Posttranslational, site-directed photochemical fluorine editing of protein sidechains to probe residue oxidation state via 19F-nuclear magnetic resonance.

The fluorination of amino acid residues represents a near-isosteric alteration with the potential to report on biological pathways, yet the site-directed editing of carbon-hydrogen (C-H) bonds in complex biomolecules to carbon-fluorine (C-F) bonds is challenging, resulting in its limited exploitation. Here, we describe a protocol for the posttranslational and site-directed alteration of native γCH2 to γCF2 in protein sidechains. This alteration allows the installation of difluorinated sidechain analogs of proteinogenic amino acids, in both native and modified states. This chemical editing is robust, mild, fast and highly efficient, exploiting photochemical- and radical-mediated C-C bonds grafted onto easy-to-access cysteine-derived dehydroalanine-containing proteins as starting materials. The heteroaryl-sulfonyl reagent required for generating the key carbon-centered C• radicals that install the sidechain can be synthesized in two to six steps from commercially available precursors. This workflow allows the nonexpert to create fluorinated proteins within 24 h, starting from a corresponding purified cysteine-containing protein precursor, without the need for bespoke biological systems. As an example, we readily introduce three γCF2-containing methionines in all three progressive oxidation states (sulfide, sulfoxide and sulfone) as D-/L- forms into histone eH3.1 at site 4 (a relevant lysine to methionine oncomutation site), and each can be detected by 19F-nuclear magnetic resonance of the γCF2 group, as well as the two diastereomers of the sulfoxide, even when found in a complex protein mixture of all three. The site-directed editing of C-H→C-F enables the use of γCF2 as a highly sensitive, 'zero-size-zero-background' label in protein sidechains, which may be used to probe biological phenomena, protein structures and/or protein-ligand interactions by 19F-based detection methods.

Non-enzymatic glycoxidation linked with nutrition enhances the tumorigenic capacity of prostate cancer epithelia through AGE mediated activation of RAGE in cancer associated fibroblasts.

The molecular implications of food consumption on cancer etiology are poorly defined. The rate of nutrition associated non-enzymatic glycoxidation, a reaction that occurs between reactive carbonyl groups on linear sugars and nucleophilic amino, lysyl and arginyl groups on fats and proteins, is rapidly increased by food cooking and manufacturing processes. In this study, we assign nutrition-associated glycoxidation with significant oncogenic potential, promoting prostate tumor growth, progression, and metastasis in vivo. Advanced glycation end products (AGEs) are the final irreversible product of non-enzymatic glycoxidation. Exogenous treatment of prostate tumor cells with a single AGE peptide replicated glycoxidation induced tumor growth in vivo. Mechanistically, receptor for AGE (RAGE) deficiency in the stroma inhibited AGE mediated tumor growth. Functionally, AGE treatment induced RAGE dimerization in activated fibroblasts which sustained and increased the migratory potential of tumor epithelial cells. These data identify a novel nutrition associated pathway that can promote a tissue microenvironment conducive for aggressive tumor growth. Targeted and/or interventional strategies aimed at reducing AGE bioavailability as a consequence of nutrition may be viewed as novel chemoprevention initiatives.

Biomedical applications of tannic acid.

Tannic Acid (TA) is a naturally occurring antioxidant polyphenol that has gained popularity over the past decade in the field of biomedical research for its unique biochemical properties. Tannic acid, typically extracted from oak tree galls, has been used in many important historical applications. TA is a key component in vegetable tanning of leather, iron gall ink, red wines, and as a traditional medicine to treat a variety of maladies. The basis of TA utility is derived from its many hydroxyl groups and its affinity for forming hydrogen bonds with proteins and other biomolecules. Today, the study of TA has led to the development of many new pharmaceutical and biomedical applications. TA has been shown to reduce inflammation as an antioxidant, act as an antibiotic in common pathogenic bacterium, and induce apoptosis in several cancer types. TA has also displayed antiviral and antifungal activity. At certain concentrations, TA can be used to treat gastrointestinal disorders such as hemorrhoids and diarrhea, severe burns, and protect against neurodegenerative diseases. TA has also been utilized in biomaterials research as a natural crosslinking agent to improve mechanical properties of natural and synthetic hydrogels and polymers, while also imparting anti-inflammatory, antibacterial, and anticancer activity to the materials. TA has also been used to develop thin film coatings and nanoparticles for drug delivery. In all, TA is fascinating molecule with a wide variety of potential uses in pharmaceuticals, biomaterials applications, and drug delivery strategies.

Degradation and release of tannic acid from an injectable tissue regeneration bead matrix in vivo.

