Evaluation of a 3D surface imaging system for deep inspiration breath-hold patient positioning and intra-fraction monitoring

PURPOSE: To determine the accuracy of a surface guided radiotherapy (SGRT) system for positioning of breast cancer patients in breath-hold (BH) with respect to cone-beam computed tomography (CBCT). Secondly, to evaluate the thorax position stability during BHs with SGRT, when using an air-volume guidance system.METHODS AND MATERIALS: Eighteen left-sided breast cancer patients were monitored with SGRT during CBCT and treatment, both in BH. CBCT scans were matched on the target volume and the patient surface. The setup error differences were evaluated, including with linear regression analysis. The intra-fraction variability and stability of the air-volume guided BHs were determined from SGRT measurements. The variability was determined from the maximum difference between the different BH levels within one treatment fraction. The stability was determined from the difference between the start and end position of each BH.RESULTS: SGRT data correlated well with CBCT data. The correlation was stronger for surface-to-CBCT (0.61) than target volume-to-CBCT (0.44) matches. Systematic and random setup error differences were ≤ 2 mm in all directions. The 95% limits of agreement (mean ± 2SD) were 0.1 ± 3.0, 0.6 ± 4.1 and 0.4 ± 3.4 mm in the three orthogonal directions, for the surface-to-CBCT matches. For air-volume guided BHs, the variability detected with SGRT was 2.2, 2.8 and 2.3 mm, and the stability - 1.0, 2.1 and 1.5 mm, in three orthogonal directions. Furthermore, the SGRT system could detect unexpected patient movement, undetectable by the air-volume BH system.CONCLUSION: With SGRT, left-sided breast cancer patients can be positioned and monitored continuously to maintain position errors within 5 mm. Low intra-fraction variability and good stability can be achieved with the air-volume BH system, however, additional patient position information is available with SGRT, that cannot be detected with air-volume BH systems.</p

A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Drug Use, Gender-Based Violence, Sex Work and (Il)Legality: Intersecting Vulnerabilities among Women who use Drugs.

The legal ambiguity surrounding sex work in Kenya makes it an operational grey area, more so for women who use drugs (WWUD) who are a “hidden population”. While the law does not criminalize prostitution, living off the proceeds of prostitution, loitering in public spaces and soliciting or importuning for immoral purposes attract legal sanction. This ambiguity encourages violations among WWUD doing sex work on streets, alleys or in drug dens (maeneo). The objectives were to assess the prevalence and lived experiences of gender-based violence among WWUD; and factors that protect and perpetuate gender-based violence among WWUD. This was a qualitative phenomenological study using focus group discussions (FGD) and in-depth interviews (IDI) was conducted in Mombasa and Kilifi counties among a convenient sample of 43 respondents (36 WWUD and seven key informants). Findings show that 75% of WWUD engaged in sex work in alleys, empty grounds and bushes at night to finance drug use, meet basic needs and as a way to keep intimate partners away from petty crime to finance drug use. Sexual violence was majorly perpetrated by non-drug users and included unwanted touch, deliberate tearing of condoms during sex, forced sex, uncomfortable sexual positions and demands for anal sex and getting paid less money or nothing for sex work. Sex workers also suffered physical, psychological and verbal abuse from clients, law enforcement officers and intimate partners. These include taunts/guilt tripping, stigma, strangulation, threats and robbery. Violations were rarely reported due to self- and societal stigma, economic vulnerability, fear of and perceptions of police as unhelpful and uninterested and lack of witnesses. WWUD in sex work also suffer discrimination in other “formal” work. Findings show that WWUD doing sex work have neither legitimate nor illegitimate means to survive. For resolution of resultant anomie, we recommend legal advocacy and law enforcement protections for WWUD in sex work; economic empowerment through training and seed funds for small and medium sized enterprises; and social support for WWUD to deal with stigma, and social and self-rejection

Gender based violence against women who use drugs (WWUD) in Kenya: Experiences and Policy Directions.

Gender-based violence (GBV) is most pervasive among vulnerable populations including sex workers, women living in poor socioeconomic conditions and women who use drugs (WWUD). Some community-based studies show that the prevalence of GBV against WWUD might be between 2-5 times higher than that of women in the general population (Gilbert et al., 2015) with higher rates in Sub-Saharan Africa (Pack et al., 2014; Swart, 2012). WWUD also have substantially higher rates of sexual assault from non-intimate partners than the general population, with perpetrators including drug dealers, sex work clients and police (UNODC, 2019). A range of factors at individual, family, community and structural levels increase the risk of perpetration and/or victimization of GBV. These factors include: poor education (Capaldi et al., 2012), past exposure to family violence and abuse, gender inequality, poverty, social norms accepting of violence (WHO, 2013), and a history of drug use (Abramsky et al., 2011; WHO, 2012). For WWUD, having drug-using partners (Okal et al., 2011; Pack et al., 2014) and engaging in transactional sex (Mburu et al., 2019) increases the risk of victimization via the ensuing stigma and discrimination. The experience of gender-based violence among this population is also related to poverty and the normalization of GBV in African culture (Kimuna & Djamba, 2008) including women’s own positive perceptions of partner violence (Pack et al., 2014). GBV against WWUD is a threat to their mental health (WHO, 2013) and is also associated with stigma (UNHIV, 2014), HIV/AIDS and unplanned pregnancies, and adverse effects on their children (Abramsky et al., 2011). It also has social and economic costs for the individual, their family and society. This policy brief relies on data from a study of lived experiences of gender-based violence, and structures that perpetuate such violence among women who use drugs in Mombasa and Kilifi counties