A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice.

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements typically characterized by repeated units of 1-6 bp. We leveraged whole-genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family of mice to map loci that modulate genome-wide patterns of new mutations arising during parent-to-offspring transmission at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and performed quantitative trait locus (QTL) analyses for each of these phenotypes. We identified a locus on Chromosome 13 at which strains inheriting the C57BL/6J (B) haplotype have a higher rate of STR expansions than those inheriting the DBA/2J (D) haplotype. The strongest candidate gene in this locus is Msh3, a known modifier of STR stability in cancer and at pathogenic repeat expansions in mice and humans, as well as a current drug target against Huntington's disease. The D haplotype at this locus harbors a cluster of variants near the 5' end of Msh3, including multiple missense variants near the DNA mismatch recognition domain. In contrast, the B haplotype contains a unique retrotransposon insertion. The rate of expansion covaries positively with Msh3 expression-with higher expression from the B haplotype. Finally, detailed analysis of mutation patterns showed that strains carrying the B allele have higher expansion rates, but slightly lower overall total mutation rates, compared with those with the D allele, particularly at tetranucleotide repeats. Our results suggest an important role for inherited variants in Msh3 in modulating genome-wide patterns of germline mutations at STRs.

Impact of inherited bleeding disorders on maternal bleeding and other pregnancy outcomes: A population-based cohort study.

INTRODUCTION: Increasing rate of postpartum haemorrhage (PPH) has been observed between 2003 and 2010 in Canada. Inherited bleeding disorders contribute to the risk of PPH. AIM: To identify the trend in PPH in the last decade, assess the impact of bleeding disorders on pregnancy outcomes and evaluate their coagulation workup during pregnancy. METHODS: We conducted a population-based retrospective cohort study using the Alberta Pregnancy Birth Cohort from 2010 to 2018. We included women with von Willebrand disease (VWD) and haemophilia, identified by previously validated algorithm and matched with controls. Logistic regression was used to compute odds of PPH and other pregnancy outcomes. RESULTS: We identified 311,330 women with a total of 454,400 pregnancies with live births. The rate of PPH did not change significantly from 10.13 per 100 deliveries (95% CI 10.10-10.16) in 2010-10.72 (95% CI 10.69-10.75) in 2018 (p for trend = .35). Women with bleeding disorders were significantly more likely to experience PPH (odds ratio [OR] 2.3; 95% CI 1.5-3.6), antepartum haemorrhage (OR 2.9; 95% CI 1.5-5.9) and red cell transfusion (OR 2.8; 95% CI 1.1-7.0). We observed a nonsignificant rise in the rate of PPH in women with VWD and haemophilia. Only 49.5% pregnancies with bleeding disorders had third trimester coagulation factor levels checked. Higher odds of PPH and antepartum haemorrhage were observed even with factor levels ≥0.50 IU/mL in third trimester. CONCLUSION: Despite comprehensive care in women with bleeding disorders, they are still at higher risk of adverse pregnancy outcomes compared to population controls.

Increased acute care utilisation, comorbidities and mortality in adults with haemophilia: A population-based cohort study from 2012 to 2019.

INTRODUCTION: Improvements in treatment strategies have led to increased life expectancy of persons with haemophilia (PWH). Consequently, age-related comorbidities become increasingly relevant. AIM: To evaluate the prevalence of age-related comorbidities, mortality, health service utilisation and predictors of hospitalisation in PWH compared to the general population. METHODS: We conducted a population-based retrospective cohort study using linked administrative data. Men with haemophilia were identified in Alberta, Canada (2012-2019) with a validated case definition and were age-matched with male population controls. We calculated the prevalence of major comorbidities, all-cause mortality, and examined health service utilisation including Emergency Department visits and hospitalisations. Logistic regression was applied to identify predictors of hospitalisation. RESULTS: We identified 198 and 329 persons with moderately severe haemophilia and mild/moderate, respectively. Moderately severe haemophilia had a higher risk of death (standardised mortality ratio 3.2, 95% confidence interval [CI] 1.4-6.3) compared to the general population. PWH had a significantly higher prevalence of hypertension, liver diseases and malignancies than controls. Moderately severe haemophilia was associated with significantly higher rates of hospitalisations (52.5% vs. 14.5%), Emergency Department visits (89.1% vs. 62.7%) and intensive care admissions (8.9% vs. 2.3%). Age > 65 years (adjusted odds ratio [aOR] 6.8) and presence of multiple comorbidities (aOR 3.9) were significant predictors of hospitalisations among PWH. CONCLUSION: Despite advanced care, haemophilia is associated with higher acute care utilisation than the general population, highlighting the substantial burden of illness on patients and the health care system.

