Bacteroides thetaiotaomicron metabolic activity decreases with polysaccharide molecular weight.

The human colon hosts hundreds of commensal bacterial species, many of which ferment complex dietary carbohydrates. To transform these fibers into metabolically accessible compounds, microbes often express a series of dedicated enzymes homologous to the starch utilization system (Sus) encoded in polysaccharide utilization loci (PULs). The genome of Bacteroides thetaiotaomicron (Bt), a common member of the human gut microbiota, encodes nearly 100 PULs, conferring a strong metabolic versatility. While the structures and functions of individual enzymes within the PULs have been investigated, little is known about how polysaccharide complexity impacts the function of Sus-like systems. We here show that the activity of Sus-like systems depends on polysaccharide size, ultimately impacting bacterial growth. We demonstrate the effect of size-dependent metabolism in the context of dextran metabolism driven by the specific utilization system PUL48. We find that as the molecular weight of dextran increases, Bt growth rate decreases and lag time increases. At the enzymatic level, the dextranase BT3087, a glycoside hydrolase (GH) belonging to the GH family 66, is the main GH for dextran utilization, and BT3087 and BT3088 contribute to Bt dextran metabolism in a size-dependent manner. Finally, we show that the polysaccharide size-dependent metabolism of Bt impacts its metabolic output in a way that modulates the composition of a producer-consumer community it forms with Bacteroides fragilis. Altogether, our results expose an overlooked aspect of Bt metabolism that can impact the composition and diversity of microbiota. IMPORTANCE: Polysaccharides are complex molecules that are commonly found in our diet. While humans lack the ability to degrade many polysaccharides, their intestinal microbiota contain bacterial commensals that are versatile polysaccharide utilizers. The gut commensal Bacteroides thetaiotaomicron dedicates roughly 20% of their genomes to the expression of polysaccharide utilization loci for the broad range utilization of polysaccharides. Although it is known that different polysaccharide utilization loci are dedicated to the degradation of specific polysaccharides with unique glycosidic linkages and monosaccharide compositions, it is often overlooked that specific polysaccharides may also exist in various molecular weights. These different physical attributes may impact their processability by starch utilization system-like systems, leading to differing growth rates and nutrient-sharing properties at the community level. Therefore, understanding how molecular weight impacts utilization by gut microbe may lead to the potential design of novel precision prebiotics.

Delivery of Topical Drugs to the Olfactory Cleft.

Olfactory dysfunction affects approximately 20% of the population globally, with incidence increasing over the age of 60. The pathophysiology is complex, not yet fully understood, and depends on many factors, including the underlying cause. Despite this, the present literature on olfaction is limited due to significant heterogeneity in methodological approaches. This has resulted in limited effective treatments available for olfactory dysfunction. Medications for olfactory dysfunction can be administered locally (directly to the olfactory epithelium) or systemically (orally or intravenously). Currently, there are various methods for local drug delivery to the olfactory epithelium (nasal drops, nasal sprays, atomisers, pressured meter-dosed inhalers, rinses, and exhalation delivery systems). The aims of this review are to summarise the different methods of drug delivery to the olfactory cleft, evaluate the current literature to assess which method is the most effective in delivering drugs to the olfactory epithelium, and review the medications currently available to treat olfactory dysfunction topically. Going forward, further research is required to better establish effective methods of drug delivery to the olfactory epithelium to treat smell disorders.

A comprehensive wireless neurological and cardiopulmonary monitoring platform for pediatrics.

Neurodevelopment in the first 10 years of life is a critical time window during which milestones that define an individual's functional potential are achieved. Comprehensive multimodal neurodevelopmental monitoring is particularly crucial for socioeconomically disadvantaged, marginalized, historically underserved and underrepresented communities as well as medically underserved areas. Solutions designed for use outside the traditional clinical environment represent an opportunity for addressing such health inequalities. In this work, we present an experimental platform, ANNE EEG, which adds 16-channel cerebral activity monitoring to the existing, USA FDA-cleared ANNE wireless monitoring platform which provides continuous electrocardiography, respiratory rate, pulse oximetry, motion, and temperature measurements. The system features low-cost consumables, real-time control and streaming with widely available mobile devices, and fully wearable operation to allow a child to remain in their naturalistic environment. This multi-center pilot study successfully collected ANNE EEG recordings from 91 neonatal and pediatric patients at academic quaternary pediatric care centers and in LMIC settings. We demonstrate the practicality and feasibility to conduct electroencephalography studies with high levels of accuracy, validated via both quantitative and qualitative metrics, compared against gold standard systems. An overwhelming majority of parents surveyed during studies indicated not only an overall preference for the wireless system, but also that its use would improve their children's physical and emotional health. Our findings demonstrate the potential for the ANNE system to perform multimodal monitoring to screen for a variety of neurologic diseases that have the potential to negatively impact neurodevelopment.

