Microneedle-Mediated Minimally Invasive Patient Monitoring

Background: The emerging field of microneedle-based minimally invasive patient monitoring and diagnosis is reviewed. Microneedle arrays consist of rows of micron-scale projections attached to a solid support. They have been widely investigated for transdermal drug and vaccine delivery applications since the late 1990s. However, researchers and clinicians have recently realized the great potential of microneedles for extraction of skin interstitial fluid and, less commonly, blood, for enhanced monitoring of patient health.

Methods: We reviewed the journal and patent literature, and summarized the findings and provided technical insights and critical analysis.

Results: We describe the basic concepts in detail and extensively review the work performed to date.

Conclusions: It is our view that microneedles will have an important role to play in clinical management of patients and will ultimately improve therapeutic outcomes for people worldwide.

Hydrogel-Forming Microneedle Arrays Can Be Effectively Inserted in Skin by Self-Application: A Pilot Study Centred on Pharmacist Intervention and a Patient Information Leaflet

Purpose: To investigate, for the first time, the influence of pharmacist intervention and the use of a patient information leaflet on self-application of hydrogel-forming microneedle arrays by human volunteers without the aid of an applicator device.
Methods: A patient information leaflet was drafted and pharmacist counselling strategy devised. Twenty human volunteers applied 11 × 11 arrays of 400 μm hydrogel-forming microneedle arrays to their own skin following the instructions provided. Skin barrier function disruption was assessed using transepidermal water loss measurements and optical coherence tomography and results compared to those obtained when more experienced researchers applied the microneedles to the volunteers or themselves.
Results: Volunteer self-application of the 400 μm microneedle design resulted in an approximately 30% increase in skin transepidermal water loss, which was not significantly different from that seen with self-application by the more experienced researchers or application to the volunteers. Use of optical coherence tomography showed that self-application of microneedles of the same density (400 μm, 600 μm and 900 μm) led to percentage penetration depths of approximately 75%, 70% and 60%, respectively, though the diameter of the micropores created remained quite constant at approximately 200 μm. Transepidermal water loss progressively increased with increasing height of the applied microneedles and this data, like that for penetration depth, was consistent, regardless of applicant.
Conclusion: We have shown that hydrogel-forming microneedle arrays can be successfully and reproducibly applied by human volunteers given appropriate instruction. If these outcomes were able to be extrapolated to the general patient population, then use of bespoke MN applicator devices may not be necessary, thus possibly enhancing patient compliance.

Streptococcus bovis bacteraemia: an evaluation of the long-term effect on cardiac outcomes

Introduction: Streptococcus bovis can lead to bacteraemia, septicaemia, and ultimately endocarditis. The objective of this study was to evaluate the long-term implications of S. bovis endocarditis on cardiac morbidity and mortality. 

Methods: A retrospective cohort study was performed between January 2000 and March 2009 to assess all patients diagnosed with S. bovis bacteraemia from the Belfast Health and Social Care Trust. The primary end-point for cardiac investigations was the presence of endocarditis. Secondary end-points included referral for cardiac surgery and overall mortality. 

Results: Sixty-one positive S. bovis blood cultures from 43 patients were included. Following echocardiography, seven patients were diagnosed with infective endocarditis (16.3 % of total patients); four patients (9.3 %) had native valve involvement while three (7.0 %) had prosthetic valve infection. Five of these seven patients had more than one positive S. bovis culture (71.4 %). Three had significant valve dysfunction that warranted surgical repair/replacement, one of whom was unfit for surgery. There was a 100 % recurrence rate amongst the valve replacement patients (n = 2) and six patients with endocarditis had colorectal pathology. Patients with endocarditis had similar long-term survival as those with non-endocarditic bacteraemia (57.1 % alive vs. 50 % of non-endocarditis patients, p = 0.73). 

Conclusion: Streptococcus bovis endocarditis patients tended to have pre-existing valvular heart disease and those with prosthetic heart valves had higher surgical intervention and relapse rates. These patients experienced a higher rate of co-existing colorectal pathology but currently have reasonable long-term outcomes. This may suggest that they represent a patient population that merits consideration for an early surgical strategy to maximise long-term results, however, further evaluation is warranted. © 2013 The Japanese Association for Thoracic Surgery.

Using postal questionnaires to evaluate physical activity and diet behaviour change: case study exploring implications of valid responder characteristics in interpreting intervention outcomes.

