Host protease activity classifies pneumonia etiology.

Community-acquired pneumonia (CAP) has been brought to the forefront of global health priorities due to the COVID-19 pandemic. However, classification of viral versus bacterial pneumonia etiology remains a significant clinical challenge. To this end, we have engineered a panel of activity-based nanosensors that detect the dysregulated activity of pulmonary host proteases implicated in the response to pneumonia-causing pathogens and produce a urinary readout of disease. The nanosensor targets were selected based on a human protease transcriptomic signature for pneumonia etiology generated from 33 unique publicly available study cohorts. Five mouse models of bacterial or viral CAP were developed to assess the ability of the nanosensors to produce etiology-specific urinary signatures. Machine learning algorithms were used to train diagnostic classifiers that could distinguish infected mice from healthy controls and differentiate those with bacterial versus viral pneumonia with high accuracy. This proof-of-concept diagnostic approach demonstrates a way to distinguish pneumonia etiology based solely on the host proteolytic response to infection.

Microenvironment-triggered multimodal precision diagnostics.

Therapeutic outcomes in oncology may be aided by precision diagnostics that offer early detection, localization and the opportunity to monitor response to therapy. Here, we report a multimodal nanosensor engineered to target tumours through acidosis, respond to proteases in the microenvironment to release urinary reporters and (optionally) carry positron emission tomography probes to enable localization of primary and metastatic cancers in mouse models of colorectal cancer. We present a paradigm wherein this multimodal sensor can be employed longitudinally to assess burden of disease non-invasively, including tumour progression and response to chemotherapy. Specifically, we showed that acidosis-mediated tumour insertion enhanced on-target release of matrix metalloproteinase-responsive reporters in urine. Subsequent on-demand loading of the radiotracer 64Cu allowed pH-dependent tumour visualization, enabling enriched microenvironmental characterization when compared with the conventional metabolic tracer 18F-fluorodeoxyglucose. Through tailored target specificities, this modular platform has the capacity to be engineered as a pan-cancer test that may guide treatment decisions for numerous tumour types.

Peptide Spiders: Peptide-Polymer Conjugates to Traffic Nucleic Acids.

Therapeutic nucleic acids hold great promise for the treatment of genetic diseases, yet the delivery of this highly charged macromolecular drug remains a challenge in the field. Peptides are promising agents to mediate nucleic acid delivery because they can encode a biological function to overcome the trafficking barriers. Electrostatic nanocomplexes of nucleic acid and peptides can achieve effective delivery, but the balance between their stability and biological function must be finely tuned. In this work, we explore two peptide building blocks that have been studied in the literature: targeting ligands and intracellular trafficking peptides. We grafted these peptides on a polyethylene glycol (PEG) backbone with eight sites for substitution to create so-called "peptide spiders". These conjugates achieve stability via the well-known hydrophilic shielding effect of PEG. In addition, the coordination of peptide building blocks into multimers may create new biological properties, such as the well-known phenomena of increased binding avidity with multivalent ligands. In this work, we linked two trafficking peptides to the PEG backbone using either nonreducible or reducible chemistries and investigated the ability of these materials to carry silencing RNAs into mammalian cells. We then investigated these nanomaterials for their pharmacokinetic properties and silencing of undruggable targets in a mouse model of cancer. While reducible linkages were more potent at silencing in vitro, this effect was reversed when applied in the context of living animals. This work offers an insight into peptide-based delivery materials and investigates peptide-polymer linkages.

Risk-reducing mastectomy for the prevention of primary breast cancer.