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

BACKGROUND: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN: Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING: Eighteen sites between February 2011 and February 2021. PATIENTS: Patients with isolated subsegmental pulmonary embolism. INTERVENTION: At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS: The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS: Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION: The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION: Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability.

BACKGROUND: Retrospective analyses suggest that pulmonary embolism is ruled out by a d-dimer level of less than 1000 ng per milliliter in patients with a low clinical pretest probability (C-PTP) and by a d-dimer level of less than 500 ng per milliliter in patients with a moderate C-PTP. METHODS: We performed a prospective study in which pulmonary embolism was considered to be ruled out without further testing in outpatients with a low C-PTP and a d-dimer level of less than 1000 ng per milliliter or with a moderate C-PTP and a d-dimer level of less than 500 ng per milliliter. All other patients underwent chest imaging (usually computed tomographic pulmonary angiography). If pulmonary embolism was not diagnosed, patients did not receive anticoagulant therapy. All patients were followed for 3 months to detect venous thromboembolism. RESULTS: A total of 2017 patients were enrolled and evaluated, of whom 7.4% had pulmonary embolism on initial diagnostic testing. Of the 1325 patients who had a low C-PTP (1285 patients) or moderate C-PTP (40 patients) and a negative d-dimer test (i.e., <1000 or <500 ng per milliliter, respectively), none had venous thromboembolism during follow-up (95% confidence interval [CI], 0.00 to 0.29%). These included 315 patients who had a low C-PTP and a d-dimer level of 500 to 999 ng per milliliter (95% CI, 0.00 to 1.20%). Of all 1863 patients who did not receive a diagnosis of pulmonary embolism initially and did not receive anticoagulant therapy, 1 patient (0.05%; 95% CI, 0.01 to 0.30) had venous thromboembolism. Our diagnostic strategy resulted in the use of chest imaging in 34.3% of patients, whereas a strategy in which pulmonary embolism is considered to be ruled out with a low C-PTP and a d-dimer level of less than 500 ng per milliliter would result in the use of chest imaging in 51.9% (difference, -17.6 percentage points; 95% CI, -19.2 to -15.9). CONCLUSIONS: A combination of a low C-PTP and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up. (Funded by the Canadian Institutes of Health Research and others; PEGeD ClinicalTrials.gov number, NCT02483442.).

All-cause mortality and causes of death in persons with haemophilia: A systematic review and meta-analysis.

INTRODUCTION: Improvements in haemophilia treatment over the last decades resulted in increased life expectancy in persons with haemophilia (PWH). AIM: We conducted a systematic review and meta-analysis to examine all-cause mortality and causes of death among PWH. METHODS: We systematically searched EMBASE, MEDLINE, Web of Science, CINAHL and Cochrane central register of controlled trials from inception through March 15, 2021. Studies that reported a mortality estimate of PWH compared with the general population and/or reported causes of death were included. Random-effects meta-analysis with inverse variance method was used to obtain pooled estimates. We stratified the analysis by the year of cohort entry (before 2000 vs after 2000). RESULT: Of the 4769 studies identified, 52 met the eligibility criteria. The pooled all-cause standardized mortality ratio (SMR) from 9 studies in PWH was 1.93 (95% CI 1.38-2.70; I2 = 97%). The pooled SMRs before and after the year 2000 were 2.40 (95% CI 1.92-3.00; I2 = 87%) and 1.20 (95% CI 1.03-1.40; I2 = 62%), respectively. Before the year 2000, 31.2% deaths occurred due to HIV followed by haemorrhage (26.0%), cardiovascular disease (18.2%), liver disease (9.0%), and cancer (8.9%). Fewer (13.9%) deaths were attributable to HIV after the year 2000 with the proportion of deaths due to haemorrhage remaining unchanged. CONCLUSION: With treatment advances, mortality in PWH has declined over the last few decades approaching that of the general population. However, haemorrhage remains a leading cause of death requiring further attention.

Temporal association between objectively measured smartphone usage, sleep quality and physical activity among Chinese adolescents and young adults.

