Principles of unconventional myosin function and targeting.

Unconventional myosins are a superfamily of actin-based motors implicated in diverse cellular processes. In recent years, much progress has been made in describing their biophysical properties, and headway has been made into analyzing their cellular functions. Here, we focus on the principles that guide in vivo motor function and targeting to specific cellular locations. Rather than describe each motor comprehensively, we outline the major themes that emerge from research across the superfamily and use specific examples to illustrate each. In presenting the data in this format, we seek to identify open questions in each field as well as to point out commonalities between them. To advance our understanding of myosins' roles in vivo, clearly we must identify their cellular cargoes and the protein complexes that regulate motor attachment to fully appreciate their functions on the cellular and developmental levels.

Multi-mode heterodyne laser interferometry realized via software defined radio.

The agile generation and control of multiple optical frequency modes combined with the realtime processing of multi-mode data provides access to experimentation in domains such as optomechanical systems, optical information processing, and multi-mode spectroscopy. The latter, specifically spectroscopy of spectral-hole burning (SHB), has motivated our development of a multi-mode heterodyne laser interferometric scheme centered around a software-defined radio platform for signal generation and processing, with development in an entirely open-source environment. A challenge to SHB is the high level of shot noise due to the laser power constraint imposed by the spectroscopic sample. Here, we have demonstrated the production, detection, and separation of multiple optical frequency modes to the benefit of optical environment sensing for realtime phase noise subtraction as well as shot noise reduction through multi-mode averaging. This has allowed us to achieve improved noise performance in low-optical-power interferometry. Although our target application is laser stabilization via SHB in cryogenic temperature rare-earth doped crystals, these techniques may be employed in a variety of different contexts.

The impact of a thin endometrial lining on fresh and frozen-thaw IVF outcomes: an analysis of over 40 000 embryo transfers.

STUDY QUESTION: Does each millimeter decrease in endometrial thickness lead to lower pregnancy and live birth rates in fresh and frozen IVF cycles? SUMMARY ANSWER: Clinical pregnancy and live birth rates decline as the endometrial thickness decreases below 8 mm in fresh IVF-ET and below 7 mm in frozen-thaw embryo transfer (ET) cycles. WHAT IS KNOWN ALREADY: Previous studies have been heterogenous and have shown conflicting results on the impact of endometrial thickness on IVF outcomes. Most studies do not include many patients with an endometrial thickness below 6 mm, and there are few studies of frozen-thaw ET cycles. STUDY DESIGN, SIZE, DURATION: This study is a retrospective cohort analysis of all Canadian IVF fresh and frozen-thaw ET cycles from the CARTR-BORN database for autologous and donor fresh and frozen-thaw IVF-ET cycles from 1 January 2013 to 31 December 2015. A total of 24 363 fresh and 20 114 frozen-thaw IVF-ET cycles were reported during this timeframe. PARTICIPANTS/MATERIALS, SETTING, METHODS: 33 Canadians clinics participated in voluntary reporting of IVF and pregnancy outcomes to the CARTR-BORN database. The impact of endometrial thickness on pregnancy, live birth and pregnancy loss rates were analyzed for fresh IVF-ET and frozen-thaw cycles. MAIN RESULTS AND THE ROLE OF CHANCE: In fresh IVF-ET cycles, clinical pregnancy and live birth rates decreased (P < 0.0001) and pregnancy loss rates increased (P = 0.01) with each millimeter decline in endometrial thickness below 8 mm. Live birth rates were 33.7, 25.5, 24.6 and 18.1% for endometrial thickness ≥8, 7-7.9, 6-6.9 and 5-5.9 mm, respectively. In frozen-thaw ET cycles, clinical pregnancy (P = 0.007) and live birth rates decreased (P = 0.002) with each millimeter decline in endometrial thickness below 7 mm, with no significant difference in pregnancy loss rates. Live birth rates were 28.4, 27.4, 23.7, 15 and 21.2% for endometrial thickness ≥8, 7-7.9, 6-6.9, 5-5.9 and 4-4.9 mm, respectively. The likelihood of achieving an endometrial thickness ≥8 mm decreased with age (89.7, 87.8 and 83.9% in women <35, 35-39 and ≥40, respectively) (P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: This study only included cycles which proceeded to ET, which may overestimate pregnancy outcomes. Approximately 8% of cycles could not be included in the analysis due to data irregularity related to data entry. Demographic data aside from age were unavailable but may be important as lower endometrial thickness may be associated with poor ovarian response. WIDER IMPLICATIONS OF THE FINDINGS: Although pregnancy and live birth rates decrease with endometrial thickness, reasonable outcomes were obtained even with lower endometrial thickness measurements. These data provide valuable guidance for both physicians and patients when confronted with decisions related to a persistently thin endometrium. STUDY FUNDING/COMPETING INTEREST(S): This study was not funded. The authors do not have any conflicts of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Risk of death from cardiovascular disease following breast cancer: a systematic review.