BACKGROUND: Recent progress in understanding the genetic basis of breast cancer and widely publicized reports of celebrities undergoing risk-reducing mastectomy (RRM) have increased interest in RRM as a method of preventing breast cancer. This is an update of a Cochrane Review first published in 2004 and previously updated in 2006 and 2010. OBJECTIVES: (i) To determine whether risk-reducing mastectomy reduces death rates from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast, and (ii) to examine the effect of risk-reducing mastectomy on other endpoints, including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. SEARCH METHODS: For this Review update, we searched Cochrane Breast Cancer's Specialized Register, MEDLINE, Embase and the WHO International Clinical Trials Registry Platform (ICTRP) on 9 July 2016. We included studies in English. SELECTION CRITERIA: Participants included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer. DATA COLLECTION AND ANALYSIS: At least two review authors independently abstracted data from each report. We summarized data descriptively; quantitative meta-analysis was not feasible due to heterogeneity of study designs and insufficient reporting. We analyzed data separately for bilateral risk-reducing mastectomy (BRRM) and contralateral risk-reducing mastectomy (CRRM). Four review authors assessed the methodological quality to determine whether or not the methods used sufficiently minimized selection bias, performance bias, detection bias, and attrition bias. MAIN RESULTS: All 61 included studies were observational studies with some methodological limitations; randomized trials were absent. The studies presented data on 15,077 women with a wide range of risk factors for breast cancer, who underwent RRM.Twenty-one BRRM studies looking at the incidence of breast cancer or disease-specific mortality, or both, reported reductions after BRRM, particularly for those women with BRCA1/2 mutations. Twenty-six CRRM studies consistently reported reductions in incidence of contralateral breast cancer but were inconsistent about improvements in disease-specific survival. Seven studies attempted to control for multiple differences between intervention groups and showed no overall survival advantage for CRRM. Another study showed significantly improved survival following CRRM, but after adjusting for bilateral risk-reducing salpingo-oophorectomy (BRRSO), the CRRM effect on all-cause mortality was no longer significant.Twenty studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have RRM but greater variation in satisfaction with cosmetic results. Worry over breast cancer was significantly reduced after BRRM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BRRM, but there was diminished satisfaction with body image and sexual feelings.Seventeen case series reporting on adverse events from RRM with or without reconstruction reported rates of unanticipated reoperations from 4% in those without reconstruction to 64% in participants with reconstruction.In women who have had cancer in one breast, removing the other breast may reduce the incidence of cancer in that other breast, but there is insufficient evidence that this improves survival because of the continuing risk of recurrence or metastases from the original cancer. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention, when considering RRM. AUTHORS' CONCLUSIONS: While published observational studies demonstrated that BRRM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies are suggested. BRRM should be considered only among those at high risk of disease, for example, BRCA1/2 carriers. CRRM was shown to reduce the incidence of contralateral breast cancer, but there is insufficient evidence that CRRM improves survival, and studies that control for multiple confounding variables are recommended. It is possible that selection bias in terms of healthier, younger women being recommended for or choosing CRRM produces better overall survival numbers for CRRM. Given the number of women who may be over-treated with BRRM/CRRM, it is critical that women and clinicians understand the true risk for each individual woman before considering surgery. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention when considering RRM.

A systematic review of performance-enhancing pharmacologicals and biotechnologies in the Army.

INTRODUCTION: In 2015, the Australian Army commissioned a systematic review to assess the evidence on effectiveness and safety of pharmacological and biotechnological products for cognitive enhancement specifically in Army personnel. METHODS: Searches for studies examining biotechnological and pharmacological products in Army populations were conducted in December 2015. Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO were searched without date or language restrictions. WHO's International Clinical Trials Registry Platform and ClinicalTrials.gov were searched to identify ongoing trials. Studies meeting inclusion criteria were evaluated for risk of bias using Cochrane's Risk of Bias tool. Due to heterogeneity of findings, meta-analysis could not be conducted. Findings were synthesised narratively and by vote-counting method. RESULTS: Sixteen pharmacological enhancement products were evaluated in 22 randomised controlled trials (RCTs), involving 1284 personnel. Only three of the studies were published since 2010. The interventions evaluated were varied, including supplements (eg, carbohydrate), stimulants (eg, caffeine) and hormones (eg, melatonin). Generally, caffeine provided an improvement in performance compared with placebo on 5/7 reported cognitive outcomes, followed by levothyroxine (four cognitive outcomes) and prazosin (three cognitive outcomes). Performance results were mixed (finding an improvement and no effect in comparison to placebo) for caffeine and melatonin on two outcomes. No evidence was found pertaining to biotechnological products. Studies rarely reported safety outcomes (eg, adverse events and addiction). CONCLUSION: Findings from this review need to be interpreted with considerable caution. Future studies should include outcomes such as acute and long-term adverse events, and should evaluate cognitive performance using cognitive tests that are specific to the Army population.