Background: Patient reported outcome measures (PROMs) are used to evaluate lifestyle interventions but littleis known about differences between patients returning valid and invalid responses, or of potential for bias inevaluations. We aimed to examine the characteristics of patients who returned valid responses to lifestylequestionnaires compared to those whose responses were invalid for evaluating lifestyle change. 
Methods: We conducted a secondary data analysis from the SPHERE Study, a trial of an intervention to improveoutcomes for patients with coronary heart disease in primary care. Postal questionnaires were used to assessphysical activity (Godin) and diet (DINE) among study participants at baseline and 18 month follow-up. Three binaryresponse variables were generated for analysis: (1) valid Godin score; (2) valid DINE Fibre score; and (3) validDINE Total Fat score. Multivariate analysis comprised generalised estimating equation regression to examine theassociation of patients’ characteristics with their return of valid responses at both timepoints. 
Results: Overall, 92.1% of participants (832/903) returned questionnaires at both baseline and 18 months. Relativelyfewer valid Godin scores were returned by those who left school aged <15 years (36.5%) than aged 18 and over(50.5%), manual workers (39.5%) than non-manual (49.5%) and those with an elevated cholesterol (>5 mmol)(34.7%) than those with a lower cholesterol (44.4%) but multivariate analysis identified that only school leaving age(p = 0.047) was of statistical significance.Relatively fewer valid DINE scores were returned by manual than non-manual workers (fibre: 80.8% v 86.8%;fat: 71.2% v 80.0%), smokers (fibre: 72.6% v 84.7%; fat: 67.5% v 76.9%), patients with diabetes (fibre: 75.9% v 82.9%;fat: 66.9% v 75.8%) and those with cholesterol >5 mmol (fat: 68.2% v 76.2%) but multivariate analysis showedstatistical significance only for smoking (fibre: p = 0.013; fat: p = 0.045), diabetes (fibre: p = 0.039; fat: p = 0.047), andcholesterol (fat: p = 0.039). 
Conclusions: Our findings illustrate the importance of detailed reporting of research methods, with clearinformation about response rates, respondents and valid outcome data. Outcome measures which are relevant to astudy population should be chosen carefully. The impact of methods of outcome measurement and valid responserates in evaluating healthcare requires further study.

Preserving arteriovenous fistula outcomes during surgical training

PURPOSE: Arteriovenous fistulae (AVFs) are the preferred option for vascular access, as they are associated with lower mortality in hemodialysis patients than in those patients with arteriovenous grafts (AVGs) or central venous catheters (CVCs). We sought to assess whether vascular access outcomes for surgical trainees are comparable to fully trained surgeons.

METHODS: A prospectively collected database of patients was created and information recorded regarding patient demographics, past medical history, preoperative investigations, grade of operating surgeon, type of AVF formed, primary AVF function, cumulative AVF survival and functional patency.

RESULTS: One hundred and sixty-two patients were identified as having had vascular access procedures during the 6 month study period and 143 were included in the final analysis. Secondary AVF patency was established in 123 (86%) of these AVFs and 89 (62.2%) were used for dialysis. There was no significant difference in survival of AVFs according to training status of surgeon (log rank x2 0.506 p=0.477) or type of AVF (log rank x2 0.341 p=0.559). Patency rates of successful AVFs at 1 and 2 years were 60.9% and 47.9%, respectively.

CONCLUSION: We have demonstrated in this prospective study that there are no significant differences in outcomes of primary AVFs formed by fully trained surgeons versus surgical trainees. Creation of a primary AVF represents an excellent training platform for intermediate stage surgeons across general and vascular surgical specialties.

Precision Teaching in IV Fluid Prescribing and Patient Safety

OBJECTIVES: Precision Teaching (PT) has been shown to be an effective intervention to assess teaching method effectiveness and evaluate learning outcomes. SAFMEDS (Say All Fast Minute Every Day Shuffled) are a practice/assessment procedure within the PT framework to assist learning and fluency. We explored the effects of a brief intervention with PT, to impart high frequency performance in safe intravenous fluid prescription in a group of final year undergraduate medical students.
METHODS: 133 final year undergraduate medical students completed a multiple choice question (MCQ) test on safe IV fluid prescription at the beginning and end of the study. The control group (n= 76) of students were taught using a current standardized teaching method. Students allocated to the intervention arm of the study were additionally instructed on PT and the use of SAFMEDS. The study group (n = 57) received 50 SAFMEDS cards containing information on the principles of IV fluid prescription scenarios. These students were trained/tested twice per day for 1 minute.
RESULTS: Interim analysis showed that the study group displayed an improvement in fluency and accuracy as the study progressed. There was a statistically significant improvement in MCQ performance for the PT group compared with the control group between the beginning and end of the study (35% vs 15%).
CONCLUSION: These results suggest PT employing SAFMEDS is an effective method for improving fluency, accuracy and patient safety in intravenous fluid prescribing amongst undergraduate medical students.

Treatment adherence and health outcomes in patients with bronchiectasis

Background: We aimed to determine adherence to inhaled antibiotics, other respiratory medicines and airway clearance and to determine the association between adherence to these treatments and health outcomes (pulmonary exacerbations, lung function and Quality of Life Questionnaire-Bronchiectasis [QOL-B]) in bronchiectasis after 12 months.