PURPOSE: Breast cancer incidence and survival is high, which results in high prevalence of breast cancer survivors. The risk of (death from) cardiovascular disease (CVD) is higher in patients exposed to cardiotoxic treatments, in particular if they have pre-existing CVD risk factors. This study systematically summarized the risk of death from CVD following breast cancer. METHODS: Databases of Medline, Embase, and the Cochrane Library were systematically searched using the following terms and synonyms: breast cancer, cardiovascular disease, and cause of death. Articles reporting on both risk and risk factors of CVD mortality following breast cancer were eligible for inclusion. The methodological quality of each article was assessed using the Newcastle Ottawa quality assessment scale for cohort studies. RESULTS: Fourteen articles were included assessing the risk of CVD mortality among 1,217,910 women with breast cancer. The methodological quality was high for the majority of the studies. Studies were heterogeneous in design, study population, length of follow-up, CVD outcomes, and risk factors. 1.6-10.4% of all women with breast cancer died of CVD. Women with breast cancer had a higher risk of CVD mortality than women from the general population. The risk of CVD mortality was higher among women with breast cancer with older age at diagnosis, left-sided tumor, diagnosis in an earlier calendar period, and black ethnic origin. CONCLUSIONS: CVD is an important cause of death following breast cancer. Identification of patients at high risk of CVD is important to optimize CVD prevention and tailor breast cancer treatment.

A randomized clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 1.

AIMS: The primary objective was to demonstrate that basal insulin peglispro (BIL) was non-inferior compared with insulin glargine (GL) for haemoglobin A1c (HbA1c) at 26 weeks with a non-inferiority margin of 0.4%. MATERIALS AND METHODS: IMAGINE 1 was a Phase 3, open-label, parallel-arm study conducted in nine countries. Adults with type 1 diabetes (n = 455) were randomized (2:1) to bedtime BIL or GL in combination with prandial insulin lispro for 78 weeks, with a primary endpoint of 26 weeks. An electronic diary facilitated data capture and insulin dosing calculations for intensive insulin management. RESULTS: At 26 weeks, mean HbA1c was 7.06% ± 0.04% and 7.43% ± 0.06% for patients assigned to BIL (N = 295) and GL (N = 160), respectively (difference -0.37% [95% CI: -0.50 to -0.23], P < .001); more patients on BIL achieved HbA1c <7% (44.9% vs 27.5%, P < .001). Compared with GL, patients using BIL lost weight, with lower fasting serum glucose and between-day fasting blood glucose variability, and 36% less nocturnal hypoglycemia, 29% more total hypoglycemia and more severe hypoglycemia. Total and prandial insulin doses were lower with BIL; basal insulin doses were higher. Alanine aminotransferase increased with BIL, with more patients having elevations ≥3 × ULN. BIL treatment was associated with more frequent injection site reactions and an increase from baseline in serum triglycerides. CONCLUSIONS: In patients with type 1 diabetes, treatment with BIL compared to GL for 26 weeks was associated with lower HbA1c, less nocturnal hypoglycemia, lower glucose variability and weight loss. Increases in total and severe hypoglycemia, triglycerides, aminotransferases and injection site reactions were also noted.

Randomized, double-blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 1 diabetes: IMAGINE 3.

