardasil vaccine would have prevented 61.0% of HPV types observed in this population. In multivariate analyses, HIV status was the only significant risk factor for any HPV (adjusted odds ratio [aOR]:23.0, 95% confidence interval [95% CI]: 7.3-86.0, p < 0.001) and for HR-HPV (aOR: 8.9, 95% CI: 2.8-36.0, p < 0.001). Similar findings were obtained for vaccine-preventable HPVs. Being married to a woman significantly increased the odds of having HR-HPV infections (aOR: 8.1, 95% CI: 1.6-52.0, p = 0.016). CONCLUSIONS: GbMSM living with HIV in Kenya are at higher risk of anal HPV infections including genotypes that are preventable with available vaccines. Our findings support the need for a targeted HPV vaccination campaign in this population.

Post-Concussion Symptoms, Cognition and Brain Connectivity in an Australian Undergraduate Population: A Quantitative Electroencephalography Study.

BACKGROUND: An estimated 99 in 100,000 people experience a traumatic brain injury (TBI), with 85% being mild (mTBI) in nature. The Post-Concussion Symptom Scale (PCSS), is a reliable and valid measure of post-mTBI symptoms; however, diagnostic specificity is challenging due to high symptom rates in the general population. Understanding the neurobiological characteristics that distinguish high and low PCSS raters may provide further clarification on this phenomenon. AIM: To explore the neurobiological characteristics of post-concussion symptoms through the association between PCSS scores, brain network connectivity (using quantitative electroencephalography; qEEG) and cognition in undergraduates. HYPOTHESES: high PCSS scorers will have (1) more network dysregulation and (2) more cognitive dysfunction compared to the low PCSS scorers. METHODS: A sample of 40 undergraduates were divided into high and low PCSS scorers. Brain connectivity was measured using qEEG, and cognition was measured via neuropsychological measures of sustained attention, inhibition, immediate attention, working memory, processing speed and inhibition/switching. RESULTS: Contrary to expectations, greater frontoparietal network dysregulation was seen in the low PCSS score group (p = 0.003). No significant difference in cognitive dysfunction was detected between high and low PCSS scorers. Post-hoc analysis in participants who had experienced mTBI revealed greater network dysregulation in those reporting a more recent mTBI. CONCLUSIONS: Measuring post-concussion symptoms alone is not necessarily informative about changes in underlying neural mechanisms. In an exploratory subset analysis, brain network dysregulation appears to be greater in the early post-injury phase compared to later. Further analysis of underlying PCSS constructs and how to measure these in a non-athlete population and clinical samples is warranted.

The precarity of mobile loan debt and repayment among female sex workers in Nairobi, Kenya: Implications for sexual health.

Financial technology tools have been utilised to create readily available mobile loan platforms for urban-based, daily-wage earners in Kenya. From a financial lending perspective, this development signals greater inclusion and equality in formal bank financing systems. In this paper, however, we examine mobile loans and their repayment from the perspective of women who sell sex in Nairobi, drawing upon the qualitative findings of two community-based studies conducted in close collaboration with sex worker-led organisations serving the sexual health needs of their peers. Our findings suggest that mobile loans may undermine the financial security strategies and economic independence of sex workers, leaving these women in more precarious economic circumstances, which have been shown in other instances to have effects on sexual risk taking and vulnerability to HIV infection.

Relationship between sociodemographics, loss of income, and mental health among two-spirit, gay, bisexual, and queer men in Manitoba during the COVID-19 pandemic.

