TEACH (Train to Enable/Achieve Culturally Sensitive Healthcare)

Personnel from diverse ethnic and demographic backgrounds come together in both civilian and military healthcare systems, facing diagnoses that at one level are equalizers: coronary disease is coronary disease, breast cancer is breast cancer. Yet the expression of disease in individuals from different backgrounds, individual patient experience of disease as a particular illness, and interactions between patients and providers occurring in any given disease scenario, all vary enormously depending on the fortuity of the equation of "which patient happens to arrive in whose exam room." Previously, providers' absorption of lessons-learned depended on learning as an apprentice would when exposed over time to multiple populations. As a result, and because providers are often thrown into situations where communications falter through inadequate direct patient experience, diversity in medicine remains a training challenge. The questions then become: Can simulation and virtual training environments (VTEs) be deployed to short-track and standardize this sort of random-walk problem? Can we overcome the unevenness of training caused by some providers obtaining the valuable exposure to diverse populations, whereas others are left to "sink or swim"? This paper summarizes developing a computer-based VTE called TEACH (Training to Enable/Achieve Culturally Sensitive Healthcare). TEACH was developed to enhance healthcare providers' skills in delivering culturally sensitive care to African-American women with breast cancer. With an authoring system under development to ensure extensibility, TEACH allows users to role-play in clinical oncology settings with virtual characters who interact on the basis of different combinations of African American sub-cultural beliefs regarding breast cancer. The paper reports on the roll-out and evaluation of the degree to which these interactions allow providers to acquire, practice, and refine culturally appropriate communication skills and to achieve cultural and individual personalization of healthcare in their clinical practices

Peripheral Synthesis of an Atypical Protein Kinase C Mediates the Enhancement of Excitability and the Development of Mechanical Hyperalgesia Produced by Nerve Growth Factor

Nerve growth factor (NGF) plays a key role in the initiation as well as the prolonged heightened pain sensitivity of the inflammatory response. Previously, we showed that NGF rapidly augmented both the excitability of isolated rat sensory neurons and the mechanical sensitivity of the rat’s hind paw. The increase in excitability and sensitivity was blocked by the myristoylated pseudosubstrate inhibitor of atypical PKCs (mPSI), suggesting that an atypical PKC may play a key regulatory role in generating this heightened sensitivity. Our findings raised the question as to whether NGF directs changes in translational control, as suggested for long-lasting long-term potentiation (LTP), or whether NGF leads to the activation of an atypical PKC by other mechanisms. The current studies demonstrate that enhanced action potential (AP) firing produced by NGF was blocked by inhibitors of translation, but not transcription. In parallel, in vitro studies showed that NGF elevated the protein levels of PKMζ, which was also prevented by inhibitors of translation. Intraplantar injection of NGF in the rat hind paw produced a rapid and maintained increase in mechanical sensitivity whose onset was delayed by translation inhibitors. Established NGF-induced hypersensitivity could be transiently reversed by injection of rapamycin or mPSI. These results suggest that NGF produces a rapid increase in the synthesis of PKMζ protein in the paw that augments neuronal sensitivity and that the ongoing translational expression of PKMζ plays a critical role in generating as well as maintaining the heightened sensitivity produced by NGF

An Open-Label, Multicenter, Phase I, Dose Escalation Study with Phase II Expansion Cohort to Determine the Safety, Pharmacokinetics, and Preliminary Antitumor Activity of Intravenous TKM-080301 in Subjects with Advanced Hepatocellular Carcinoma.

Lessons learnedTKM-080301 showed a favorable toxicity profile at the studied dose.TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent.BackgroundPolo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation.MethodsA 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days.ResultsThe study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months.ConclusionTKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted

Drug use and HIV infection status of detainees in re-education through labour camps in Guangxi Province, China

This study describes HIV disease burden and patterns of drug use before and during incarceration among detainees in Re-education-Through-Labour-Camps (RTLCs) in China. A cross-sectional survey of 576 men and 179 women from three RTLCs was conducted in Guangxi Province, China. Over three-quarters of study participants were detained due to drug-related offences. Over half of the women (n = 313, 54.3%) and twothirds of men (n = 119, 66.5%) had been previously been incarcerated in a compulsory detoxification treatment centre (CDTC), and around one-third (men n = 159, 27.6%; women n = 50, 27.9%) in a RTLC. Of those surveyed, 49 men (8.5%) and one (0.6%) woman reported ever using drugs while in a CDTC and/or RTLC. Previous incarceration in CDTCs and RTLCs were associated with HIV infection among both male (OR = 2.15 [1.11–4.15]) and female (OR = 3.87 [1.86–9.04]) detainees. Being married/cohabiting with a partner (OR = 0.53, [0.30–0.93]) and being employed (OR = 0.46, [0.22–0.95]) were associated with a reduced odds of HIV infection among male detainees. A significant proportion of RTLC detainees had a history of drug use and a limited number of inmates had used illegal substances whilst in custody. Repeat incarcerations in CDTCs/RTLCs were associated with higher risks of HIV infection

Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis

Background: Mucositis is a toxic side effect of anti-cancer treatments and is a major focus in cancer research. Pro-inflammatory cytokines have previously been implicated in the pathophysiology of chemotherapy-induced gastrointestinal mucositis. However, whether they play a key role in the development of radiotherapy-induced gastrointestinal mucositis is still unknown. Therefore, the aim of the present study was to characterise the expression of pro-inflammatory cytokines in the gastrointestinal tract using a rat model of fractionated radiotherapy-induced toxicity. Methods: Thirty six female Dark Agouti rats were randomly assigned into groups and received 2.5 Gys abdominal radiotherapy three times a week over six weeks. Real time PCR was conducted to determine the relative change in mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF in the jejunum and colon. Protein expression of IL-1β, IL-6 and TNF in the intestinal epithelium was investigated using qualitative immunohistochemistry. Results: Radiotherapy-induced sub-acute damage was associated with significantly upregulated IL-1β, IL-6 and TNF mRNA levels in the jejunum and colon. The majority of pro-inflammatory cytokine protein expression in the jejunum and colon exhibited minimal change following fractionated radiotherapy. Conclusions: Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.Zhi Yi Ong, Rachel J. Gibson, Joanne M. Bowen, Andrea M. Stringer, Jocelyn M. Darby, Richard M. Logan, Ann S.J. Yeoh, Dorothy M. Keef

The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells

Implantation requires coordinated interactions between the conceptus and surrounding decidual cells, but the involvement of clock genes in this process is incompletely understood. Circadian oscillations are predicated on transcriptional-translational feedback loops, which balance the activities of the transcriptional activators CLOCK (circadian locomotor output cycles kaput) and brain muscle arnt-like 1 and repressors encoded by PER (Period) and Cryptochrome genes. We show that loss of PER2 expression silences circadian oscillations in decidualizing human endometrial stromal cells (HESCs). Down-regulation occurred between 12 and 24 hours following differentiation and coincided with reduced CLOCK binding to a noncanonical E-box enhancer in the PER2 promoter. RNA sequencing revealed that premature inhibition of PER2 by small interfering RNA knockdown leads to a grossly disorganized decidual response. Gene ontology analysis highlighted a preponderance of cell cycle regulators among the 1121 genes perturbed upon PER2 knockdown. Congruently, PER2 inhibition abrogated mitotic expansion of differentiating HESCs by inducing cell cycle block at G2/M. Analysis of 70 midluteal endometrial biopsies revealed an inverse correlation between PER2 transcript levels and the number of miscarriages in women suffering reproductive failure (Spearman rank test, ρ = -0.3260; P = 0.0046). Thus, PER2 synchronizes endometrial proliferation with initiation of aperiodic decidual gene expression; uncoupling of these events may cause recurrent pregnancy loss.-Muter, J., Lucas, E. S., Chan, Y.-W., Brighton, P. J., Moore, J. D., Lacey, L., Quenby, S., Lam, E. W.-F., Brosens, J. J. The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells

Implementation of a complex intervention to improve care for patients whose situations are clinically uncertain in hospital settings: A multi-method study using normalisation process theory

Purpose: To examine the use of Normalisation Process Theory (NPT) to establish if, and in what ways, the AMBER care bundle can be successfully normalised into acute hospital practice, and to identify necessary modifications to optimise its implementation. Method: Multi-method process evaluation embedded within a mixed-method feasibility cluster randomised controlled trial in two district general hospitals in England. Data were collected using (i) focus groups with health professionals (HPs), (ii) semi-structured interviews with patients and/or carers, (iii) non-participant observations of multi-disciplinary team meetings and (iv) patient clinical note review. Thematic analysis and descriptive statistics, with interpretation guided by NPT components (coherence; cognitive participation; collective action; reflexive monitoring). Data triangulated across sources. Results: Two focus groups (26 HPs), nine non-participant observations, 12 interviews (two patients, 10 relatives), 29 clinical note reviews were conducted. While coherence was evident, with HPs recognising the value of the AMBER care bundle, cognitive participation and collective action presented challenges. Specifically: (1) HPs were unable and unwilling to operationalise the concept of ‘risk of dying’ intervention eligibility criteria (2) integration relied on a ‘champion’ to drive participation and ensure sustainability; and (3) differing skills and confidence led to variable engagement with difficult conversations with patients and families about, for example, nearness to end of life. Opportunities for reflexive monitoring were not routinely embedded within the intervention. Reflections on the use of the AMBER care bundle from HPs and patients and families, including recommended modifications became evident through this NPT-driven analysis. Conclusion: To be successfully normalised, new clinical practices, such as the AMBER care bundle, must be studied within the wider context in which they operate. NPT can be used to the aid identification of practical strategies to assist in normalisation of complex interventions where the focus of care is on clinical uncertainty in acute hospital settings