AIMS: To compare the efficacy and safety of basal insulin peglispro (BIL), which has a flat pharmacokinetic and pharmacodynamic profile and a long duration of action, with insulin glargine (GL) in patients with type 1 diabetes. MATERIALS AND METHODS: In this phase III, 52-week, blinded study, we randomized 1114 adults with type 1 diabetes in a 3 : 2 distribution to receive either BIL (n = 664) or GL (n = 450) at bedtime, with preprandial insulin lispro, using intensive insulin management. The primary objective was to compare glycated haemoglobin (HbA1c) in the groups at 52 weeks, with a non-inferiority margin of 0.4%. RESULTS: At 52 weeks, mean (standard error) HbA1c was 7.38 (0.03)% with BIL and 7.61 (0.04)% with GL {difference -0.22% [95% confidence interval (CI) -0.32, -0.12]; p < 0.001}. At 52 weeks more BIL-treated patients reached HbA1c <7% (35% vs 26%; p < 0.001), the nocturnal hypoglycaemia rate was 47% lower (p < 0.001) and the total hypoglycaemia rate was 11% higher (p = 0.002) than in GL-treated patients, and there was no difference in severe hypoglycaemia rate. Patients receiving BIL lost weight, while those receiving GL gained weight [difference -1.8 kg (95% CI -2.3, -1.3); p < 0.001]. Treatment with BIL compared with GL at 52 weeks was associated with greater increases from baseline in levels of serum triglyceride [difference 0.19 mmol/l (95% CI 0.11, 0.26); p < 0.001] and alanine aminotransferase (ALT) levels [difference 6.5 IU/l (95% CI 4.1, 8.9), p < 0.001], and more frequent injection site reactions. CONCLUSIONS: In patients with type 1 diabetes, treatment with BIL compared with GL for 52 weeks resulted in a lower HbA1c, more patients with HbA1c levels <7%, and reduced nocturnal hypoglycaemia, but more total hypoglycaemia and injection site reactions and higher triglyceride and ALT levels.

Basal insulin peglispro: Overview of a novel long-acting insulin with reduced peripheral effect resulting in a hepato-preferential action.

Basal insulin peglispro (BIL) is a novel basal insulin with a flat, prolonged activity profile. BIL has been demonstrated in a dog model, in healthy men and in patients with type 1 diabetes (T1D) to have significant hepato-preferential action resulting from reduced peripheral activity. In the IMAGINE-Phase 3 clinical trial program, more than 6000 patients were included, of whom ~3900 received BIL. Of the 7 pivotal IMAGINE trials, 3 studies were double-blinded and 3 were in T1D patients. BIL consistently demonstrated a greater HbA1c reduction, less glycaemic variability and a clinically relevant reduction in the rates of nocturnal hypoglycaemia across comparator [glargine and isophane insulin (NPH)] studies. Trials using basal/bolus regimens had higher rates of total hypoglycaemia with BIL due to higher rates of daytime hypoglycaemia. Severe hypoglycaemia rates were similar to comparator among both patients with T1D or type 2 diabetes (T2D). T1D patients lost weight compared with glargine (GL). Patients with T2D tended to gain less weight with BIL than with glargine. Compared to glargine, BIL was associated with higher liver fat, triglycerides and alanine aminotransferase (ALT) levels, including a higher frequency of elevation of ALT ≥3 times the upper limit of normal, but without severe, acute drug-induced liver injury. Injection site reactions, primarily lipohypertrophy, were more frequent with BIL. In conclusion, BIL demonstrated better glycaemic control with reduced glucose variability and nocturnal hypoglycaemia but higher triglycerides, ALT and liver fat relative to conventional comparator insulin. The hepato-preferential action of BIL with reduced peripheral activity may account for these findings.

Basal insulin peglispro versus insulin glargine in insulin-naïve type 2 diabetes: IMAGINE 2 randomized trial.

AIMS: To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naïve adults with type 2 diabetes. MATERIAL AND METHODS: The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. RESULTS: Peglispro was non-inferior to glargine in HbA1c reduction [least-squares (LS) mean difference: -0.29%, 95% confidence interval (CI) -0.40, -0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio (OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro-treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/L), and aspartate transaminase levels (27 vs 24 IU/L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro-treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001). CONCLUSIONS: Compared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions.

Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes.