Fluid flow structures gut microbiota biofilm communities by distributing public goods.

Bacterial gut commensals experience a biologically and physically complex mucosal environment. While many chemical factors mediate the composition and structure of these microbial communities, less is known about the role of mechanics. Here, we demonstrate that fluid flow impacts the spatial organization and composition of gut biofilm communities by shaping how different species interact metabolically. We first demonstrate that a model community composed of Bacteroides thetaiotaomicron (Bt) and Bacteroides fragilis (Bf), two representative human commensals, can form robust biofilms in flow. We identified dextran as a polysaccharide readily metabolized by Bt but not Bf, but whose fermentation generates a public good enabling Bf growth. By combining simulations with experiments, we demonstrate that in flow, Bt biofilms share dextran metabolic by-products, promoting Bf biofilm formation. By transporting this public good, flow structures the spatial organization of the community, positioning the Bf population downstream from Bt. We show that sufficiently strong flows abolish Bf biofilm formation by limiting the effective public good concentration at the surface. Physical factors such as flow may therefore contribute to the composition of intestinal microbial communities, potentially impacting host health.

The sensorimotor system modulates muscular co-contraction relative to visuomotor feedback responses to regulate movement variability.

The naturally occurring variability in our movements often poses a significant challenge when attempting to produce precise and accurate actions, which is readily evident when playing a game of darts. Two differing, yet potentially complementary, control strategies that the sensorimotor system may use to regulate movement variability are impedance control and feedback control. Greater muscular co-contraction leads to greater impedance that acts to stabilize the hand, while visuomotor feedback responses can be used to rapidly correct for unexpected deviations when reaching toward a target. Here, we examined the independent roles and potential interplay of impedance control and visuomotor feedback control when regulating movement variability. Participants were instructed to perform a precise reaching task by moving a cursor through a narrow visual channel. We manipulated cursor feedback by visually amplifying movement variability and/or delaying the visual feedback of the cursor. We found that participants decreased movement variability by increasing muscular co-contraction, aligned with an impedance control strategy. Participants displayed visuomotor feedback responses during the task but, unexpectedly, there was no modulation between conditions. However, we did find a relationship between muscular co-contraction and visuomotor feedback responses, suggesting that participants modulated impedance control relative to feedback control. Taken together, our results highlight that the sensorimotor system modulates muscular co-contraction, relative to visuomotor feedback responses, to regulate movement variability and produce accurate actions.NEW & NOTEWORTHY The sensorimotor system has the constant challenge of dealing with the naturally occurring variability in our movements. Here, we investigated the potential roles of muscular co-contraction and visuomotor feedback responses to regulate movement variability. When we visually amplified movements, we found that the sensorimotor system primarily uses muscular co-contraction to regulate movement variability. Interestingly, we found that muscular co-contraction was modulated relative to inherent visuomotor feedback responses, suggesting an interplay between impedance and feedback control.

Rare case of sudden onset sensorineural hearing loss in a patient diagnosed with sarcoidosis.

We report the case of a woman in her 30s who was referred to the ear, nose and throat department with sudden onset left-sided sensorineural hearing loss (SNHL), left anterior uveitis and erythematous lower limb lesions with bilateral pitting oedema. Based on her symptoms, an underlying inflammatory systemic disease was suspected. Autoantibodies were negative but an X-ray and high-resolution CT scan of the chest were suggestive of sarcoidosis, which was confirmed on endoscopic bronchial biopsy. Following treatment with a course of oral steroids, the patient's hearing has improved but she still suffers from episodes of uveitis. While immune-mediated inner ear disorders are a recognised cause of SNHL, sarcoidosis is a very rare cause. This case demonstrates the importance of screening for systemic autoimmune aetiology in SNHL and highlights the importance of an effective multidisciplinary team in the diagnosis and management of these patients.

