Efficacy of tetroxoprim/sulphadiazine in the treatment of Pneumocystis cannii pneumonitis in rats

Pneumocystis carinii pneumonitis was induced using dexamethasone in male Sprague-Dawley rats. After the first death due to Pn. carinii occurred, nine rats received 50mg/kg/day tetroxoprim and 120mg/kg/day sulphadiazdne. Four additional rats were given no therapy and served as a positive control. All the surviving rats including five negative controls were sacrificed four weeks after the last positive control rat died. All four rats in the positive control group and two of nine in the treated group developed Pn. carinii pneumonitis, whereas none of the five negative controls had evidence of Pn. carinii infection. The difference between the treated and untreated rats was significant (P=0-05). These results suggest that combination therapy with tetroxoprim/sulphadiazine is effective in the treatment of Pn. carinii pneumonitis in this animal model

Research is ‘a step into the unknown’: an exploration of pharmacists’ perceptions of factors impacting on research participation in the NHS

Objective This study explored National Health Service (NHS) pharmacists’ perceptions and experiences of pharmacist-led research in the workplace.  Design Semistructured, face-to-face discussions continued until distinct clusters of opinion characteristics formed. Verbatim transcripts of audio-recordings were subjected to framework analysis.  Setting Interviews were carried out with 54 pharmacists with diverse backgrounds and roles from general practices and secondary care in the UK's largest health authority.  Results The purpose and potential of health services research (HSR) was understood and acknowledged to be worthwhile by participants, but a combination of individual and system-related themes tended to make participation difficult, except when this was part of formal postgraduate education leading to a qualification. Lack of prioritisation was routinely cited as the greatest barrier, with motivation, confidence and competence as additional impediments. System-related themes included lack of practical support and pharmacy professional issues. A minority of highly motivated individuals managed to embed research participation into routine activity.  Conclusions Most pharmacists realised the desirability and necessity of research to underpin pharmacy service expansion, but a combination of individual and professional level changes is needed to increase activity. Our findings provide a starting point for better understanding the mindset of hospital-based and general practice-based pharmacists towards research, as well as their perceived barriers and supports

A roadmap for patient-public involvement and engagement (PPIE) : recounting the untold stories of breast cancer patient experiences

Introduction Breast cancer remains a prevalent disease in women worldwide. Though significant advancements in the standard of care for breast cancer have contributed to improved patient survival and quality of life, a breast cancer diagnosis and subsequent treatment interventions have a long-lasting impact on patients’ lived experiences. A high-quality healthcare system uses a patient-centred approach to healthcare, with patient engagement being a central pillar in the delivery of patient-centred care. However, the disconnect between patients and researchers can translate into research lacking real-world relevance to patient health needs. Here, we report a patient and stakeholder engagement workshop series that was conceptualized with the goal of promoting dialogue between patients with breast cancer, breast cancer researchers and the clinician involved in their care. We present the collaborative learning process and emerging opportunities from this patient engagement workshop series as a community-academic partnership. Method We report on a three-part storytelling workshop, with the scope of the workshops including topics related to raising awareness of the patient lived experience following a breast cancer diagnosis, breast cancer research activities undertaken by researchers, and the approach used by multidisciplinary healthcare teams in the management of breast cancer using storytelling as a tool. We used an iterative approach to cohort trust and relationship building, narrative development, and the use of multiple media formats to capture patient stories. This included the use of object memories, storytelling prompt cards and open-mic audio format to capture patient stories from diagnosis to treatment, and remission. Results 20 patients shared their stories with key themes emerging from the qualitative analysis of audio recordings. For many, this was the first time they had spoken about their breast cancer experience beyond family and friends. Emerging themes included common public misconceptions about a breast cancer diagnosis, the importance of self-advocacy in patient decision making about treatment, and the complex emotional journey experienced by patients diagnosed with breast cancer. The group-based storytelling approach provided collective empowerment to share personal experiences and connect meaningfully across the peer community. Conclusion While a breast cancer diagnosis can be overwhelming from a physical, social, emotional and cognitive perspective, storytelling as a patient engagement approach can build patient trust in researchers, ensuring that as key stakeholders they are involved in the process of research. Understanding the patient perspective of a breast cancer diagnosis and subsequent experiences can support healthcare professionals in developing an empathetic approach to sharing information, and involving patients in shared decision making about their healthcare

Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer

INTRODUCTION: Endocrine therapy is the most important treatment option for women with hormone-receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and crosstalk between ER and other growth factor signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. METHODS: Using immunohistochemical techniques, we focused on the expression and phosphorylation of hormone receptors themselves and examined the phosphorylation of ER-α Ser118 and ER-α Ser167 and the expression of ER-α, ER-β1, ER-βcx/β2, progesterone receptor (PR), PRA, and PRB in the primary breast carcinomas of 75 patients with metastatic breast cancer who received first-line treatment with endocrine therapy after relapse. RESULTS: Phosphorylation of ER-α Ser118, but not Ser167, was positively associated with overexpression of HER2, and HER2-positive tumors showed resistance to endocrine therapy. The present study has shown for the first time that phosphorylation of ER-α Ser167, but not Ser118, and expression of PRA and PRB, as well as ER-α and PR in primary breast tumors are predictive of response to endocrine therapy, whereas expression of ER-β1 and ER-βcx/β2 did not affect response to the therapy. In addition, patients with either high phosphorylation of ER-α Ser167, or high expression of ER-α, PR, PRA, or PRB had a significantly longer survival after relapse. CONCLUSION: These data suggest that phosphorylation of ER-α Ser167 is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in metastatic breast cancer

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

The Prolyl Isomerase Pin1 Acts Synergistically with CDK2 to Regulate the Basal Activity of Estrogen Receptor α in Breast Cancer

In hormone receptor-positive breast cancers, most tumors in the early stages of development depend on the activity of the estrogen receptor and its ligand, estradiol. Anti-estrogens, such as tamoxifen, have been used as the first line of therapy for over three decades due to the fact that they elicit cell cycle arrest. Unfortunately, after an initial period, most cells become resistant to hormonal therapy. Peptidylprolyl isomerase 1 (Pin1), a protein overexpressed in many tumor types including breast, has been demonstrated to modulate ERalpha activity and is involved in resistance to hormonal therapy. Here we show a new mechanism through which CDK2 drives an ERalpha-Pin1 interaction under hormone- and growth factor-free conditions. The PI3K/AKT pathway is necessary to activate CDK2, which phosphorylates ERalphaSer294, and mediates the binding between Pin1 and ERalpha. Site-directed mutagenesis demonstrated that ERalphaSer294 is essential for Pin1-ERalpha interaction and modulates ERalpha phosphorylation on Ser118 and Ser167, dimerization and activity. These results open up new drug treatment opportunities for breast cancer patients who are resistant to anti-estrogen therapy. © 2013 Lucchetti et al

Incentivised chronic disease management and the inverse equity hypothesis: findings from a longitudinal analysis of Scottish primary care practice-level data

Background: The inverse equity hypothesis asserts that new health policies initially widen inequality, then attenuate inequalities over time. Since 2004, the UK’s pay-for-performance scheme for chronic disease management (CDM) in primary care general practices (the Quality and Outcomes Framework) has permitted practices to except (exclude) patients from attending annual CDM reviews, without financial penalty. Informed dissent (ID) is one component of exception rates, applied to patients who have not attended due to refusal or non-response to invitations. ‘Population achievement’ describes the proportion receiving care, in relation to those eligible to receive it, including excepted patients. Examination of exception reporting (including ID) and population achievement enables the equity impact of the UK pay-for-performance contract to be assessed. We conducted a longitudinal analysis of practice-level rates and of predictors of ID, overall exceptions and population achievement for CDM to examine whether the inverse equity hypothesis holds true. Methods: We carried out a retrospective, longitudinal study using routine primary care data, analysed by multilevel logistic regression. Data were extracted from 793 practices (83% of Scottish general practices) serving 4.4 million patients across Scotland from 2010/2011 to 2012/2013, for 29 CDM indicators covering 11 incentivised diseases. This provided 68,991 observations, representing a total of 15 million opportunities for exception reporting. Results: Across all observations, the median overall exception reporting rate was 7.0% (7.04% in 2010–2011; 7.02% in 2011–2012 and 6.92% in 2012–2013). The median non-attendance rate due to ID was 0.9% (0.76% in 2010–2011; 0.88% in 2011–2012 and 0.96% in 2012–2013). Median population achievement was 83.5% (83.51% in 2010–2011; 83.41% in 2011–2012 and 83.63% in 2012–2013). The odds of ID reporting in 2012/2013 were 16.0% greater than in 2010/2011 (p < 0.001). Practices in Scotland’s most deprived communities were twice as likely to report non-attendance due to ID (odds ratio 2.10, 95% confidence interval 1.83–2.40, p < 0.001) compared with those in the least deprived; rural practices reported lower levels of non-attendance due to ID. These predictors were also independently associated with overall exceptions. Rates of population achievement did not change over time, with higher levels (higher remuneration) associated with increased rates of overall and ID exception and more affluent practices. Conclusions: Non-attendance for CDM due to ID has risen over time, and higher rates are seen in patients from practices located in disadvantaged areas. This suggests that CDM incentivisation does not conform to the inverse equity hypothesis, because inequalities are widening over time with lower uptake of anticipatory care health checks and CDM reviews noted among those most in need. Incentivised CDM needs to include incentives for engaging with the ‘hard to reach’ if inequalities in healthcare delivery are to be tackled