Making hospitals innovative: Macro-level policy to sustain micro-innovations in healthcare.

Successful innovation clusters are notoriously difficult to establish, and many attempts fail. How can we go about designing such systems reliably? We describe how ecosystems can be strengthened through grassroots bottom-up efforts that empower user and community innovation, as opposed to economic policies that dictate innovation. Specifically focusing on the healthcare industry, we advocate that community hospitals which constitute 90% of all hospitals in Canada are the ideal setting for such community innovation efforts. We investigated the distribution of innovation output from hospitals over the past 13 years and found a decrease in predominance of major teaching hospitals, supporting the potential role for community hospitals in this space. We categorize different types of innovations and recommend institutional policies that can sustain bottom-up, micro-level efforts. Such policies could improve and enhance the development of micro-innovations and the creation of health innovation clusters.

Examining the relationships between data-guided innovations and pre-k students' social-emotional development.

The present study examined the effects of data-guided innovations on students' social-emotional (SE) development within prekindergarten settings. Specifically, this study examined the effects of a pilot effort that sought to improve instructional quality through the use of structured classroom observations by coaches to help support teacher implementation of curricula and evidence-based practices. In addition, teachers used formative assessments of students' SE functioning to guide and individualize their instruction. To examine the effects of the multicomponent intervention, this study compared the SE functioning of students across three conditions: (1) students whose teachers received no data-guided innovations; (2) students whose teachers received SE formative assessments; and (3) students whose teachers received both SE formative assessments and performance-based feedback using structured classroom observations. Students whose teachers received both SE formative assessments and performance-based feedback using structured classroom observations evidenced significantly greater SE competencies than those in the control group. Additionally, students whose teachers just received SE formative assessments evidenced greater SE competencies than those in the control group, however, the differences were not significant. Results indicate the potential value of these data-guided innovations for improving prekindergarten student outcomes such as SE development and point to the next steps for future research.

Focal, remote-controlled, chronic chemical modulation of brain microstructures.

Direct delivery of fluid to brain parenchyma is critical in both research and clinical settings. This is usually accomplished through acutely inserted cannulas. This technique, however, results in backflow and significant dispersion away from the infusion site, offering little spatial or temporal control in delivering fluid. We present an implantable, MRI-compatible, remotely controlled drug delivery system for minimally invasive interfacing with brain microstructures in freely moving animals. We show that infusions through acutely inserted needles target a region more than twofold larger than that of identical infusions through chronically implanted probes due to reflux and backflow. We characterize the dynamics of in vivo infusions using positron emission tomography techniques. Volumes as small as 167 nL of copper-64 and fludeoxyglucose labeled agents are quantified. We further demonstrate the importance of precise drug volume dosing to neural structures to elicit behavioral effects reliably. Selective modulation of the substantia nigra, a critical node in basal ganglia circuitry, via muscimol infusion induces behavioral changes in a volume-dependent manner, even when the total dose remains constant. Chronic device viability is confirmed up to 1-y implantation in rats. This technology could potentially enable precise investigation of neurological disease pathology in preclinical models, and more efficacious treatment in human patients.

Steerable Microinvasive Probes for Localized Drug Delivery to Deep Tissue.

Enhanced understanding of neuropathologies has created a need for more advanced tools. Current neural implants result in extensive glial scarring and are not able to highly localize drug delivery due to their size. Smaller implants reduce surgical trauma and improve spatial resolution, but such a reduction requires improvements in device design to enable accurate and chronic implantation in subcortical structures. Flexible needle steering techniques offer improved control over implant placement, but often require complex closed-loop control for accurate implantation. This study reports the development of steerable microinvasive neural implants (S-MINIs) constructed from borosilicate capillaries (OD = 60 µm, ID = 20 µm) that do not require closed-loop guidance or guide tubes. S-MINIs reduce glial scarring 3.5-fold compared to prior implants. Bevel steered needles are utilized for open-loop targeting of deep-brain structures. This study demonstrates a sinusoidal relationship between implant bevel angle and the trajectory radius of curvature both in vitro and ex vivo. This relationship allows for bevel-tipped capillaries to be steered to a target with an average error of 0.23 mm ± 0.19 without closed-loop control. Polished microcapillaries present a new microinvasive tool for chronic, predictable targeting of pathophysiological structures without the need for closed-loop feedback and complex imaging.