Engineering Agrobacterium tumefaciens Adhesion to Target Cells.

Agrobacterium tumefaciens is a plant pathogen commonly repurposed for genetic modification of crops. Despite its versatility, it remains inefficient at transferring DNA to many hosts, including to animal cells. Like many pathogens, physical contact between A. tumefaciens and host cells promotes infection efficacy. Thus, improving the strength and specificity of A. tumefaciens to target cells has the potential for enhancing DNA transfer for biotechnological and therapeutic purposes. Here, we demonstrate a methodology for engineering genetically encoded exogeneous adhesins at the surface of A. tumefaciens. We identified an autotransporter gene we named Aat that is predicted to show canonical ß-barrel and passenger domains. We engineered the ß-barrel scaffold and linker (Aatß) to display synthetic adhesins susceptible to rewire A. tumefaciens to alternative host targets. As a proof of concept, we leveraged the versatility of a VHH domain to rewire A. tumefaciens adhesion to yeast and mammalian hosts displaying a GFP target receptor. Finally, to demonstrate how synthetic A. tumefaciens adhesion can improve transfer to host cells, we showed improved protein translocation into HeLa cells using a sensitive split luciferase reporter system. Engineering A. tumefaciens adhesion has therefore a strong potential in generating complex heterogeneous cellular assemblies and in improving DNA transfer efficiency against non-natural hosts.

Improving nutritional assessment in acute medical admissions at a district general hospital.

BACKGROUND: Malnutrition adversely affects clinical outcomes, necessitating a prompt and accurate assessment of nutritional status on admission. A variety of tools exist to aid nutritional assessment, of which the malnutrition universal screening tool (MUST) is recommended, but remains difficult to implement in practice. OBJECTIVE: The aim of this audit was to improve the utilisation of the malnutrition universal screening tool (MUST) in the Acute Medical Unit (AMU) at Queen Elizabeth Hospital, King's Lynn. Specifically, patients should have a completed and accurate MUST score within 6 hours of arrival to AMU and high-risk patients (MUST score ≥2) should be referred to dieticians within 48 hours of admission. The first cycle was conducted by March 2019 and the second cycle was completed 1 year later to allow assessment of interventions actioned after the first cycle. METHODS: We conducted a two-cycle audit evaluating the MUST completion and dietician referral rate of high-risk patients (defined as MUST ≥2) on the Acute Medical Unit in a district general hospital, with the standards of 80% and 100% respectively. A questionnaire was distributed after the first cycle exploring nurses' current experience and competence in using MUST. RESULTS: In the first cycle, MUST scores were calculated correctly in 111/150 patients (74%) and 1/9 (11%) high-risk patients were referred to dieticians. After interventions, MUST scores were calculated correctly in 77/101 patients (76%) and 2/4 high-risk patients (50%) were referred to dieticians. The nurses (n = 19) who took part in the questionnaire felt confident in MUST completion, but the average score in an objective assessment was 67%. CONCLUSIONS: As per the literature, the first cycle demonstrated the under-utilisation of MUST in clinical practice. In response, we proposed additional face-to-face training for existing staff, the inclusion of an e-learning module within the staff's induction, and provision of ward MUST 'troubleshooting' booklets. MUST utilisation rates improved upon re-auditing, but not to target standards. We will need to consider potential barriers to sustainable change and implement interventions such as identification of nursing champions to overcome them.

Through the Looking Glass: Unraveling the Stage-Shift of Acute Rejection in Renal Allografts.

Sub-optimal sensitivity and specificity in current allograft monitoring methodologies underscore the need for more accurate and reflexive immunosurveillance to uncover the flux in alloimmunity between allograft health and the onset and progression of rejection. QSant-a urine based multi-analyte diagnostic test-was developed to profile renal transplant health and prognosticate injury, risk of evolution, and resolution of acute rejection. Q-Score-the composite score, across measurements of DNA, protein and metabolic biomarkers in the QSant assay-enables this risk prognostication. The domain of immune quiescence-below a Q-Score threshold of 32-is well established, based on published AUC of 98% for QSant. However, the trajectory of rejection is variable, given that causality is multi-factorial. Injury and subtypes of rejection are captured by the progression of Q-Score. This publication explores the clinical utility of QSant across the alloimmunity gradient of 32-100 for the early diagnosis of allograft injury and rejection.