Sustainability in health care by allocating resources effectively (SHARE) 4: exploring opportunities and methods for consumer engagement in resource allocation in a local healthcare setting.

BACKGROUND: This is the fourth in a series of papers reporting a program of Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. Healthcare decision-makers have sought to improve the effectiveness and efficiency of services through removal or restriction of practices that are unsafe or of little benefit, often referred to as 'disinvestment'. A systematic, integrated, evidence-based program for disinvestment was being established within a large Australian health service network. Consumer engagement was acknowledged as integral to this process. This paper reports the process of developing a model to integrate consumer views and preferences into an organisation-wide approach to resource allocation. METHODS: A literature search was conducted and interviews and workshops were undertaken with health service consumers and staff. Findings were drafted into a model for consumer engagement in resource allocation which was workshopped and refined. RESULTS: Although consumer engagement is increasingly becoming a requirement of publicly-funded health services and documented in standards and policies, participation in organisational decision-making is not widespread. Several consistent messages for consumer engagement in this context emerged from the literature and consumer responses. Opportunities, settings and activities for consumer engagement through communication, consultation and participation were identified within the resource allocation process. Sources of information regarding consumer values and perspectives in publications and locally-collected data, and methods to use them in health service decision-making, were identified. A model bringing these elements together was developed. CONCLUSION: The proposed model presents potential opportunities and activities for consumer engagement in the context of resource allocation.

Tunable osteogenic differentiation of hMPCs in tubular perfusion system bioreactor.

The use of bioreactors for bone tissue engineering has been widely investigated. While the benefits of shear stress on osteogenic differentiation are well known, the underlying effects of dynamic culture on subpopulations within a bioreactor are less evident. In this work, we explore the influence of applied flow in the tubular perfusion system (TPS) bioreactor on the osteogenic differentiation of human mesenchymal progenitor cells (hMPCs), specifically analyzing the effects of axial position along the growth chamber. TPS bioreactor experiments conducted with unidirectional flow demonstrated enhanced expression of osteogenic markers in cells cultured downstream from the inlet flow. We utilized computational fluid dynamic modeling to confirm uniform shear stress distribution on the surface of the scaffolds and along the length of the growth chamber. The concept of paracrine signaling between cell populations was validated with the use of alternating flow, which diminished the differences in osteogenic differentiation between cells cultured at the inlet and outlet of the growth chamber. After the addition of controlled release of bone morphogenic protein-2 (BMP-2) into the system, osteogenic differentiation among subpopulations along the growth chamber was augmented, yet remained homogenous. These results allow for greater understanding of axial bioreactor cultures, their microenvironment, and how well-established parameters of osteogenic differentiation affect bone tissue development. With this work, we have demonstrated the capability of tuning osteogenic differentiation of hMPCs through the application of fluid flow and the addition of exogenous growth factors. Such precise control allows for the culture of distinct subpopulation within one dynamic system for the use of complex engineered tissue constructs. Biotechnol. Bioeng. 2016;113: 1805-1813. © 2016 Wiley Periodicals, Inc.

COVID-19 research response to immediate demands: setting priorities with key stakeholders to enable health services research in NSW, Australia.