Methods: Patients with bronchiectasis prescribed inhaled antibiotics for Pseudomonas aeruginosa infection were recruited into a one-year study. Participants were categorised as " adherent" to medication (medication possession ratio ≥80% using prescription data) or airway clearance (score ≥80% in the Modified Self-Reported Medication-Taking Scale). Pulmonary exacerbations were defined as treatment with a new course of oral or intravenous antibiotics over the one-year study. Spirometry and QOL-B were completed at baseline and 12 months. Associations between adherence to treatment and pulmonary exacerbations, lung function and QOL-B were determined by regression analyses.

Results: Seventy-five participants were recruited. Thirty-five (53%), 39 (53%) and 31 (41%) participants were adherent to inhaled antibiotics, other respiratory medicines, and airway clearance, respectively. Twelve (16%) participants were adherent to all treatments. Participants who were adherent to inhaled antibiotics had significantly fewer exacerbations compared to non-adherent participants (2.6 vs 4, p = 0.00) and adherence to inhaled antibiotics was independently associated with having fewer pulmonary exacerbations (regression co-efficient = -0.51, 95% CI [-0.81,-0.21], p < 0.001). Adherence to airway clearance was associated with lower QOL-B Treatment Burden (regression co-efficient = -15.46, 95% CI [-26.54, -4.37], p < 0.01) and Respiratory Symptoms domain scores (regression co-efficient = -10.77, 95% CI [-21.45; -0.09], p < 0.05). There were no associations between adherence to other respiratory medicines and any of the outcomes tested. Adherence to treatment was not associated with FEV₁ % predicted.

Conclusions: Treatment adherence is low in bronchiectasis and affects important health outcomes including pulmonary exacerbations. Adherence should be measured as part of bronchiectasis management and future research should evaluate bronchiectasis-specific adherence strategies. 

Recipient obesity and outcomes after kidney transplantation: a systematic review and meta-analysis

BACKGROUND: The prevalence of obesity is increasing globally and is associated with chronic kidney disease and premature mortality. However, the impact of recipient obesity on kidney transplant outcomes remains unclear. This study aimed to investigate the association between recipient obesity and mortality, death-censored graft loss and delayed graft function (DGF) following kidney transplantation.

METHODS: A systematic review and meta-analysis was conducted using Medline, Embase and the Cochrane Library. Observational studies or randomized controlled trials investigating the association between recipient obesity at transplantation and mortality, death-censored graft loss and DGF were included. Obesity was defined as a body mass index (BMI) of ≥30 kg/m(2). Obese recipients were compared with those with a normal BMI (18.5-24.9 kg/m(2)). Pooled estimates of hazard ratios (HRs) for patient mortality or death-censored graft loss and odds ratios (ORs) for DGF were calculated.

RESULTS: Seventeen studies including 138 081 patients were analysed. After adjustment, there was no significant difference in mortality risk in obese recipients [HR = 1.24, 95% confidence interval (CI) = 0.90-1.70, studies = 5, n = 83 416]. However, obesity was associated with an increased risk of death-censored graft loss (HR = 1.06, 95% CI = 1.01-1.12, studies = 5, n = 83 416) and an increased likelihood of DGF (OR = 1.68, 95% CI = 1.39-2.03, studies = 4, n = 28 847).

CONCLUSIONS: Despite having a much higher likelihood of DGF, obese transplant recipients have only a slightly increased risk of graft loss and experience similar survival to recipients with normal BMI.

Cultivating Compassion through analysis of online patient narratives

Compassion is at the forefront of national and international healthcare policy, practice and educational debates as a result of a series of recent reports (Mid Staffordshire NHS Foundation Trust Inquiry, 2010, Lown et al 2011, Mannion, 2014). Arguably, this emphasis on compassion is in juxtaposition to an increasingly complex technological healthcare system focused upon outcomes, efficiency, productivity and competence. Within this fast paced and time pressured environment innovative strategies are required to cultivate and sustain compassion among healthcare professionals.

Understanding the person’s experience of illness and making an emotional connection are key processes in cultivating compassion (Dewar, 2013). The exponential growth in unsolicited patient narratives has the potential to provide invaluable insight into what matters to patients and their experience of illness. For many patients these stories ‘reclaim’ their illnesses from the traditional biomedical model of disease and reveal otherwise hidden aspects of their experience. The content though freely accessible, is however unedited and lacks safeguards in relation to the quality or accuracy of the information provided. Despite these concerns, healthcare professionals are now challenged to pay attention to these unsolicited patient stories and to consider how they can inform and improve patient care.