Refractory Epilepsy as a Late Effect of Chemoradiation in Childhood Cancer: A Case Series.

BACKGROUND: Seizures are a common complication of both primary central nervous system (CNS) tumors and other oncologic processes with CNS involvement. They occur most frequently during induction or consolidation therapy, but there is a growing body of evidence that they can also develop later in life. Refractory epilepsy can develop as a late complication for survivors of pediatric cancer with CNS involvement who undergo chemoradiation therapy. PATIENT DESCRIPTIONS: We report three patients who presented with atypical nonconvulsive seizures (behavioral arrest, falls, nonsensical speech) up to 14 years after cancer diagnosis. All underwent whole-brain radiation in addition to chemotherapy. None had a prior epilepsy diagnosis or known prior seizures. One patient suddenly passed away of unclear causes five months after diagnosis, and the other two continued to have EEG findings consistent with cerebral dysfunction and epileptogenicity years after diagnosis. CONCLUSION: We hypothesize that the development of refractory epilepsy may be a late effect of radiation treatment. Given the high morbidity and mortality associated with epilepsy, early identification is crucial to improve outcomes and quality of life for this vulnerable population. This is especially true for patients with medication-refractory epilepsy as there is an increasing breadth of effective surgical options.

The energetic basis for smooth human arm movements.

The central nervous system plans human reaching movements with stereotypically smooth kinematic trajectories and fairly consistent durations. Smoothness seems to be explained by accuracy as a primary movement objective, whereas duration seems to economize energy expenditure. But the current understanding of energy expenditure does not explain smoothness, so that two aspects of the same movement are governed by seemingly incompatible objectives. Here, we show that smoothness is actually economical, because humans expend more metabolic energy for jerkier motions. The proposed mechanism is an underappreciated cost proportional to the rate of muscle force production, for calcium transport to activate muscle. We experimentally tested that energy cost in humans (N = 10) performing bimanual reaches cyclically. The empirical cost was then demonstrated to predict smooth, discrete reaches, previously attributed to accuracy alone. A mechanistic, physiologically measurable, energy cost may therefore explain both smoothness and duration in terms of economy, and help resolve motor redundancy in reaching movements.

The Mammalian Membrane Microenvironment Regulates the Sequential Attachment of Bacteria to Host Cells.

Pathogen attachment to host tissue is critical in the progress of many infections. Bacteria use adhesion in vivo to stabilize colonization and subsequently regulate the deployment of contact-dependent virulence traits. To specifically target host cells, they decorate themselves with adhesins, proteins that bind to mammalian cell surface receptors. One common assumption is that adhesin-receptor interactions entirely govern bacterial attachment. However, how adhesins engage with their receptors in an in vivo-like context remains unclear, in particular under the influence of a heterogeneous mechanical microenvironment. We here investigate the biophysical processes governing bacterial adhesion to host cells using a tunable adhesin-receptor system. By dynamically visualizing attachment, we found that bacterial adhesion to host cell surface, unlike adhesion to inert surfaces, involves two consecutive steps. Bacteria initially attach to their host without engaging adhesins. This step lasts about 1 min, during which bacteria can easily detach. We found that at this stage, the glycocalyx, a layer of glycosylated proteins and lipids, shields the host cell by keeping adhesins away from their receptor ligand. In a second step, adhesins engage with their target receptors to strengthen attachment for minutes to hours. The active properties of the membrane, endowed by the actin cytoskeleton, strengthen specific adhesion. Altogether, our results demonstrate that adhesin-ligand binding is not the sole regulator of bacterial adhesion. In fact, the host cell's surface mechanical microenvironment mediates the physical interactions between host and bacteria, thereby playing an essential role in the onset of infection. IMPORTANCE Microbial adhesion to host cells is the initial step toward many infections. Despite playing a pivotal role in the onset of disease, we still know little about how bacteria attach in an in vivo-like context. By employing a biophysical approach where we investigated host-microbe physical interactions at the single-cell level, we unexpectedly discovered that bacteria attach to mammalian cell membranes in two successive steps. We found that mechanical factors of the cell microenvironment regulate each of these steps, and even dominate biochemical factors, thereby challenging preconceptions on how pathogens interact with their hosts.