Inhibition of Tyrosine-Phosphorylated STAT3 in Human Breast and Lung Cancer Cells by Manuka Honey is Mediated by Selective Antagonism of the IL-6 Receptor.

Aberrantly high levels of tyrosine-phosphorylated signal transducer and activator of transcription 3 (p-STAT3) are found constitutively in ~50% of human lung and breast cancers, acting as an oncogenic transcription factor. We previously demonstrated that Manuka honey (MH) inhibits p-STAT3 in breast cancer cells, but the exact mechanism remained unknown. Herein, we show that MH-mediated inhibition of p-STAT3 in breast (MDA-MB-231) and lung (A549) cancer cell lines is accompanied by decreased levels of gp130 and p-JAK2, two upstream components of the IL-6 receptor (IL-6R) signaling pathway. Using an ELISA-based assay, we demonstrate that MH binds directly to IL-6Rα, significantly inhibiting (~60%) its binding to the IL-6 ligand. Importantly, no evidence of MH binding to two other cytokine receptors, IL-11Rα and IL-8R, was found. Moreover, MH did not alter the levels of tyrosine-phosphorylated or total Src family kinases, which are also constitutively activated in cancer cells, suggesting that signaling via other growth factor receptors is unaffected by MH. Binding of five major MH flavonoids (luteolin, quercetin, galangin, pinocembrin, and chrysin) was also tested, and all but pinocembrin could demonstrably bind IL-6Rα, partially (30-35%) blocking IL-6 binding at the highest concentration (50 µM) used. In agreement, each flavonoid inhibited p-STAT3 in a dose-dependent manner, with estimated IC50 values in the 3.5-70 µM range. Finally, docking analysis confirmed the capacity of each flavonoid to bind in an energetically favorable configuration to IL-6Rα at a site predicted to interfere with ligand binding. Taken together, our findings identify IL-6Rα as a direct target of MH and its flavonoids, highlighting IL-6R blockade as a mechanism for the anti-tumor activity of MH, as well as a viable therapeutic target in IL-6-dependent cancers.

Unexplained spikes in lamotrigine serum concentration: nonlinear elimination?

OBJECTIVES: The objective of this study was to evaluate possible nonlinear lamotrigine (LTG) pharmacokinetics at elevated concentration. LTG is reported to have linear kinetics, so that elimination rate is linearly proportional to blood concentration and a change in dose is accompanied by a proportionate change in serum concentration. We encountered patients in whom LTG serum concentration increased dramatically in response to minor or no change in LTG dose. We studied this phenomenon in patients with LTG toxicity in one clinic. MATERIALS AND METHODS: Using electronic medical records from 1997 to 2014, we identified patients who developed clinical LTG toxicity with LTG serum concentrations >20 mg/l, after tolerating lamotrigine at lower serum concentrations. We reviewed LTG dose change and other changes that preceded the episode of toxicity. RESULTS: Twenty-two patients had at least one episode of LTG toxicity with levels higher than 20 mg/l (of 922 patients with available levels). The peak serum concentration varied from 21.1 to 40.3 mg/l (mean 28.7). The increase in level was explained in three patients (post-delivery in one, addition of valproate in two). In the 18 others, the increase was not explained or it was disproportionate to an increase in LTG dose. CONCLUSIONS: Spikes in LTG levels and associated clinical toxicity may occur unexpectedly, suggesting that elimination kinetics may be nonlinear in some individuals at serum concentrations in the upper range. Measurement and close monitoring of LTG levels is warranted for new symptoms that could be consistent with lamotrigine toxicity, particularly when the baseline serum concentration has been >10 mg/l.

Plasmonic Contact Lenses Based on Silver Nanoparticles for Blue Light Protection.