AIMS: To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). MATERIALS AND METHODS: Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naïve T2D patients and 163 T2D patients previously treated with basal insulin. RESULTS: Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine-treated patients at 4-78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P < .001), and decreased after discontinuation of BIL. More BIL patients had ALT ≥3× upper limit of normal (ULN) than glargine. No patient had ALT ≥3× ULN with bilirubin ≥2× ULN that was considered causally related to BIL. In insulin-naїve T2D patients, LFC decreased with glargine but was unchanged with BIL. In T1D and T2D patients previously treated with basal insulin, LFC was unchanged with glargine but increased with BIL. In all three populations, LFC was higher after treatment with BIL vs glargine (difference at 52 weeks: 2.2% to 5.3%, all P < .01). CONCLUSIONS: Compared to glargine, patients treated with BIL had higher ALT and LFC at 52-78 weeks. No severe drug-induced liver injury was apparent with BIL treatment for up to 78 weeks.

Is arterial base deficit still a useful prognostic marker in trauma? A systematic review.

BACKGROUND: Arterial base deficit (BD) has been widely used in trauma patients since 1960. However, trauma management has also evolved significantly in the last 2 decades. The first objective of this study was to systematically review the literature on the relationship between arterial BD as a prognostic marker for trauma outcomes (mortality, significant injuries, and major complications) in the acute setting. The second objective was to evaluate arterial BD as a prognosis marker, specifically, in the elderly and in patients with positive blood alcohol levels. METHODS: MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were searched from January 1, 1990, to August 6, 2015. Bibliographies of articles were also hand searched for relevant citations. RESULTS: Thirty-four studies were included in this review. The studies consistently showed that a higher arterial BD was associated with increased mortality, significant injuries, and major complications. The threshold BD value of 6 mmol/L was also useful in discriminating for poorer outcomes. The presence of alcohol did not affect the ability of arterial BD to discriminate between major and minor injuries. Elderly patients had higher mortality in all arterial BD categories compared to the younger age group. CONCLUSIONS: Despite the advances in trauma care in the last 2 decades, arterial BD remains a useful prognostic marker in trauma patients, even in elderly patients and in patients who had consumed alcohol. The threshold BD value of 6 mmol/L was useful to prognosticate poorer outcomes.

Improving outcomes in breast cancer for low and middle income countries.

Breast cancer is the most common cancer in women world-wide. Incidence rates in low- and middle-income countries (LMICs) are lower than in high income countries; however, the rates are increasing very rapidly in LMICs due to social changes that increase the risk of breast cancer. Breast cancer mortality rates in LMICs remain high due to late presentation and inadequate access to optimal care. Breast Surgery International brought together a group of breast surgeons from different parts of the world to address strategies for improving outcomes in breast cancer for LMICs at a symposium during International Surgical Week in Helsinki, Finland in August 2013. A key strategy for early detection is public health education and breast awareness. Sociocultural barriers to early detection and treatment need to be addressed. Optimal management of breast cancer requires a multidisciplinary team. Surgical treatment is often the only modality of treatment available in low-resource settings where modified radical mastectomy is the most common operation performed. Chemotherapy and radiotherapy require more resources. Endocrine therapy is available but requires accurate assessment of estrogen receptors status. Targeted therapy with trastuzumab is generally unavailable due to cost. The Breast Health Global Initiative guidelines for the early detection and appropriate treatment of breast cancer in LMICs have been specifically designed to improve breast cancer outcomes in these regions. Closing the cancer divide between rich and poor countries is a moral imperative and there is an urgent need to prevent breast cancer deaths with early detection and optimal access to treatment.

Dieulafoy lesion: CT diagnosis of this lesser-known cause of gastrointestinal bleeding.

A Dieulafoy lesion describes a tortuous, submucosal artery in the gastrointestinal tract--most commonly the posterior stomach--that penetrates through the mucosa over time, eventually perforating to cause severe gastrointestinal bleeding. Due to its insidious onset, tendency to cause intermittent but severe bleeding, and difficulty of endoscopic diagnosis, Dieulafoy lesion has a very high mortality rate. Although originally thought not to be a radiologically diagnosable entity, Dieulafoy lesions can be seen at enhanced CT of the abdomen. The purpose of this review is to summarize the pathophysiology, epidemiology, diagnosis, and management of Dieulafoy lesions with a focus on diagnostic findings at enhanced CT imaging.

Access to oncology consultation in a cancer cohort in northeastern Ontario.