The development of multifunctional biomaterials as both tissue regeneration and drug delivery devices is currently a major focus in biomedical research. Tannic Acid (TA), a naturally occurring plant polyphenol, displays unique medicinal abilities as an antioxidant, an antibiotic, and as an anticancer agent. TA has applications in biomaterials acting as a crosslinker in polymer hydrogels improving thermal stability and mechanical properties. We have developed injectable cell seeded collagen beads crosslinked with TA for breast reconstruction and anticancer activity following lumpectomy. This study determined the longevity of the bead implants by establishing a degradation time line and TA release profile in vivo. Beads crosslinked with 0.1% TA and 1% TA were compared to observe the differences in TA concentration on degradation and release. We found collagen/TA beads degrade at similar rates in vivo, yet are resistant to complete degradation after 16 weeks. TA is released over time in vivo through diffusion and cellular activity. Changes in mechanical properties in collagen/TA beads before implantation to after 8 weeks in vivo also indicate loss of TA over a longer period of time. Elastic moduli decreased uniformly in both 0.1% and 1% TA beads. This study establishes that collagen/TA materials can act as a drug delivery system, rapidly releasing TA within the first week following implantation. However, the beads retain TA long term allowing them to resist degradation and remain in situ acting as a cell scaffold and tissue filler. This confirms its potential use as an anticancer and minimally invasive breast reconstructive device following lumpectomy.

Cell-permeable lanthanide-platinum(IV) anti-cancer prodrugs.

Platinum compounds are a vital part of our anti-cancer arsenal, and determining the location and speciation of platinum compounds is crucial. We have synthesised a lanthanide complex bearing a salicylic group (Ln = Gd, Eu) which demonstrates excellent cellular accumulation and minimal cytotoxicity. Derivatisation enabled access to bimetallic lanthanide-platinum(ii) and lanthanide-platinum(iv) complexes. Luminescence from the europium-platinum(iv) system was quenched, and reduction to platinum(ii) with ascorbic acid resulted in a "switch-on" luminescence enhancement. We used diffusion-based 1H NMR spectroscopic methods to quantify cellular accumulation. The gadolinium-platinum(ii) and gadolinium-platinum(iv) complexes demonstrated appreciable cytotoxicity. A longer delay following incubation before cytotoxicity was observed for the gadolinium-platinum(iv) compared to the gadolinium-platinum(ii) complex. Functionalisation with octanoate ligands resulted in enhanced cellular accumulation and an even greater latency in cytotoxicity.

Branched internal mammary conduit permits non-sequenced total arterial revascularization.

Recent trends in cardiac surgery have encouraged total arterial coronary revascularization, citing advantages in long-term patency and overall mortality. Often relying on sequenced, composite, and free-graft strategies, total arterial coronary revascularization is limited by conduit availability and surgical complexity. We present the use of bilateral internal mammary artery grafts to achieve nonsequential 3-vessel total arterial coronary revascularization using the preserved distal bifurcation of the right internal mammary artery. Utilization of distal internal mammary artery branches should be considered a viable strategy in select patients and can broaden the opportunities for total arterial coronary revascularization in patients with multivessel coronary disease.

Local frustration determines loop opening during the catalytic cycle of an oxidoreductase.

Local structural frustration, the existence of mutually exclusive competing interactions, may explain why some proteins are dynamic while others are rigid. Frustration is thought to underpin biomolecular recognition and the flexibility of protein-binding sites. Here, we show how a small chemical modification, the oxidation of two cysteine thiols to a disulfide bond, during the catalytic cycle of the N-terminal domain of the key bacterial oxidoreductase DsbD (nDsbD), introduces frustration ultimately influencing protein function. In oxidized nDsbD, local frustration disrupts the packing of the protective cap-loop region against the active site allowing loop opening. By contrast, in reduced nDsbD the cap loop is rigid, always protecting the active-site thiols from the oxidizing environment of the periplasm. Our results point toward an intricate coupling between the dynamics of the active-site cysteines and of the cap loop which modulates the association reactions of nDsbD with its partners resulting in optimized protein function.

Surgical tracheostomies in COVID-19 patients: A multidisciplinary approach and lessons learned.

Surgical tracheostomies have a role in the weaning process of COVID-19 patients treated in intensive care units. A multidisciplinary team approach (MDT) is required for decision making. This process is augmented by specific standard operating practices implemented by senior clinicians. Here, we report on our early experience and outcomes with open tracheostomies in a cohort of COVID-19 patients. We outline the criteria that guide decision making and explore the challenges faced by our intensive care colleagues in the management of these patients. The cohort was 100% male with 90% of them having a raised Body Mass Index (BMI) and other comorbidities (hypertension and diabetes). 60% have been decannulated and have been stepped down the intensive care unit. We recorded no surgical complications or adverse events. The service to date has been shown to be effective, safe, largely reproducible and reflective.

Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort.

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

Impact of concomitant mitral valve repair for severe mitral regurgitation at the time of continuous-flow left ventricular assist device insertion.

OBJECTIVES: Mitral regurgitation (MR) is common in patients with end-stage heart failure. We assessed the effect of performing concomitant mitral valve repair during continuous-flow left ventricular assist device (CF-LVAD) implantation in patients with severe preoperative MR. METHODS: We performed a single-centre, retrospective review of all patients who underwent CF-LVAD implantation between December 1999 and December 2013 (n = 469). Patients with severe preoperative MR (n = 78) were identified and then stratified according to whether they underwent concomitant valve repair. Univariate and survival analyses were performed, and multivariable regression was used to determine predictors of survival. RESULTS: Of the 78 patients with severe MR, 21 underwent valve repair at the time of CF-LVAD implantation (repair group) and 57 did not (non-repair group). A comparison of the 2 groups showed significant differences between groups: INTERMACS I 16.985 vs 9.52%, (P = 0.039), cardiopulmonary bypass time 82.09 vs 109.4 min (P = 0.0042) and the use of HeartMate II 63.16 vs 100% (P = 0.001). Survival analysis suggested trends towards improved survival and a lower incidence of heart failure-related readmissions in the repair group. Multivariable regression analysis showed no significant independent predictors of survival (mitral valve repair: odds ratio 0.4, 95% confidence interval 0.8-1.5; P = 0.2). CONCLUSIONS: Despite the lack of statistical significance, trends towards improved survival and a lower incidence of heart failure events suggest that mitral valve repair may be beneficial in patients undergoing CF-LVAD implantation. Given the known relationship between severe MR and mortality, further study is encouraged to confirm the value of mitral valve repair in these patients.

Structural and hydrodynamic properties of an intrinsically disordered region of a germ cell-specific protein on phase separation.

Membrane encapsulation is frequently used by the cell to sequester biomolecules and compartmentalize their function. Cells also concentrate molecules into phase-separated protein or protein/nucleic acid "membraneless organelles" that regulate a host of biochemical processes. Here, we use solution NMR spectroscopy to study phase-separated droplets formed from the intrinsically disordered N-terminal 236 residues of the germ-granule protein Ddx4. We show that the protein within the concentrated phase of phase-separated Ddx4, [Formula: see text], diffuses as a particle of 600-nm hydrodynamic radius dissolved in water. However, NMR spectra reveal sharp resonances with chemical shifts showing [Formula: see text] to be intrinsically disordered. Spin relaxation measurements indicate that the backbone amides of [Formula: see text] have significant mobility, explaining why high-resolution spectra are observed, but motion is reduced compared with an equivalently concentrated nonphase-separating control. Observation of a network of interchain interactions, as established by NOE spectroscopy, shows the importance of Phe and Arg interactions in driving the phase separation of Ddx4, while the salt dependence of both low- and high-concentration regions of phase diagrams establishes an important role for electrostatic interactions. The diffusion of a series of small probes and the compact but disordered 4E binding protein 2 (4E-BP2) protein in [Formula: see text] are explained by an excluded volume effect, similar to that found for globular protein solvents. No changes in structural propensities of 4E-BP2 dissolved in [Formula: see text] are observed, while changes to DNA and RNA molecules have been reported, highlighting the diverse roles that proteinaceous solvents play in dictating the properties of dissolved solutes.

Posttranslational mutagenesis: A chemical strategy for exploring protein side-chain diversity.

Posttranslational modification of proteins expands their structural and functional capabilities beyond those directly specified by the genetic code. However, the vast diversity of chemically plausible (including unnatural but functionally relevant) side chains is not readily accessible. We describe C (sp3)-C (sp3) bond-forming reactions on proteins under biocompatible conditions, which exploit unusual carbon free-radical chemistry, and use them to form Cß-Cγ bonds with altered side chains. We demonstrate how these transformations enable a wide diversity of natural, unnatural, posttranslationally modified (methylated, glycosylated, phosphorylated, hydroxylated), and labeled (fluorinated, isotopically labeled) side chains to be added to a common, readily accessible dehydroalanine precursor in a range of representative protein types and scaffolds. This approach, outside of the rigid constraints of the ribosome and enzymatic processing, may be modified more generally for access to diverse proteins.