This paper discusses the use of online patient narratives in undergraduate nurse education to cultivate compassion. Critical analysis of online patient narratives is advocated as a potential educational strategy to cultivate compassion among future health care professionals.

References
Dewar,B. (2013) Cultivating compassionate care Nursing Standard 27, (34) 48-55

Lown B, Rosen J, Martilla J.(2011) An agenda for improving compassionate care: a survey shows about half of patients say such care is missing. Health Affairs (Millwood) 30, 1772–8.
Mannion,R. (2014) Enabling compassionate healthcare: perils, prospects and perspectives International Journal of Health Policy and Management 2, 115-7
Mid Staffordshire NHS Foundation Trust Inquiry (2010). Independent Inquiry into care provided by Mid Staffordshire NHS Foundation London: Stationery Office.

Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study

Background
Among clinical trials of interventions that aim to modify time spent on mechanical ventilation for critically ill patients there is considerable inconsistency in chosen outcomes and how they are measured. The Core Outcomes in Ventilation Trials (COVenT) study aims to develop a set of core outcomes for use in future ventilation trials in mechanically ventilated adults and children.

Methods/design
We will use a mixed methods approach that incorporates a randomised trial nested within a Delphi study and a consensus meeting. Additionally, we will conduct an observational cohort study to evaluate uptake of the core outcome set in published studies at 5 and 10 years following core outcome set publication. The three-round online Delphi study will use a list of outcomes that have been reported previously in a review of ventilation trials. The Delphi panel will include a range of stakeholder groups including patient support groups. The panel will be randomised to one of three feedback methods to assess the impact of the feedback mechanism on subsequent ranking of outcomes. A final consensus meeting will be held with stakeholder representatives to review outcomes.

Discussion
The COVenT study aims to develop a core outcome set for ventilation trials in critical care, explore the best Delphi feedback mechanism for achieving consensus and determine if participation increases use of the core outcome set in the long term.

Molecular markers for predicting recurrence, progression and outcomes of bladder cancer (do the poster boys need new posters

Purpose of review
Molecular markers for bladder cancer recurrence and
progression continue to drive many research programmes.
Translating the laboratory findings into the clinical environment
where these markers are used in clinical decision making has
proved problematic. In the clinical arena, stage and grade are
still the main focus for decisions about patient management.
There is however an evolution in bladder cancer research from
single-marker/single-pathway research to a more global
assessment of the tumour cell with DNA microarrays and
proteomics.
Recent findings
In the last year, DNA microarray assessment has revealed
several interesting molecular markers such as p33ING1 and
DEK. Parallel ‘conventional’ single-pathway research has
focused on new novel markers such as HER2/neu, survivin and
matrix metalloproteinase 2 (MMP-2). Molecular markers that
have a long-standing association with bladder cancer
progression such as p53, E-cadherin and Ki-67 have been
reviewed by both single-marker studies and by microarray
studies and their status remains important.
Summary
It is an exciting time in the molecular biology research of bladder
cancer as the focus changes to assess the global genetic and
protein expression within tumour cells. From such a wealth of
information it is likely that molecular markers will make the
translation from benchside to bedside.

Cancer and serious mental illness – patient, caregiver and professional perspectives: study protocol

Aim: To explore the experience of serious mental illness and cancer from the perspective of patients, significant others and healthcare professionals involved in their care. Background: Serious mental illness is associated with poorer cancer outcomes. Those suffering from this comorbidity receive fewer specialist interventions and die earlier than the general population. Prior qualitative research in this area has comprised of a single study focussing on healthcare professionals and there is little evidence regarding the experiences of patients and caregivers.Design: A qualitative exploration using approximately 36 semi-structured interviews.Methods: Semi-structured digitally recorded interviews conducted with: adults living with serious mental illness and diagnosed with cancer; those providing them with informal support and care; and healthcare professionals. Questions will focus on the experience of having cancer and serious mental illness or caring for someone with this comorbidity, experiences of healthcare and priorities for patients and carers. Framework analysis will be used. Research Ethics Committee and Trust Research & Development approval was obtained. A steering group comprising six people with experience of either cancer or mental illness provided feedback and ratified the patient information sheets and interview schedules. Discussion: There is a paucity of research addressing stakeholder perspectives on the experience of cancer and of cancer services for people with serious mental illness. Dissemination of findings will inform practice relating to the care of an often neglected population, informing better support for their significant others and the professionals involved in their care.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND: Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

METHODS: We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

FINDINGS: We received data on 18 766 women (18 206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02).

INTERPRETATION: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

FUNDING: Cancer Research UK, Medical Research Council.

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

BACKGROUND: The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.

METHODS: We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).

FINDINGS: In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar.

INTERPRETATION: Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment.

FUNDING: Cancer Research UK, Medical Research Council.