Constant exposure to blue light emanating from screens, lamps, digital devices, or other artificial sources at night can suppress melatonin secretion, potentially compromising both sleep quality and overall health. Daytime exposure to elevated levels of blue light can also lead to permanent damage to the eyes. Here, we have developed blue light protective plasmonic contact lenses (PCLs) to mitigate blue light exposure. Crafted from poly(hydroxyethyl methacrylate) (pHEMA) and infused with silver nanoparticles, these contact lenses serve as a protective barrier to filter blue light. Leveraging the plasmonic properties of silver nanoparticles, the lenses effectively filtered out the undesirable blue light (400-510 nm), demonstrating substantial protection (22-71%) while maintaining high transparency (80-96%) for the desirable light (511-780 nm). The maximum protection level reaches a peak of 79% at 455 nm, aligned with the emission peak for the blue light sourced from LEDs in consumer displays. The presence of silver nanoparticles was found to have an insignificant impact on the water content of the developed contact lenses. The lenses maintained high water retention levels within the range of 50-70 wt %, comparable to commercial contact lenses. The optical performance of the developed lenses remains unaffected in both artificial tears and contact lens storage solution over a month with no detected leakage of the nanoparticles. Additionally, the MTT assay confirmed that the lenses were biocompatible and noncytotoxic, maintaining cell viability at over 85% after 24 h of incubation. These lenses could be a potential solution to protect against the most intense wavelengths emitted by consumer displays and offer a remedy to counteract the deleterious effects of prolonged blue light exposure.

An ingestible, battery-free, tissue-adhering robotic interface for non-invasive and chronic electrostimulation of the gut.

Ingestible electronics have the capacity to transform our ability to effectively diagnose and potentially treat a broad set of conditions. Current applications could be significantly enhanced by addressing poor electrode-tissue contact, lack of navigation, short dwell time, and limited battery life. Here we report the development of an ingestible, battery-free, and tissue-adhering robotic interface (IngRI) for non-invasive and chronic electrostimulation of the gut, which addresses challenges associated with contact, navigation, retention, and powering (C-N-R-P) faced by existing ingestibles. We show that near-field inductive coupling operating near 13.56 MHz was sufficient to power and modulate the IngRI to deliver therapeutically relevant electrostimulation, which can be further enhanced by a bio-inspired, hydrogel-enabled adhesive interface. In swine models, we demonstrated the electrical interaction of IngRI with the gastric mucosa by recording conductive signaling from the subcutaneous space. We further observed changes in plasma ghrelin levels, the "hunger hormone," while IngRI was activated in vivo, demonstrating its clinical potential in regulating appetite and treating other endocrine conditions. The results of this study suggest that concepts inspired by soft and wireless skin-interfacing electronic devices can be applied to ingestible electronics with potential clinical applications for evaluating and treating gastrointestinal conditions.

Early structured surgical management plan for neonates with short bowel syndrome may improve outcomes.

BACKGROUND: In children with short bowel syndrome, maximal adaptation of the bowel after extensive resection is thought to occur during the first 2 years of life. The aim of the present study was to review children with short bowel syndrome from two intestinal rehabilitation centers, comparing those undergoing lengthening procedures <365 days of age (early) versus those whose lengthening procedure was carried out >365 days of age (late). METHODS: Retrospective data collection was performed from January 2004 to December 2010 in Manchester, UK, and from December 2006 to December 2010 in Brussels, Belgium. Both medical centers follow a similar intestinal rehabilitation program (IRP). Data collected included population demographics, bowel length preoperatively and postoperatively, age at operation, parenteral nutrition (PN), central access, and complications. RESULTS: Complete data were available for eight children who underwent lengthening surgery at <365 days of age, and six who underwent the procedure at >365 days of age. Diagnoses were similar. Groups were matched for gestation and birthweight, with no statistical difference in preoperative and postoperative bowel lengths. The mean duration of PN postoperatively was 378 days in the early cohort and 589 days in the late cohort. This trended toward statistical significance (p = 0.071). Full enteral autonomy was achieved at 17 months (early) and 59 months (late) (p = 0.01). Patients in the early group required fewer central lines than those operated on later (p = 0.035). CONCLUSIONS: Enrolling children into an IRP involving early (<365 days of age) lengthening surgery allows a shorter postoperative time to allow weaning to full enteral nutrition, as well as fewer central lines. Both outcomes provide benefits for the child and family, allowing an earlier return to normal life.

Location-aware ingestible microdevices for wireless monitoring of gastrointestinal dynamics.