PURPOSE: COVID-19 has caused unprecedented disruption to health systems. There is much to be gained by capturing what was learned from changes and adaptations made by health services and systems. The Ministry of Health in New South Wales (NSW), Australia, sought to prioritise health services research (HSR) to address critical issues arising from the COVID-19 pandemic. We tested a priority setting methodology to create priorities for a specific funding opportunity and to extract generalisable lessons. DESIGN/METHODOLOGY/APPROACH: A virtual roundtable meeting of key stakeholders was held in June 2020. We used a modified Nominal Group Technique (NGT) for priority setting, with potential items (n = 35) grouped under headings. Data was analysed through a reflective deliberative process. FINDINGS: We engaged 89 senior policy makers, health service executives, clinicians and researchers in the roundtable. The NGT proved an efficient method with participants reaching consensus on eight priorities. Findings included strong support for learning from the rapid response to COVID-19 and addressing needs of vulnerable populations and the health workforce. Opinions differed about strategic areas investment and where learnings should be via internal evaluation rather than funded research. Three of the eight recommended priorities were included in the funding opportunity. RESEARCH LIMITATIONS/IMPLICATIONS: Coronavirus disease 2019 (COVID-19) required unprecedented change and adaptations within health systems, and rapid, applied health services research can help to create, understand and (where relevant) sustain change beyond the immediate impact of the pandemic. While final decisions may be dependent on a wider range of considerations by government, stakeholder enthusiasm for engagement in priority setting exercises may be dampened if they do not perceive their application in decision-making. PRACTICAL IMPLICATIONS: A modified nominal group technique can be used to set research priorities in constrained conditions by engaging large numbers of stakeholders in rankings and then using an online delivery of a roundtable and to reach consensus on priorities in real time. Recommended priorities for health services research can be readily generated through rapid engagement but does not guarantee their application. SOCIAL IMPLICATIONS: Australia's swift response to COVID-19 pandemic in 2020 was perceived as a relative success due to the rapid public health and policy response and a relatively low number of cases. This response was underpinned by systematic knowledge mobilisation including support for targeted and prioritised health services research to fill knowledge gaps. ORIGINALITY/VALUE: Setting priority processes can provide rich, engaged input to support government funding decisions about HSR. A wide range of dynamic and iterative processes influence decision-making in a rapidly evolving situation in the health system response to COVID-19. It is crucial to consider how major investment decisions will support a value-based healthcare system.

CRISPR-Cas-amplified urinary biomarkers for multiplexed and portable cancer diagnostics.

Synthetic biomarkers, bioengineered sensors that generate molecular reporters in diseased microenvironments, represent an emerging paradigm in precision diagnostics. Despite the utility of DNA barcodes as a multiplexing tool, their susceptibility to nucleases in vivo has limited their utility. Here we exploit chemically stabilized nucleic acids to multiplex synthetic biomarkers and produce diagnostic signals in biofluids that can be 'read out' via CRISPR nucleases. The strategy relies on microenvironmental endopeptidase to trigger the release of nucleic acid barcodes and polymerase-amplification-free, CRISPR-Cas-mediated barcode detection in unprocessed urine. Our data suggest that DNA-encoded nanosensors can non-invasively detect and differentiate disease states in transplanted and autochthonous murine cancer models. We also demonstrate that CRISPR-Cas amplification can be harnessed to convert the readout to a point-of-care paper diagnostic tool. Finally, we employ a microfluidic platform for densely multiplexed, CRISPR-mediated DNA barcode readout that can potentially evaluate complex human diseases rapidly and guide therapeutic decisions.

Systematic review of safety checklists for use by medical care teams in acute hospital settings--limited evidence of effectiveness.

BACKGROUND: Patient safety is a fundamental component of good quality health care. Checklists have been proposed as a method of improving patient safety. This systematic review, asked "In acute hospital settings, would the use of safety checklists applied by medical care teams, compared to not using checklists, improve patient safety?" METHODS: We searched the Cochrane Library, MEDLINE, CINAHL, and EMBASE for randomised controlled trials published in English before September 2009. Studies were selected and appraised by two reviewers independently in consultation with colleagues, using inclusion, exclusion and appraisal criteria established a priori. RESULTS: Nine cohort studies with historical controls studies from four hospital care settings were included-intensive care unit, emergency department, surgery, and acute care. The studies used a variety of designs of safety checklists, and implemented them in different ways, however most incorporated an educational component to teach the staff how to use the checklist. The studies assessed outcomes occurring a few weeks to a maximum of 12 months post-implementation, and these outcomes were diverse.The studies were generally of low to moderate quality and of low levels of evidence, with all but one of the studies containing a high risk of bias.The results of these studies suggest some improvements in patient safety arising from use of safety checklists, but these were not consistent across all studies or for all outcomes. Some studies showed no difference in outcomes between checklist use and standard care without a checklist. Due to the variations in setting, checklist design, educational training given, and outcomes measured, it was unfeasible to accurately summarise any trends across all studies. CONCLUSIONS: The included studies suggest some benefits of using safety checklists to improve protocol adherence and patient safety, but due to the risk of bias in these studies, their results should be interpreted with caution. More high quality and studies, are needed to enable confident conclusions about the effectiveness of safety checklists in acute hospital settings.

Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants.