BACKGROUND: To enhance cancer symptom management for residents of Sudbury-Manitoulin District, an ambulatory palliative clinic (pac) was established at the Northeast Cancer Centre of Health Sciences North. The pac is accessed from a medical or radiation oncology consultation. The primary purpose of the present population-based retrospective study was to estimate the percentage of cancer patients who died without ever having a medical or radiation oncology consultation. A secondary purpose was to determine factors associated with never having received one of those specialized consultations. METHODS: Administrative data was obtained through the Ontario Cancer Data Linkage Project. For each index case, we constructed a timeline, in days, of all Ontario Health Insurance Plan billing codes and associated service dates starting with the primary cancer diagnosis and ending with death. RESULTS: Within the 5-year study period (2004-2008), 6683 people in the area of interest with a valid record of primary cancer diagnosis died from any cause. Most (n = 5988, 89.6%) had 1 primary cancer diagnosis. For that subgroup, excluding those with a disease duration of 0 days (n = 67), about 18.4% (n = 1088) never had a consultation with a medical or radiation oncologist throughout their disease trajectory. Patients who were older or who resided in a rural area were significantly less likely to have had a consultation. CONCLUSIONS: Specific strategies directed toward older and rural patients might help to address this important access-to-care issue.

Spectrum of very early breast cancer in a setting without organised screening.

BACKGROUND: Within a setting without organised breast cancer screening, the characteristics and survival of very early breast cancer were determined. METHODS: All 4930 women diagnosed with breast cancer in University Malaya Medical Center, Malaysia from 1993 to 2011 were included. Factors associated with very early presentation (stage I) at diagnosis were identified. Tumour characteristics, management patterns, and survival of very early breast cancer were described, and where appropriate, compared with other settings. RESULTS: Proportion of women presenting with stage I breast cancer significantly increased from 15.2% to 25.2% over two decades. Factors associated with very early presentation were Chinese ethnicity, positive family history of breast cancer, and recent period of diagnosis. Within stage I breast cancers, median tumour size at presentation was 1.5 cm. A majority of stage I breast cancer patients received mastectomy, which was associated with older age, Chinese ethnicity, postmenopausal status, and larger tumours. Chemotherapy was administered in 36% of patients. Five-year age-adjusted relative survival for women with stage I breast cancer was 99.1% (95% CI: 97.6-99.6%). CONCLUSIONS: The proportion of women presenting with very early breast cancer in this setting without organised screening is increasing. These women seem to survive just as well as their counterparts from affluent settings.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Prognostic information of a previously diagnosed sister is an independent prognosticator for a newly diagnosed sister with breast cancer.

BACKGROUND: Breast cancer survival has been shown to be associated among relatives. In this study, we used a population-based cohort of Swedish sisters, both diagnosed with breast cancer, to determine whether prognostic information of a previously diagnosed sibling is useful for the clinical management of a newly diagnosed sibling. PATIENTS AND METHODS: The population-based cohort included all sister pairs, 1617 sisters, diagnosed with breast cancer in Sweden, from 1 January 1992, through 31 December 2006, with complete follow-up. All information was collected manually from original pathology reports and patient records. The Kappa statistic was used to measure the agreement of primary tumor characteristics between the sisters. We modeled the breast cancer-specific survival using multivariate (Cox) proportional hazard analyses in two steps categorizing the older sister's survival. RESULTS: Estrogen receptor status was the only tumor characteristic significantly associated between the sisters [κ 0.18 (95% confidence interval (CI) 0.089-0.27)]. Younger sisters with poor older sister survival showed significantly worse survival compared with patients with good older sister survival (log rank, P = 0.017). A twofold increased hazard ratio (HR) for death from breast cancer was found in younger sisters with poor older sister survival compared with patients with good sister survival [HR 2.56 (95% CI 1.16-5.65)], adjusting for age and calendar period of diagnosis, socioeconomic factors, number of children and hospital of primary tumor diagnosis. When further adjusting for primary tumor characteristics and adjuvant therapy, the risk for death from breast cancer in younger sisters with poor older sister survival became more pronounced [HR 3.35 (1.34-8.34)]. CONCLUSIONS: Our findings derived from a population-based cohort of Swedish sister pairs suggest that breast cancer-specific survival is inherited independent of tumor characteristics and treatment in the sibling later diagnosed with the disease. Prognostic information of a previously diagnosed sibling with breast cancer could be important in the clinical management.