Localization and tracking of ingestible microdevices in the gastrointestinal (GI) tract is valuable for the diagnosis and treatment of GI disorders. Such systems require a large field-of-view of tracking, high spatiotemporal resolution, wirelessly operated microdevices and a non-obstructive field generator that is safe to use in practical settings. However, the capabilities of current systems remain limited. Here, we report three dimensional (3D) localization and tracking of wireless ingestible microdevices in the GI tract of large animals in real time and with millimetre-scale resolution. This is achieved by generating 3D magnetic field gradients in the GI field-of-view using high-efficiency planar electromagnetic coils that encode each spatial point with a distinct magnetic field magnitude. The field magnitude is measured and transmitted by the miniaturized, low-power and wireless microdevices to decode their location as they travel through the GI tract. This system could be useful for quantitative assessment of the GI transit-time, precision targeting of therapeutic interventions and minimally invasive procedures.

Bioinspired, ingestible electroceutical capsules for hunger-regulating hormone modulation.

The gut-brain axis, which is mediated via enteric and central neurohormonal signaling, is known to regulate a broad set of physiological functions from feeding to emotional behavior. Various pharmaceuticals and surgical interventions, such as motility agents and bariatric surgery, are used to modulate this axis. Such approaches, however, are associated with off-target effects or post-procedure recovery time and expose patients to substantial risks. Electrical stimulation has also been used to attempt to modulate the gut-brain axis with greater spatial and temporal resolution. Electrical stimulation of the gastrointestinal (GI) tract, however, has generally required invasive intervention for electrode placement on serosal tissue. Stimulating mucosal tissue remains challenging because of the presence of gastric and intestinal fluid, which can influence the effectiveness of local luminal stimulation. Here, we report the development of a bioinspired ingestible fluid-wicking capsule for active stimulation and hormone modulation (FLASH) capable of rapidly wicking fluid and locally stimulating mucosal tissue, resulting in systemic modulation of an orexigenic GI hormone. Drawing inspiration from Moloch horridus, the "thorny devil" lizard with water-wicking skin, we developed a capsule surface capable of displacing fluid. We characterized the stimulation parameters for modulation of various GI hormones in a porcine model and applied these parameters to an ingestible capsule system. FLASH can be orally administered to modulate GI hormones and is safely excreted with no adverse effects in porcine models. We anticipate that this device could be used to treat metabolic, GI, and neuropsychiatric disorders noninvasively with minimal off-target effects.

Short bowel syndrome: a practical pathway leading to successful enteral autonomy.

BACKGROUND: Short bowel syndrome is a multisystemic disorder that results from the loss of a significant amount of small bowel. The goal of treatment in these patients is to achieve complete enteral autonomy while minimizing complications. Our unit has 30 years of experience in the management of short gut patients. During the past decade, our results have improved significantly, especially in children with severe short bowel syndrome. This brief communication looks at the algorithm presently used in our unit. METHODS: In this communication, the principles in management of short bowel syndrome in our unit are discussed. In addition, our algorithm is published for the first time. A brief summary of our results is provided. RESULTS: Twenty-seven children were enrolled from 2000 to 2009. In this cohort, two patients died because of significant liver disease: one after having two liver and bowel transplants. Overall, survival stands at 92%. All had autologous gastrointestinal reconstruction, and 19 patients underwent bowel lengthening (longitudinal intestinal lengthening and tailoring). The median residual length of bowel of this subgroup at first operation was 25 cm in those who had their gut measured. Two patients were lost to follow-up. Two patients remain on supplemental total parenteral nutrition (TPN), with an overall 91% of surviving patients off TPN at a median of 6 months after reconstruction. CONCLUSIONS: We believe this improvement is related to the development-over many years-of a structured pathway for managing these patients.

Grass-roots entrepreneurship complements traditional top-down innovation in lung and breast cancer.

The majority of biomedical research is funded by public, governmental, and philanthropic grants. These initiatives often shape the avenues and scope of research across disease areas. However, the prioritization of disease-specific funding is not always reflective of the health and social burden of each disease. We identify a prioritization disparity between lung and breast cancers, whereby lung cancer contributes to a substantially higher socioeconomic cost on society yet receives significantly less funding than breast cancer. Using search engine results and natural language processing (NLP) of Twitter tweets, we show that this disparity correlates with enhanced public awareness and positive sentiment for breast cancer. Interestingly, disease-specific venture activity does not correlate with funding or public opinion. We use outcomes from recent early-stage innovation events focused on lung cancer to highlight the complementary mechanism by which bottom-up "grass-roots" initiatives can identify and tackle under-prioritized conditions.