BACKGROUND: While the use of supplemental oxygen has a long history in neonatal care, resulting in both significant health care benefits and harms, uncertainty remains as to the most appropriate range to target blood oxygen levels in preterm and low birth weight infants. Potential benefits of higher oxygen targeting may include more stable sleep patterns and improved long-term growth and development. However, there may be significant deleterious pulmonary effects and health service use implications resulting from such a policy. OBJECTIVES: To determine whether targeting ambient oxygen concentration to achieve a lower vs. higher blood oxygen range, or administering restricted vs. liberal supplemental oxygen, effects mortality, retinopathy of prematurity, lung function, growth or development in preterm or low birth weight infants. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. An additional literature search was conducted of the MEDLINE and CINAHL databases in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR). Search updated to week two July 2008. SELECTION CRITERIA: All trials in preterm or low birth weight infants utilising random or quasi-random patient allocation in which ambient oxygen concentrations were targeted to achieve a lower vs. higher blood oxygen range, or restricted vs. liberal oxygen was administered were eligible for inclusion. DATA COLLECTION AND ANALYSIS: The methodological quality of the eligible trials was assessed independently by each review author for the degree of selection, performance, attrition and detection bias. Data were extracted and reviewed independently by the each author. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: In the meta-analysis of the five trials included in this review, the restriction of oxygen significantly reduced the incidence and severity of retinopathy of prematurity without unduly increasing death rates The one prospective, multicenter, double-blind, randomized trial investigating lower vs. higher blood oxygen levels from 32 weeks postmenstrual age showed no significant differences in the rates of ROP, mortality or growth and development between the two groups. However, this study did show increased rates of chronic lung disease and home oxygen use. AUTHORS' CONCLUSIONS: The results of this systematic review confirm that (the now historical) policy of unrestricted, unmonitored oxygen therapy has potential harms without clear benefits. However, the question of what is the optimal target range for maintaining blood oxygen levels in preterm/LBW infants was not answered by the data available for inclusion in this review.

Engineering thick tissues--the vascularisation problem.

The ability to create thick tissues is a major tissue engineering challenge, requiring the development of a suitable vascular supply. Current trends are seeing the utilization of cells seeded into hybrid matrix/scaffold systems to create in vitro vascular analogues. Approaches that aim to create vasculature in vitro include the use of biological extracellular matrices such as collagen hydrogels, porous biodegradable polymeric scaffolds with macro- and micro-lumens and micro-channels, co-culture of cells, incorporation of growth factors, culture in dynamic bioreactor environments, and combinations of these. Of particular interest are those approaches that aim to create bioengineered tissues in vitro that can be readily connected to the host's vasculature following implantation in order to maintain cell viability.

In science communication, why does the idea of a public deficit always return? How do the shifting information flows in healthcare affect the deficit model of science communication?

The healthcare field contains a multitude of opportunities for science communication. Given the many stakeholders dancing together in a multidirectional tango of communication, we need to ask how much does the deficit model apply to the health field? History dictates that healthcare professionals are the holders of all knowledge, and the patients and other stakeholders are the ones that need the scientific information communicated to them. This essay argues otherwise, in part due to the rise of shared decision-making and patients and other stakeholders acting as partners in healthcare. The traditional deficit model in health held that: (1) doctors were experts and patients were consumers, (2) it is impossible for the public to grasp the many disciplines of knowledge in medicine, (3) if experts have trouble keeping up with medical research then the public surely can't keep up, and (4) it is safer for healthcare professionals to communicate to the public using a deficit model. However, with the rise of partnerships with patients in healthcare decision-making, the deficit model might be weakening. Examples of public participation in healthcare decision-making include: (1) crowd-sourcing public participation in systematic reviews, (2) public participation in health policy, (3) public collaboration in health research, and (4) health consumer groups acting as producers of health information. With the challenges to the deficit model in science communication in health, caution is needed with the increasing role of technology and social media, and how these may affect the legitimacy of healthcare information flows away from the healthcare professional.