We studied the association between objectively measured smartphone usage and objectively measured sleep quality and physical activity for seven consecutive days among Hong Kong adolescents and young adults aged 11-25 years (n = 357, 67% female). We installed an app that tracked the subjects' smartphone usage and had them wear an ActiGraph GT3X accelerometer on their wrist to measure their sleep quality and physical activity level. Smartphone usage data were successfully obtained from 187 participants (52.4%). The participants on average spent 2 h 46 min per day on their smartphone. Multilevel regression showed that 1 min of daytime smartphone usage was associated with 0.07 min decrease in total sleeping time that night (p = .043, 95% confidence interval [CI]: -0.14, -0.003). Broken down for different usage purposes, 1 min of daytime social network usage and games and comics was associated with a 0.28 (p = .02, 95% CI: -0.52, -0.04) min and 0.18 min (p = .01, 95% CI: -0.32, -0.04) decrease in total sleeping time that night, respectively. One minute of daytime smartphone usage was associated with an increase of 4.55 steps in the number of steps (p = .001, 95% CI: 1.77, 7.34) on the next day. To conclude, time spent on a smartphone in the daytime was associated with total sleeping time that night and number of steps the next day, but was not associated with sleep efficiency, wake after sleep onset and moderate-to-vigorous-intensity activity (MVPA) among Hong Kong adolescents and young adults.

Risk of arterial and venous thromboembolic events among patients with colorectal carcinoma: a real-world, population-based study.

Objective: To assess real-world patterns of arterial and venous thromboembolism among patients with colorectal carcinoma. Methods: The Alberta provincial cancer registry and other provincial medical records were used to identify patients with colorectal cancer (2004-2018) with no preceding or succeeding cancer diagnosis. The incidence of both arterial and venous thromboembolism in this patient population as well as factors associated with these thromboembolic events were examined through logistic regression analysis. Results: A total of 17,296 patients were found eligible and were included into the current study. We observed that 1564 patients (9%) experienced a thromboembolic event and 15,732 patients (91%) did not. The following factors were associated with any thromboembolic event: male sex (odds ratio [OR]: 1.20; 95% CI: 1.08-1.34), higher comorbidity (OR: 1.36; 95% CI: 1.31-1.41), metastatic disease (OR for nonmetastatic vs metastatic disease: 0.53; 95% CI: 0.47-0.60), living within North zone (OR for Edmonton zone vs North zone: 0.70; 95% CI: 0.59-0.84), treatment with fluoropyrimidines (OR for no fluoropyrimidines vs fluoropyrimidines: 0.53; 95% CI: 0.47-0.60) and treatment with bevacizumab (OR: for no bevacizumab vs bevacizumab: 0.53; 95% CI: 0.47-0.60). Factors associated with venous thromboembolism include, younger age (continuous OR with increasing age: 0.99; 95% CI: 0.98-0.99), higher comorbidity (OR: 1.10; 95% CI: 1.04-1.17), metastatic disease (OR for nonmetastatic disease vs metastatic disease: 0.40; 95% CI: 0.35-0.47), North zone (OR for Edmonton zone vs North zone: 0.70; 95% CI: 0.56-0.86), treatment with fluoropyrimidines (OR for no fluoropyrimidines vs fluoropyrimidines: 0.45; 95% CI: 0.39-0.53) and treatment with bevacizumab (OR for no bevacizumab vs bevacizumab: 0.73; 95% CI: 0.58-0.93). Conclusion: Thromboembolic events are not uncommon among colorectal cancer patients, and the risk is increased with male sex, higher comorbidity, presence of metastatic disease, living within the North zone of the province (where there is limited access to tertiary care centers) and treatment with fluoropyrimidines or bevacizumab.

Lay abstract In this analysis of patients who have been diagnosed of colon and rectal cancers in Alberta, Canada, development of blood clots was not uncommon. Certain patient and treatment risk factors seem to increase the risk of this phenomenon.

The Clinical Conundrum of Managing Ischemic Stroke in Patients with Immune Thrombocytopenia.