This study examined the relationship between loss of income due to the COVID-19 pandemic and worsening mental health among a sample of 366 Two-Spirit, gay, bisexual, queer (2SGBQ+) men in Manitoba. Data were drawn from a cross-sectional online survey among 2SGBQ+ men in Manitoba. Logistic regression assessed the relationship between sociodemographics, loss of income due to COVID-19 (independent variable) and worsening of mental health (analytic outcome). Among all respondents in the sample (N = 366), 55% indicated worsening of their mental health. In logistic regression, compared to participants who did not experience any loss of income, those who experienced loss of income due to the COVID-19 pandemic were significantly more likely to report worsening mental health (Adjusted Odds Ratio [AOR] = 8.32, 95% Confidence Interval[CI] = 3.54-19.54). Compared to participants who self-identified as gay, bisexual-identifying participants were less likely to report worsening mental health (AOR = .35, 95%CI = 0.13-0.96). Finally, as compared to participants who were married or partnered, participants who were dating (AOR = 3.14, 95%CI = 1.60-6.17), single (AOR = 4.08, 95%CI = 1.75-9.52), and separated/divorced/widowed (AOR = 15.08, 95%CI = 2.22-102.51) were all significantly more likely to report experiencing a worsening of mental health due to the COVID-19 pandemic. This study highlights the need to develop robust public strategies for sub-populations of 2SGBQ+ men (non-gay identified sexual minorities and 2SGBQ+ men who may be more socially isolated). Specific targeted and tailored public health interventions designed with the unique needs of 2SGBQ+ men in Manitoba may be required to increase their access to socio-economic and mental health supports.

Cervical Lymphadenopathy and Airway Masses in a Child.

A previously healthy 12-year-old boy presented with a 3-month history of nasal obstruction, progressive dysphonia, recurrent deep neck abscesses, and tender, bulky cervical lymphadenopathy. What is your diagnosis?

Mllt11 Regulates Migration and Neurite Outgrowth of Cortical Projection Neurons during Development.

The formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. There are two types of cortical projection neurons (CPNs): those that project locally and interhemispherically and those that project to subcerebral structures such as the thalamus, hindbrain, and spinal cord. The regulation of cortical projection morphologies is not yet fully understood at the molecular level. Here, we report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during mouse brain formation. We show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate (CP) during the formation of the superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis we show that Mllt11 is required for neuritogenesis and proper migration of upper layer CPNs. Loss of Mllt11 in the superficial cortex of male and female neonates leads to a severe reduction in fibers crossing the corpus callosum (CC), a progressive loss in the maintenance of upper layer projection neuron gene expression, and reduced complexity of dendritic arborization. Proteomic analysis revealed that Mllt11 associates with stabilized microtubules, and Mllt11 loss affected microtubule staining in callosal axons. Taken together, our findings support a role for Mllt11 in promoting the formation of mature upper-layer neuron morphologies and connectivity in the cerebral cortex.SIGNIFICANCE STATEMENT The regulation of cortical projection neuron (CPN) morphologies is an area of active investigation since the time of Cajal. Yet the molecular mechanisms of how the complex dendritic and axonal morphologies of projection neurons are formed remains incompletely understood. Although conditional mutagenesis analysis in the mouse, coupled with overexpression assays in the developing fetal brain, we show that a novel protein called Mllt11 is sufficient and necessary to regulate the dendritic and axonal characteristics of callosal projection neurons in the developing mammalian neocortex. Furthermore, we show that Mllt11 interacts with microtubules, likely accounting for its role in neuritogenesis.

Core motifs predict dynamic attractors in combinatorial threshold-linear networks.

Combinatorial threshold-linear networks (CTLNs) are a special class of inhibition-dominated TLNs defined from directed graphs. Like more general TLNs, they display a wide variety of nonlinear dynamics including multistability, limit cycles, quasiperiodic attractors, and chaos. In prior work, we have developed a detailed mathematical theory relating stable and unstable fixed points of CTLNs to graph-theoretic properties of the underlying network. Here we find that a special type of fixed points, corresponding to core motifs, are predictive of both static and dynamic attractors. Moreover, the attractors can be found by choosing initial conditions that are small perturbations of these fixed points. This motivates us to hypothesize that dynamic attractors of a network correspond to unstable fixed points supported on core motifs. We tested this hypothesis on a large family of directed graphs of size n = 5, and found remarkable agreement. Furthermore, we discovered that core motifs with similar embeddings give rise to nearly identical attractors. This allowed us to classify attractors based on structurally-defined graph families. Our results suggest that graphical properties of the connectivity can be used to predict a network's complex repertoire of nonlinear dynamics.

Relationship between sociodemographics, healthcare providers' competence and healthcare access among two-spirit, gay, bisexual, queer and other men who have sex with men in Manitoba: results from a community-based cross-sectional study.