Environmental sustainability assessment of wooden furniture produced in Pakistan.

Life cycle assessment was carried out for a conventional wooden furniture set produced in Mardan division of the Khyber Pakhtunkhwa province of Pakistan during 2018-19. Primary data regarding inputs and outputs were collected through questionnaire surveys from 100 conventional wooden furniture set manufacturers, 50 in district Mardan and 50 in district Swabi. In the present study, cradle-to-gate life cycle assessment approach was applied for a functional unit of one conventional wooden furniture set. Production weighted average data were modelled in the environmental impacts modelling software i.e., SimaPro v.8.5. The results showed that textile used in sofa set, wood preservative for polishing and preventing insects attack and petrol used in generator had the highest contribution to all the environmental impact categories evaluated. Total cumulative energy demand for wooden furniture set manufactured was 30,005 MJ with most of the energy acquired from non-renewable fossil fuel resources.

Machine-learning aided in situ drug sensitivity screening predicts treatment outcomes in ovarian PDX tumors.

Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility. We describe a drug sensitivity screening assay using a drug delivery microdevice implanted for 24 h in subcutaneous (SQ) ovarian PDX tumors to predict treatment outcomes in matched IP PDX tumors in a clinically relevant time frame. The SQ tumor response to local microdose drug exposure was found to be predictive of the growth of matched IP tumors after multi-week systemic therapy using significantly fewer animals (10 SQ vs 206 IP). Multiplexed immunofluorescence image analysis of phenotypic tumor response combined with a machine learning classifier could predict IP treatment outcomes against three second-line cytotoxic therapies with an average AUC of 0.91.

Acute limb ischaemia due to embolisation of biological glue 45 days after surgery.

INTRODUCTION: Since their introduction, biological glues have been more often used in cardiac and vascular surgery in order to control bleeding and reinforce surgical anastomotic sites. REPORT: We report a case of a 54-year-old woman diagnosed with acute limb ischaemia due to embolisation of biological glue, 45 days after her surgery for ascending aortic dissection. Her ischaemia was successfully relieved by an urgent thrombectomy. DISCUSSION: Complications due to the use of biological glues remain rare but are very serious. Preventive measures and intra-operative precautions must be considered in order to avoid most of these complications.

Controlled tissue expansion in the initial management of the short bowel state.

The treatment of short gut syndrome has evolved dramatically during the past decade. The combination of surgical techniques and medical management in the context of a multidisciplinary approach has improved the outcomes of these children. The authors describe in detail their technique of controlled tissue expansion of the bowel before lengthening procedures. Monitoring of the child and troubleshooting actions during the controlled tissue expansion program also are discussed.

A statistical approach for the assessment and redesign of the Nile Delta drainage system water-quality-monitoring locations.

There are several deficiencies in the statistical approaches proposed in the literature for the assessment and redesign of surface water-quality-monitoring locations. These deficiencies vary from one approach to another, but generally include: (i) ignoring the attributes of the basin being monitored; (ii) handling multivariate water quality data sequentially rather than simultaneously; (iii) focusing mainly on locations to be discontinued; and (iv) ignoring the reconstitution of information at discontinued locations. In this paper, a methodology that overcomes these deficiencies is proposed. In the proposed methodology, the basin being monitored is divided into sub-basins, and a hybrid-cluster analysis is employed to identify groups of sub-basins with similar attributes. A stratified optimum sampling strategy is then employed to identify the optimum number of monitoring locations at each of the sub-basin groups. An aggregate information index is employed to identify the optimal combination of locations to be discontinued. The proposed approach is applied for the assessment and redesign of the Nile Delta drainage water quality monitoring locations in Egypt. Results indicate that the proposed methodology allows the identification of (i) the optimal combination of locations to be discontinued, (ii) the locations to be continuously measured and (iii) the sub-basins where monitoring locations should be added. To reconstitute information about the water quality variables at discontinued locations, regression, artificial neural network (ANN) and maintenance of variance extension (MOVE) techniques are employed. The MOVE record extension technique is shown to result in a better performance than regression or ANN for the estimation of information about water quality variables at discontinued locations.