Guidelines are lacking for management of acute ischemic stroke and stroke prevention in patients with immune thrombocytopenia (ITP). Our aim is to highlight the dilemma inherent in managing patients with both significant bleeding and thrombotic risk factors. In this review, we present two patients with history of ITP who presented with acute ischemic stroke and received tissue plasminogen activator (tPA) and endovascular thrombectomy (EVT), a rare management strategy in this patient population. In addition, we identified 27 case reports of ischemic stroke in patients with ITP; none of them received tPA or EVT. Furthermore, there are 92 patients with significant thrombocytopenia with no available data regarding the cause of thrombocytopenia, who were acutely treated with tPA or EVT. Conclusive evidence cannot be determined based on these limited number of cases. Future multicenter prospective cohort studies in patients with ITP are needed to provide better evidence-based treatment plans. At present, treatment of acute ischemic stroke in patients with ITP requires close collaboration between hematology and vascular neurology experts to find a balance between the benefit and risk of hemorrhagic complications.

Rivaroxaban Compared to Placebo for the Treatment of Leg Superficial Vein Thrombosis: A Randomized Trial.

The role of rivaroxaban in the treatment of leg superficial venous thrombosis (SVT) is uncertain. This article aims to determine if rivaroxaban is an effective and safe treatment for leg SVT. Patients with symptomatic leg SVT of at least 5 cm length were randomized to 45 days of rivaroxaban 10 mg daily or to placebo, and followed for a total of 90 days. Treatment failure (required a nonstudy anticoagulant; had proximal deep vein thrombosis or pulmonary embolism; or had surgery for SVT) at 90 days was the primary efficacy outcome. Secondary efficacy outcomes included leg pain severity, and venous disease-specific and general health-related quality of life over 90 days. Major bleeding at 90 days was the primary safety outcome. Poor enrollment led to the trial being stopped after 85 of the planned 600 patients were randomized to rivaroxaban (n = 43) or placebo (n = 42). One rivaroxaban and five placebo patients had a treatment failure by 90 days (absolute risk reduction = 9.0%, 95% confidence interval: -22 to 5.9%). Leg pain improvement did not differ at 7 (p = 0.16) or 45 days (p = 0.89), but was greater with rivaroxaban at 90 days (p = 0.011). There was no difference in venous disease-specific (p = 0.99) or general health-related (p = 0.37) quality of life over 45 days. There were no major bleeds or deaths in either group. There were no identifiable differences in efficacy or safety between rivaroxaban and placebo in patients with symptomatic SVT but comparisons were undermined by a much smaller than planned sample size (NCT1499953).

Direct Oral Anticoagulants in Cancer Patients.

Cancer-associated thrombosis (CAT) is a common occurrence in the journey of a cancer patient and its management poses significant challenges. Low molecular weight heparin (LMWH) is the standard of care but the high cost and the inconvenience of daily injections have led to low persistence with therapy. Direct oral anticoagulants (DOACs) are effective and safe for the treatment of venous thromboembolism (VTE) compared with vitamin K antagonist (VKA) therapy in noncancer patients, and emerging data comparing their use with LMWH in CAT are rapidly changing clinical practice. Recent randomized controlled trials also reported that specific DOACs are effective for primary prevention of CAT in patients undergoing systemic cancer therapy, but this benefit might be offset by an increased risk of bleeding. Undoubtedly, the option of an effective and safe oral anticoagulant is appealing to physicians and patients but critical limitations of DOACs, particularly bleeding and drug-drug interaction, need careful consideration. Understanding the scientific data, as well as each patient's preferences and values, are paramount in individualizing therapy in this special population of patients. This review summarizes the current evidence for DOACs for the treatment and prevention of CAT, discusses the importance of careful patient selection, and highlights upcoming new studies that will inform guideline recommendations.

Short- and long-term mortality after pulmonary embolism in patients with and without cancer.

Pulmonary embolism (PE) is a major cause of mortality and morbidity. It is known that the risk of death varies by provoking factors; however, it is unknown if the risk of death persists beyond the initial diagnosis among patients with cancer-associated and non-cancer provoked patients. In this study, we aimed to investigate the effect of cancer on overall, short- and long-term mortality in a cohort of consecutive incident PE patients. Using administrative databases, we identified all incident cases of PE between 2004 and 2012 in Alberta, Canada. Cases were stratified by provoking factors (i.e. unprovoked, provoked, and cancer-associated). A multivariate Cox survival model was used to estimate the hazard ratios of short- and long-term death. We identified 8641 patients with PE, among which 42.2% were unprovoked, 37.9% were provoked and 19.9% were cancer-associated. The 1-year and 5-year survival probabilities were 60% (95% CI: 57-64%) and 39% (95% CI: 36-43%) in patients with cancer-associated PE, 93% (95% CI: 92-94%) and 80% (95% CI: 78-81%) in provoked PE, and 94% (95% CI: 93-95%) and 85% (95% CI: 83-87%) in unprovoked PE, respectively. Compared to patients with unprovoked events, both short-term and long-term survival in patients with cancer-associated PE have a higher observed risk of all-cause mortality in all age groups ( p<0.001). In contrast, patients with provoked events had a similar short- and long-term all-cause mortality. While PE has a significant mortality in all risk groups, patients with cancer have a higher risk of short-term mortality compared to patients with unprovoked PE.