OBJECTIVE: Little is known about barriers to healthcare access for two-spirit, gay, bisexual and queer (2SGBQ+) men in Manitoba. DESIGN: Data were drawn from a community-based, cross-sectional survey designed to examine health and healthcare access among 2SGBQ+ men. SETTING: Community-based cross-sectional study in Manitoba, Canada. PARTICIPANTS: Community-based sample of 368 2SGBQ+ men. OUTCOMES: Logistic regression analyses assessed the relationship between sociodemographics, healthcare discrimination, perceived healthcare providers' 2SGBQ+ competence/knowledge and two indicators of healthcare access (analytic outcome variables): (1) having a regular healthcare provider and (2) having had a healthcare visit in the past 12 months. RESULTS: In multivariate analyses, living in Brandon (adjusted OR (AOR)=0.08, 95% CI 0.03 to 0.22), small cities (AOR=0.20, 95% CI 0.04 to 0.98) and smaller towns (AOR=0.26, 95% CI 0.08 o 0.81) in Manitoba (compared with living in Winnipeg), as well as having a healthcare provider with poor (AOR=0.19, 95% CI 0.04 to 0.90) or very poor competence/knowledge (AOR=0.03, 95% CI 0.03 to 0.25) of 2SGBQ+ men's issues (compared with very good competence) was associated with lower odds of having a regular healthcare provider. Living in Brandon (AOR=0.05, 95% CI 0.02 to 0.17) and smaller towns (AOR=0.25, 95% CI 0.67 to 0.90) in Manitoba (compared with living in Winnipeg) was associated with lower odds of having a healthcare visit in the past 12 months, while identifying as a gay man compared with bisexual (AOR=12.57, 95% CI 1.88 to 83.97) was associated with higher odds of having a healthcare visit in the past 12 months. CONCLUSIONS: These findings underscore the importance of reducing the gap between the healthcare access of rural and urban 2SGBQ+ men, improving healthcare providers' cultural competence and addressing their lack of knowledge of 2SGBQ+ men's issues.

Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020.

OBJECTIVES: B cell depletion therapy based on rituximab in patients with RA was pioneered at University College London Hospitals/University College London in 1998. The objective of this study was to evaluate long-term persistence of rituximab and identify factors associated with discontinuation of treatment. METHODS: Retrospective review of medical records from all rituximab-treated RA patients followed up in a dedicated clinic (1998-2020). Data collected included gender, disease duration, previous DMARDs, autoantibody status, age and concomitant therapy at first cycle, length of follow-up, and number of cycles. Drug survival and factors associated with drug discontinuation were analysed using Kaplan-Meier survival curves, log-rank test and Cox regression analysis. RESULTS: A total of 404 patients were included. Median disease duration and age at time of first rituximab cycle were 10 and 57 years, respectively. Median total follow-up was 55 months and median number of cycles five. 93.1% of patients were seropositive. Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan-Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD). Cox regression analysis revealed that rituximab discontinuation was associated with a greater number of previous bDMARDs. CONCLUSION: Many patients with RA achieve good control of their disease with repeated cycles of rituximab treatment. The most common reasons for treatment discontinuation were either primary or secondary inefficacy. Patients who were seronegative and who had previously failed other bDMARDs were more at risk of drug discontinuation.

Percutaneous Dilational Tracheostomy at the Epicenter of the SARS-CoV-2 Pandemic: Impact on Critical Care Resource Utilization and Early Outcomes.