Determination of an optimally sensitive and specific chemical exchange saturation transfer MRI quantification metric in relevant biological phantoms.

The purpose of this study was to develop realistic phantom models of the intracellular environment of metastatic breast tumour and naïve brain, and using these models determine an analysis metric for quantification of CEST MRI data that is sensitive to only labile proton exchange rate and concentration. The ability of the optimal metric to quantify pH differences in the phantoms was also evaluated. Novel phantom models were produced, by adding perchloric acid extracts of either metastatic mouse breast carcinoma cells or healthy mouse brain to bovine serum albumin. The phantom model was validated using 1 H NMR spectroscopy, then utilized to determine the sensitivity of CEST MRI to changes in pH, labile proton concentration, T1 time and T2 time; six different CEST MRI analysis metrics (MTRasym , APT*, MTRRex , AREX and CESTR* with and without T1 /T2 compensation) were compared. The new phantom models were highly representative of the in vivo intracellular environment of both tumour and brain tissue. Of the analysis methods compared, CESTR* with T1 and T2 time compensation was optimally specific to changes in the CEST effect (i.e. minimal contamination from T1 or T2 variation). In phantoms with identical protein concentrations, pH differences between phantoms could be quantified with a mean accuracy of 0.6 pH units. We propose that CESTR* with T1 and T2 time compensation is the optimal analysis method for these phantoms. Analysis of CEST MRI data with T1 /T2 time compensated CESTR* is reproducible between phantoms, and its application in vivo may resolve the intracellular alkalosis associated with breast cancer brain metastases without the need for exogenous contrast agents.

Aflibercept for neovascular age-related macular degeneration.

BACKGROUND: Central vision loss caused by age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Neovascular AMD is characterized by choroidal neovascularization (CNV). Growth of new blood vessels in patients with neovascular AMD is driven by a complex process that involves a signal protein called vascular endothelial growth factor A (VEGF-A). Anti-VEGF drugs that block this protein include ranibizumab, bevacizumab, and aflibercept. OBJECTIVES: To assess and compare the effectiveness and safety of intravitreal injections of aflibercept versus ranibizumab, bevacizumab, or sham for treatment of patients with neovascular AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (Issue 11, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched December 4, 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on November 30, 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which aflibercept monotherapy was compared with ranibizumab, bevacizumab, or sham for participants with neovascular AMD who were treatment-naive. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures of The Cochrane Collaboration for screening, data abstraction, and study assessment. Two review authors independently screened records, abstracted data, and assessed risk of bias of included studies; we resolved discrepancies by discussion or with the help of a third review author when needed. MAIN RESULTS: We included two RCTs (total of 2457 participants, 2457 eyes). Trial participants had neovascular AMD with active subfoveal choroidal neovascular lesions. Both trials followed the same protocol and compared aflibercept at various doses versus ranibizumab, but they were carried out in different countries. One trial enrolled participants from the United States and Canada, and the second trial was conducted at 172 sites in Europe, Asia Pacific, Latin America, and the Middle East. The overall quality of the evidence was high, and included trials were at low risk for most bias domains assessed; however, both trials were funded by the manufacturers of aflibercept. For the purposes of analysis, we combined aflibercept groups regardless of dosing and analyzed them as a single group.Visual acuity outcomes were similar between aflibercept and ranibizumab groups; at one year, participants in the aflibercept groups showed mean change in best-corrected visual acuity (BCVA) from baseline similar to that of participants in the ranibizumab groups (mean difference (MD) -0.15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (95% CI) -1.47 to 1.17; high-quality evidence). At two years, the mean change in BCVA from baseline was 7.2 ETDRS letters for aflibercept groups versus 7.9 for ranibizumab groups. Sufficient data were not available for calculation of confidence intervals.The proportion of participants who gained 15 or more letters of BCVA by one year of follow-up was approximately 32% for both aflibercept and ranibizumab (RR 0.97, 95% CI 0.85 to 1.11; high-quality evidence), and by two years of follow-up was approximately 31% (RR 0.98, 95% CI 0.85 to 1.12; high-quality evidence). Similar small proportions of participants in the aflibercept and ranibizumab groups lost 15 or more letters of BCVA at one year (RR 0.89, 95% CI 0.61 to 1.30; high-quality evidence); this outcome was not reported for two-year follow-up. Data were not reported on the proportion of participants with BCVA worse than 20/200 at one- or two-year follow-up.Participants treated with aflibercept or ranibizumab showed similar improvement in morphological outcomes, as assessed from images (central retinal thickness and CNV size). At one year, the proportion of eyes that achieved dry retina was similar between aflibercept and ranibizumab groups (absence of cystic intraretinal fluid and subretinal fluid on optical coherence tomography (OCT); RR 1.06, 95% CI 0.98 to 1.14; high-quality evidence). In addition, investigators reported no difference in reduction of CNV area between aflibercept- and ranibizumab-treated eyes at one year (MD -0.24 mm(2), 95% CI -0.78 to 0.29; high-quality evidence). Data were not reported for the proportion of eyes with absence of leakage on fluorescein angiography at one- or two-year follow-up.Overall, occurrence of serious systemic adverse events was similar and comparable in aflibercept- and ranibizumab-treated groups at one year (RR 0.99, 95% CI 0.79 to 1.25). Risk of any serious ocular adverse event was lower in the aflibercept group than in the ranibizumab group, but the risk estimate is imprecise (RR 0.62, 95% CI 0.36 to 1.07). As the result of imprecision, we graded the quality of evidence for all adverse events as moderate. AUTHORS' CONCLUSIONS: Results of this review document the comparative effectiveness of aflibercept versus ranibizumab for visual acuity and morphological outcomes in eyes with neovascular AMD. Current available information on adverse effects of each medication suggests that the safety profile of aflibercept is comparable with that of ranibizumab; however, the number of participants who experienced adverse events was small, leading to imprecise estimates of absolute and relative effect sizes. The eight-week dosing regimen of aflibercept represents reduced treatment requirements in comparison with monthly dosing regimens and thus has the potential to reduce treatment burden and risks associated with frequent injections.