Sex disparities in hospitalization and mortality rates for venous thromboembolism.

Venous thromboembolism (VTE) is a major health problem for both men and women. Whether sex disparities exist for outcomes after acute VTE is unknown. We sought to measure sex-specific rates of hospitalization for and mortality from acute VTE. We used a population-based administrative dataset from Alberta, Canada, covering the years 2002 to 2012. We used Poisson regression to measure the incidence rate ratio for hospitalization and Cox regression to test for sex disparities in short-term all-cause mortality after adjusting for potential confounders. Of those diagnosed with VTE, 55.9% were women. The proportion of hospitalized women for VTE was 24.4 versus 27.8% in men (p < 0.001). The risk adjusted incidence rate ratio for VTE hospitalization increased with age for both sex. While women younger than 80 years old were less likely to be hospitalized than men, sex disparities for the risk of hospitalization were not significant after age 80 (p = 0.93). The adjusted 90-day all-cause mortality rate for women was 4.0% compared to 4.9% in men (adjusted HR = 1.0, p = 0.49). Women with acute VTE were less likely than men to be hospitalized in most age groups, but sex disparities in short-term all-cause mortality were not found.

Role of Extended Thromboprophylaxis After Abdominal and Pelvic Surgery in Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Abdominopelvic cancer surgery increases the risk of postoperative venous thromboembolism (VTE). Low-molecular-weight heparin (LMWH) thromboprophylaxis is recommended, and the role of extended thromboprophylaxis (ETP) is controversial. We performed a systematic review to determine the effect of ETP on deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, and all-cause mortality after abdominal or pelvic cancer surgery. METHODS: A search of the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was undertaken, and studies were included if they compared extended duration (2-6 weeks) with conventional duration of thromboprophylaxis (2 weeks or less) after cancer surgery. Pooled relative risk (RR) was estimated using a random effects model. RESULTS: Seven randomized and prospective studies were included, comprising 4807 adult patients. ETP was associated with a significantly reduced incidence of all VTEs [2.6 vs. 5.6 %; RR 0.44, 95 % confidence interval (CI) 0.28-0.70, number needed to treat (NNT) = 39] and proximal DVT (1.4 vs. 2.8 %; RR 0.46, 95 % CI 0.23-0.91, NNT = 71). There was no statistically significant difference in the incidence of symptomatic PE (0.8 vs. 1.3 %; RR 0.56, 95 % CI 0.23-1.40), major bleeding (1.8 vs. 1.0 %; RR 1.19, 95 % CI 0.47-2.97), and all-cause mortality (4.2 vs. 3.6 %; RR 0.79, 95 % CI 0.47-1.33). None of the outcomes differed if randomized trials were analyzed independently. CONCLUSIONS: ETP after abdominal or pelvic surgery for cancer significantly decreased the incidence of all VTEs and proximal DVTs, but had no impact on symptomatic PE, major bleeding, or 3-month mortality. ETP should be routinely considered in the setting of abdominal and pelvic surgery for cancer patients.

Incidence of catheter-related thrombosis in acute leukemia patients: a comparative, retrospective study of the safety of peripherally inserted vs. centrally inserted central venous catheters.