BACKGROUND: The COVID-19 pandemic overwhelmed New York City hospitals early in the pandemic. Shortages of ventilators and sedatives prompted tracheostomy earlier than recommended by professional societies. This study evaluates the impact of percutaneous dilational tracheostomy (PDT) in COVID+ patients on critical care capacity. METHODS: This is a single-institution prospective case series of mechanically ventilated COVID-19 patients undergoing PDT from April 1 to June 4, 2020 at a public tertiary care center. RESULTS: Fifty-five patients met PDT criteria and underwent PDT at a median of 13 days (IQR 10, 18) from intubation. Patient characteristics are found in Table 1. Intravenous midazolam, fentanyl, and cisatracurium equivalents were significantly reduced 48 hours post-PDT (Table 2). Thirty-five patients were transferred from the ICU and liberated from the ventilator. Median time from PDT to ventilator liberation and ICU discharge was 10 (IQR 4, 14) and 12 (IQR 8, 17) days, respectively. Decannulation occurred in 45.5% and 52.7% were discharged from acute inpatient care (Figure 1). Median follow-up for the study was 62 days. Four patients had bleeding complications postoperatively and 11 died during the study period. Older age was associated with increased odds of complication (OR 1.12, 95% CI 1.04, 1.23) and death (OR=1.15, 95% CI 1.05, 1.30). All operators tested negative for COVID-19 during the study period. CONCLUSION: These findings suggest COVID-19 patients undergoing tracheostomy within the standard time frame can improve critical care capacity in areas strained by the pandemic with low risk to operators. Long-term outcomes after PDT deserve further study.

Opposing Roles of GSK3α and GSK3ß Phosphorylation in Platelet Function and Thrombosis.

One of the mechanisms by which PI3 kinase can regulate platelet function is through phosphorylation of downstream substrates, including glycogen synthase kinase-3 (GSK3)α and GSK3ß. Platelet activation results in the phosphorylation of an N-terminal serine residue in GSK3α (Ser21) and GSK3ß (Ser9), which competitively inhibits substrate phosphorylation. However, the role of phosphorylation of these paralogs is still largely unknown. Here, we employed GSK3α/ß phosphorylation-resistant mouse models to explore the role of this inhibitory phosphorylation in regulating platelet activation. Expression of phosphorylation-resistant GSK3α/ß reduced thrombin-mediated platelet aggregation, integrin αIIbß3 activation, and α-granule secretion, whereas platelet responses to the GPVI agonist collagen-related peptide (CRP-XL) were significantly enhanced. GSK3 single knock-in lines revealed that this divergence is due to differential roles of GSK3α and GSK3ß phosphorylation in regulating platelet function. Expression of phosphorylation-resistant GSK3α resulted in enhanced GPVI-mediated platelet activation, whereas expression of phosphorylation-resistant GSK3ß resulted in a reduction in PAR-mediated platelet activation and impaired in vitro thrombus formation under flow. Interestingly, the latter was normalised in double GSK3α/ß KI mice, indicating that GSK3α KI can compensate for the impairment in thrombosis caused by GSK3ß KI. In conclusion, our data indicate that GSK3α and GSK3ß have differential roles in regulating platelet function.

Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner.

Sphingosine 1-phosphate (S1P) is a bioactive signalling sphingolipid that is increased in diseases such as obesity and diabetes. S1P can modulate platelet function, however the direction of effect and S1P receptors (S1PRs) involved are controversial. Here we describe the role of S1P in regulating human platelet function and identify the receptor subtypes responsible for S1P priming. Human platelets were treated with protease-activated receptor 1 (PAR-1)-activating peptide in the presence or absence of S1P, S1PR agonists or antagonists, and sphingosine kinases inhibitors. S1P alone did not induce platelet aggregation but at low concentrations S1P enhanced PAR1-mediated platelet responses, whereas PAR1 responses were inhibited by high concentrations of S1P. This biphasic effect was mimicked by pan-S1PR agonists. Specific agonists revealed that S1PR1 receptor activation has a positive priming effect, S1PR2 and S1PR3 have no effect on platelet function, whereas S1PR4 and S1PR5 receptor activation have an inhibitory effect on PAR-1 mediated platelet function. Although platelets express both sphingosine kinase 1/2, enzymes which phosphorylate sphingosine to produce S1P, only dual and SphK2 inhibition reduced platelet function. These results support a role for SphK2-mediated S1P generation in concentration-dependent positive and negative priming of platelet function, through S1PR1 and S1PR4/5 receptors, respectively.

Development of the mammalian cortical hem and its derivatives: the choroid plexus, Cajal-Retzius cells and hippocampus.