Surgical approach to continuous-flow left ventricular assist device explantation: A comparison of outcomes.

OBJECTIVE: Ventricular reconditioning and device weaning in select patients with continuous-flow left ventricular assist devices (CF LVADs) has been shown to be feasible. However, little is known regarding the outcomes associated with different surgical methods of device removal. We examined the effect of surgical explantation approach on early and late outcomes. METHODS: We retrospectively reviewed data from all patients who underwent successful ventricular weaning and CF LVAD explantation at our center. Patients were stratified by surgical approach. Descriptive univariate statistics, multivariate regression, and survival analyses were performed. Patients were censored by transplant, device reimplantation, or end of follow-up. RESULTS: Twenty-seven patients were identified who underwent successful removal of a CF LVAD (25 HeartMate II, 2 HeartWare) after 532 ± 424 days of support (range, 42-1937 days). Four approaches were used that vary primarily in the degree of retained pump material: complete pump removal with plug ventriculotomy closure (n = 13; 48%), pump housing explant with ligation of the inflow and outflow grafts (n = 7; 26%), ligation of the outflow graft and driveline transection (n = 5; 19%), and driveline transection alone (n = 2; 7%). Mean overall postexplant survival was 1286 ± 947 days (range, 143-3072 days). Overall time-to-event and survival analyses showed no significant association between surgical approach and postoperative length of stay (P = .7), stroke (P = .12), reoperation (P = .4), or survival (P = .12). CONCLUSIONS: For patients who receive device therapy, pump deactivation and removal represents a favorable outcome. All methods are feasible and produce similar early and late survival and clinical outcomes.

Through the Looking Glass: Real-Time Video Using 'Smart' Technology Provides Enhanced Intraoperative Logistics.

INTRODUCTION: In the setting of increasingly complex medical therapies and limited physician resources, the recent emergence of 'smart' technology offers tremendous potential for improved logistics, efficiency, and communication between medical team members. In an effort to harness these capabilities, we sought to evaluate the utility of this technology in surgical practice through the employment of a wearable camera device during cardiothoracic organ recovery. METHODS: A single procurement surgeon was trained for use of an Explorer Edition Google Glass (Google Inc., Mountain View, CA) during the recovery process. Live video feed of each procedure was securely broadcast to allow for members of the home transplant team to remotely participate in organ assessment. Primary outcomes involved demonstration of technological feasibility and validation of quality assurance through group assessment. RESULTS: The device was employed for the recovery of four organs: a right single lung, a left single lung, and two bilateral lung harvests. Live video of the visualization process was remotely accessed by the home transplant team, and supplemented final verification of organ quality. In each case, the organs were accepted for transplant without disruption of standard procurement protocols. Media files generated during the procedures were stored in a secure drive for future documentation, evaluation, and education purposes without preservation of patient identifiers. CONCLUSIONS: Live video streaming can improve quality assurance measures by allowing off-site members of the transplant team to participate in the final assessment of donor organ quality. While further studies are needed, this project suggests that the application of mobile 'smart' technology offers not just immediate value, but the potential to transform our approach to the practice of medicine.