Analysis of the barriers and enablers to implementing lifestyle management practices for women with PCOS in Singapore.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a condition that affects women of reproductive age and manifests with adverse reproductive, metabolic and psychological consequences. Evidence-based PCOS guidelines recommend lifestyle management first line for infertility. In Singapore women with PCOS can attend the PCOS Clinic at the Kandang Kerbau Women and Children's Hospital for infertility treatment. However lifestyle integration into infertility management is currently limited and barriers and enablers to progress remain unclear. METHODS: All PCOS clinic staff undertook semi-structured interviews to investigate perceived barriers for staff and consumers for the integration of lifestyle into infertility management. This study utilised various tools including an 8P Ishikawa diagram model to identify and categorise barriers. A modified Hanlon method was then used to prioritise barriers within the Singaporean context considering organisational, cultural and financial constraints. Propriety, economics, acceptability, resources and legality (PEARL) criteria were also incorporated into this decision-making tool. RESULTS: In the 8P model, there were five factors contributing to the 'procedure (consultations and referral processes)' barrier, one 'policy (government and hospitals)' factor, five 'place' factors, two 'product (lifestyle management programme)' barriers, two 'people (programme capacity)' factors, four 'process (integration)' factors, three 'promotion' barriers and three 'price' factors. Of the prioritised barriers, two were identified across each of 'procedures', 'place', 'product' and 'people' and four related to 'processes'. There were no barriers identified that for 'policies', 'promotion' and 'price' that can be addressed. CONCLUSIONS: There is a clear need to integrate lifestyle into infertility management in PCOS, in line with current national and international evidence-based guidelines. The highest priority identified improvement opportunity was to develop a collaborative lifestyle management programme across hospital services. Reductions in variation of delivery and strengthening support within the lifestyle programme are other identified priorities. The strength of this study is that this is the first study to utilise a pragmatic quality improvement method for barriers identification and prioritisation in the area of lifestyle management for women with PCOS. This project identified factors that may provide easy improvements, but also identified some local factors that may be very difficult to change. The major limitation of this study is that it is only looking at the Singapore setting, so may have limited applicability to other countries. However, results from quality improvement projects are meant to be context specific.

Dynamic Bioreactor Culture of High Volume Engineered Bone Tissue.

Within the field of tissue engineering and regenerative medicine, the fabrication of tissue grafts of any significant size--much less a whole organ or tissue--remains a major challenge. Currently, tissue-engineered constructs cultured in vitro have been restrained in size primarily due to the diffusion limit of oxygen and nutrients to the center of these grafts. Previously, we developed a novel tubular perfusion system (TPS) bioreactor, which allows the dynamic culture of bead-encapsulated cells and increases the supply of nutrients to the entire cell population. More interestingly, the versatility of TPS bioreactor allows a large range of engineered tissue volumes to be cultured, including large bone grafts. In this study, we utilized alginate-encapsulated human mesenchymal stem cells for the culture of a tissue-engineered bone construct in the size and shape of the superior half of an adult human femur (∼ 200 cm(3)), a 20-fold increase over previously reported volumes of in vitro engineered bone grafts. Dynamic culture in TPS bioreactor not only resulted in high cell viability throughout the femur graft, but also showed early signs of stem cell differentiation through increased expression of osteogenic genes and proteins, consistent with our previous models of smaller bone constructs. This first foray into full-scale bone engineering provides the foundation for future clinical applications of bioengineered bone grafts.

Antibiotic prophylaxis for preventing recurrent cellulitis: a systematic review and meta-analysis.