The dorsal medial region of the developing mammalian telencephalon plays a central role in the patterning of the adjacent brain regions. This review describes the development of this specialized region of the vertebrate brain, called the cortical hem, and the formation of the various cells and structures it gives rise to, including the choroid plexus, Cajal-Retzius cells and the hippocampus. We highlight the ontogenic processes that create these different forebrain derivatives from their shared embryonic origin and discuss the key signalling pathways and molecules that influence the patterning of the cortical hem. These include BMP, Wnt, FGF and Shh signalling pathways acting with Homeobox factors to carve the medial telencephalon into district progenitor regions, which in turn give rise to the choroid plexus, dentate gyrus and hippocampus. We then link the formation of the lateral ventricle choroid plexus with embryonic and postnatal neurogenesis in the hippocampus.

Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response.

Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies. SIGNIFICANCE: These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.

Weight-based enoxaparin with anti-factor Xa assay-based dose adjustment for venous thromboembolic event prophylaxis in adult trauma patients results in improved prophylactic range targeting.

BACKGROUND: Venous thromboembolism (VTE) is a common morbidity in trauma patients. Standard VTE chemoprophylaxis is often inadequate. We hypothesized that weight-based dosing would result in appropriate prophylaxis more reliably than fixed dosing. METHODS: All patients admitted to a Level 1 trauma center over a 6-month period were included unless contra-indications for VTE prophylaxis existed. A prospective adjusted-dosing group was compared to a retrospective uniform-dosing group. The adjusted-dosing approach consisted of initial weight-based dosing of 0.5 mg/kg subcutaneously (subQ) every 12 h (q12h). Peak anti-factor Xa was measured. Patients outside of the prophylactic range had their dose adjusted by ± 10 mg. The uniform-dosing group received 30 mg subQ q12h, without adjustments. RESULTS: Eighty-four patients were included: 44 in the retrospective control cohort and 40 in the prospective experimental cohort. More patients were sub-prophylactically dosed in the uniform-dosing group relative to the adjusted-dosing group (25% vs 5%, p = 0.03). There was no difference in overall prophylactic range targeting, because the supra-prophylactically dosed patients in the adjusted-dosing group eliminated the effect (p = 0.173). However, after a single dose adjustment, zero patients were outside of prophylactic range (25% versus 0%, RR = infinite, p = 0.003). In the uniform-dosing group, anti-Xa level correlated with body surface area (BSA; R2 = 0.33, p < 0.0001) and weight (R2 = 0.26, p = 0.0005). Weight-based dosing both pre- and post-readjustment normalized the correlation of anti-Xa with BSA (R2 = 0.07, p = 0.1) and weight (R2 = 0.07, p = 0.1). CONCLUSIONS: Weight-based VTE prophylaxis with anti-Xa-based dose adjustment improves prophylactic range targeting relative to uniform dosing and eliminates variances secondary to BSA and weight in trauma patients.

NUT Carcinoma in a Patient with Unusually Long Survival and False Negative FISH Results.

Nuclear protein in testis (NUT) carcinoma is a rare and highly aggressive epithelial malignancy defined by rearrangement of the NUTM1 gene on chromosome 15q14. Histologically, NUT carcinoma is an undifferentiated carcinoma formed by sheets and nests of primitive and monotonous "round blue cells" with foci of abrupt keratinization in a subset. NUT carcinoma runs a fulminant clinical course and is almost always quickly lethal, with a median overall survival of only 6.7 months. There is no consensus regarding treatment for this disease, and most patients respond poorly to conventional chemotherapy and radiation. We report a case of NUT carcinoma in an African-American man who initially presented in 2009 with a tracheal mass at age 28. Although fluorescence in situ hybridization (FISH) assays for NUTM1 and BRD4 rearrangements were negative, he was diagnosed based on diffusely positive NUT immunostaining and BRD4-NUTM1 on RNA sequencing. Since his initial presentation, he has undergone multiple surgical procedures and radiation therapy. His tumor has recurred twice, but he has survived for 129 months and is currently alive without disease. Long-term survival of patients with NUT carcinoma is incredibly unusual, especially in patients with tumors that exhibit a BRD4 rearrangement. False negative FISH is a pitfall in diagnosing NUT carcinoma; NUT immunostaining and RNA sequencing are more sensitive diagnostic methods.