Central venous catheters are a leading cause of upper-extremity deep vein thrombosis. Concomitant severe thrombocytopenia makes anticoagulation for catheter-related thrombosis (CRT) in patients with acute leukemia (AL) a challenge. Incidence of CRT has been reported to be increased in those with peripherally inserted central catheters (PICC) vs. those with centrally inserted ones (CICC). Our objective is to compare the incidence rate of CRT in leukemia inpatients who received either a PICC vs. CICC. We retrospectively reviewed adult inpatients admitted to hematology wards with a new diagnosis of AL and who received either a PICC or a CICC. Baseline patient and catheter characteristics were recorded. Our primary outcome was the incidence rate of CRT in each group. The secondary outcomes included rates of infectious and mechanical complications. Six hundred sixty-three patients received at least one PICC (338) or CICC (325) insertion. A total of 1331 insertions were recorded, with 82 (11.7 %) and 41 (6.5 %) CRT in the PICC and CICC groups, respectively. The incidence rates were 1.89 and 0.52 per 1000 catheter day in the PICC and CICC groups, respectively. A PICC, when compared to CICC, was a significant risk factor for CRT (sHR 2.5, p < 0.0001). The prevalence and incidence rates of CRT in our AL patients were higher than predicted for a general cancer patient population. These rates were higher in the PICC group compared to the CICC group. We recommend careful consideration of thrombotic and bleeding risks of AL inpatients when choosing a central venous catheter.

The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease.

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.

Parenting approaches, family functionality, and internet addiction among Hong Kong adolescents.

BACKGROUND: Internet addiction (IA) among adolescents has become a global health problem, and public awareness of it is increasing. Many IA risk factors relate to parents and the family environment. This study examined the relationship between IA and parenting approaches and family functionality. METHODS: A cross-sectional study was conducted with 2021 secondary students to identify the prevalence of IA and to explore the association between adolescent IA and familial variables, including parents' marital status, family income, family conflict, family functionality, and parenting approaches. RESULTS: The results revealed that 25.3 % of the adolescent respondents exhibited IA, and logistic regression positively predicted the IA of adolescents from divorced families, low-income families, families in which family conflict existed, and severely dysfunctional families. Interestingly, adolescents with restricted Internet use were almost 1.9 times more likely to have IA than those whose use was not restricted. CONCLUSIONS: Internet addiction is common among Chinese adolescents in Hong Kong, and family-based prevention strategies should be aligned with the risk factors of IA.

Novel or non-vitamin K antagonist oral anticoagulants and the treatment of cancer-associated thrombosis.

Cancer-associated thrombosis remains a common and challenging clinical presentation. Despite advances in therapy using low-molecular-weight heparins, both venous thromboembolic recurrence and clinically relevant bleeding while on therapeutic anticoagulation occur at high rates. Multiple novel (or non-vitamin K antagonist) oral anticoagulants have recently been developed for the treatment and prevention of venous thromboembolism. There are many attractive features of these agents including convenience and simplicity of administration. Unfortunately, there are also several limitations such as dependency on gastrointestinal absorption, renal clearance, and some significant drug-drug interactions. The use of these newer oral agents in cancer patients is not recommended, as their safety and efficacy are not yet established and the complexity of these patients warrants further cancer-specific clinical trials.

Management and outcomes of cancer-associated venous thromboembolism in patients with concomitant thrombocytopenia: a retrospective cohort study.

Venous thromboembolism (VTE) and thrombocytopenia are both more common in cancer patients than in general populations. Both the outcomes and optimal management of cancer-associated VTE in thrombocytopenic patients are unknown. The objective of the current  study is to describe a cohort of patients presenting with acute cancer-associated VTE with concomitant thrombocytopenia, including management patterns and outcomes. We conducted a retrospective cohort study of all cancer patients admitted to a regional cancer centre and the main university hospital's hematology service in Edmonton, Alberta, from 2005-2011, who had thrombocytopenia at the time of acute VTE. We report rates of recurrent symptomatic thromboembolism, major and clinically relevant non-major bleeding, within the initial 3 months following VTE diagnosis. Seventy-four patients were identified as eligible and reviewed. Seventeen (23.0 %) patients did not receive any antithrombotic therapy, 30 (40.5 %) received a minimum of 3 months of full-dose anticoagulation, and 27 (36.5 %) received partial treatment, which was either dose-reduced, interrupted, or shortened in duration. Twenty-three (31.1 %) experienced recurrent thromboembolism and 13 (17.6 %) had bleeding events, of which 3 (4.1 %) were major. In conclusion, patients with acute cancer-associated VTE and concomitant thrombocytopenia were managed heterogeneously at our institution, without a predominant strategy. There was a high rate of short-term complications, including recurrent thromboembolism and hemorrhage in this cohort. Future research should focus on determining the optimal management strategy in this challenging clinical scenario.