IMPORTANCE: A significant proportion of patients who have had a first episode of erysipelas or uncomplicated cellulitis will subsequently develop a recurrence. There is disagreement about how effective antibiotic prophylaxis is for preventing recurrent cellulitis. OBJECTIVE: To determine if antibiotic prophylaxis is effective in preventing recurrent cellulitis compared to no prophylaxis using a systematic review and meta-analysis. DATA SOURCES: Studies in any language identified by searching Medline, EMBASE, Cochrane Library, CINAHL, TRIP database, clinical practice guidelines websites, and ongoing trials databases up to 31st August 2012. Search terms included cellulitis, erysipelas, controlled clinical trial, randomized, placebo, clinical trials, randomly, and trial. STUDY SELECTION: Only controlled trials comparing antibiotic prophylaxis to no antibiotic prophylaxis in patients age 16 years and above, and after 1 or more episodes of cellulitis, were included. DATA EXTRACTION AND SYNTHESIS: Independent extraction of articles was done by 2 investigators using predefined data extraction templates, including study quality indicators. PROSPERO registration number: CRD42012002528. Meta-analyses were done using random-effects models. MAIN OUTCOMES AND MEASURES: The primary outcome was the number of patients with a recurrence of cellulitis. Secondary outcomes were (1) the time to next episode of recurrence, (2) quality of life measures, and (3) adverse events (e.g. allergic reactions, nausea). RESULTS: Five randomized controlled trials (n = 535), with 260 patients in the intervention arm and 275 in the comparator group met our inclusion criteria. 44 patients (8%) in the antibiotic prophylaxis group and 97 patients (18%) in the comparator group had an episode of cellulitis. Antibiotic prophylaxis significantly reduced the number of patients having recurrent cellulitis, with a risk ratio (RR) of 0.46 (95% CI 0.26-0.79). None of the studies reported severe adverse effects to antibiotics. There was methodological heterogeneity amongst the studies in terms of types of antibiotic used, delivery modes, number of recurrences of cellulitis at study entry, and study quality. CONCLUSION AND RELEVANCE: Antibiotic prophylaxis can prevent recurrent cellulitis. Future research should aim to identify the ideal type, dosage, and duration of antibiotics for prophylaxis, as well as to identify the group of patients who will benefit most from antibiotic prophylaxis.

Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines.

While lifestyle management is recommended as first-line treatment of polycystic ovary syndrome (PCOS), the optimal dietary composition is unclear. The aim of this study was to compare the effect of different diet compositions on anthropometric, reproductive, metabolic, and psychological outcomes in PCOS. A literature search was conducted (Australasian Medical Index, CINAHL, EMBASE, Medline, PsycInfo, and EBM reviews; most recent search was performed January 19, 2012). Inclusion criteria were women with PCOS not taking anti-obesity medications and all weight-loss or maintenance diets comparing different dietary compositions. Studies were assessed for risk of bias. A total of 4,154 articles were retrieved and six articles from five studies met the a priori selection criteria, with 137 women included. A meta-analysis was not performed due to clinical heterogeneity for factors including participants, dietary intervention composition, duration, and outcomes. There were subtle differences between diets, with greater weight loss for a monounsaturated fat-enriched diet; improved menstrual regularity for a low-glycemic index diet; increased free androgen index for a high-carbohydrate diet; greater reductions in insulin resistance, fibrinogen, total, and high-density lipoprotein cholesterol for a low-carbohydrate or low-glycemic index diet; improved quality of life for a low-glycemic index diet; and improved depression and self-esteem for a high-protein diet. Weight loss improved the presentation of PCOS regardless of dietary composition in the majority of studies. Weight loss should be targeted in all overweight women with PCOS through reducing caloric intake in the setting of adequate nutritional intake and healthy food choices irrespective of diet composition.

Patient-held medical records for patients with chronic disease: a systematic review.

OBJECTIVES: To determine whether in patients with chronic disease a patient-held medical record (PHR), compared to usual care, improves clinical care, patient outcomes or satisfaction. DESIGN: Systematic review. DATA SOURCES: Databases searched were All EBM (The Cochrane Database of Systematic Reviews, DARE CENTRAL), Medline, CINAHL and EMBASE from 1980 to 16 February 2009. STUDY SELECTION: Two reviewers assessed comparative studies that compared paper-based PHR to usual care for inclusion using a priori study selection criteria. STUDIES REVIEWED: Four hundred and eighty-one articles were reviewed by title and abstract. Full text was retrieved for 120 articles. Fourteen studies met the inclusion and exclusion criteria and were appraised using a priori criteria for methodological quality. RESULTS: Fourteen studies were included in diabetes, oncology, mental health, rheumatoid arthritis, stroke and palliative care. The studies used a variety of designs of PHR and compared this with usual care. PHR were implemented with varying degrees of patient and staff support and education, mainly for six months or less. Outcomes included attitudes on the usefulness of PHR, the quality of information exchange, process indicators, and clinical and physiological indicators. The effectiveness of PHRs is generally of low or very low quality, with the majority of studies having a high risk of bias. These studies do not demonstrate a significant benefit of introducing PHR. CONCLUSIONS: There is no clear benefit of implementing a PHR, and due to medium to high risk of bias these findings should be interpreted with caution. More high quality studies are needed to evaluate properly the effectiveness of PHRs in chronic disease populations.