Detection of naphthenic acid uptake into root and shoot tissues indicates a direct role for plants in the remediation of oil sands process-affected water.

Bitumen extraction from surface-mined oil sands deposits results in the accumulation of large volumes of oil sands process-affected water (OSPW). Naphthenic acids (NAs) are primary contributors to OSPW toxicity and have been a focal point for the development of OSPW remediation strategies. Phytoremediation is an approach that utilizes plants and their associated microbes to remediate contaminants from soil and groundwater. While previous evidence has indicated a role for phytoremediation in OSPW treatment through the transformation and degradation of NAs, there are no reports that demonstrate the direct uptake of NAs into plant tissue. Using NAs labelled with 14C radioisotopes (14C-NAs) paired with whole-plant autoradiography, we show that NAs representing aliphatic (linear), single-ring, and diamondoid compounds were effectively removed from hydroponic solution and OSPW-treated soil by sandbar willow (Salix interior) and slender wheatgrass (Elymus trachycaulus) and their associated microbiomes. The NA-derived 14C label accumulated in root and shoot tissues of both plant species and was concentrated in vascular tissue and rapidly growing sink tissues, indicating that 14C-NAs or their metabolic derivatives were incorporated into physiological processes within the plants. Slender wheatgrass seedlings grown under axenic (sterile) hydroponic and soil conditions also effectively removed all 14C-NAs, including a highly stable diamondoid NA, demonstrating that plants can directly take up simple and complex NAs without the assistance of microbes. Furthermore, root and shoot tissue fractionation into major biomolecule groups suggests that NA-derived carbon is allocated toward biomolecule synthesis rapidly after NA treatment. These findings provide evidence of plant-mediated uptake of NAs and support a direct role for plants and their associated microbes in the development of future large-scale OSPW phytoremediation strategies.

Predictive models of individual risk of elective caesarean section complications: a systematic review.

INTRODUCTION: With increasing caesarean section (c-section) rates, personalized communication of risk has become paramount. A reliable tool to predict complications would support evidence-based discussions around planned mode of birth. This systematic review aimed to identify, synthesize and quality appraise prognostic models of maternal complications of elective c-section. METHODS: MEDLINE, Embase, Web of Science, CINAHL and the Cochrane Library were searched on 27 January using terms relating to 'c-section', 'prognostic models' and complications such as 'infection'. Any study developing and/or validating a prognostic model for a maternal complication of elective c-section in the English language after January 1995 was selected for analysis. Data were extracted using a predetermined checklist: source of data; participants; outcome to be predicted; candidate predictors; sample size; missing data; model development; model performance; model evaluation; results; and interpretation. Quality was assessed using the Prediction model Risk Of Bias ASsessment Tool (PROBAST) tool. RESULTS: In total, 7752 studies were identified; of these, 16 full papers were reviewed and three eligible studies were identified, containing three prognostic models derived from hospitals in Japan, South Africa and the UK. The models predicted risk of blood transfusion, spinal hypotension and postpartum haemorrhage. The study authors deemed their studies to be exploratory, exploratory and confirmatory, respectively. From the three studies, a total of 29 unique candidate predictors were identified, with 15 predictors in the final models. Maternal age (n = 3), previous c-section (n = 2), placenta praevia (n = 2) and pre-operative haemoglobin (n = 2) were found to be common predictors amongst the included studies. None of the studies were externally validated and all had a high risk of bias due to the analysis technique used. CONCLUSION: Few models have been developed to predict complications of elective c-section. Existing models predicting blood transfusion, spinal hypotension and postpartum haemorrhage cannot be recommended for clinical practice. Future research should focus on identifying predictors known before surgery and validating the resulting models.

Increasing the gradient of energetic cost does not initiate adaptation in human walking.

When in a new situation, the nervous system may benefit from adapting its control policy. In determining whether or not to initiate this adaptation, the nervous system may rely on some features of the new situation. Here, we tested whether one such feature is salient cost savings. We changed cost saliency by manipulating the gradient of participants' energetic cost landscape during walking. We hypothesized that steeper gradients would cause participants to spontaneously adapt their step frequency to lower costs. To manipulate the gradient, a mechatronic system applied controlled fore-aft forces to the waist of participants as a function of their step frequency as they walked on a treadmill. These forces increased the energetic cost of walking at high step frequencies and reduced it at low step frequencies. We successfully created three cost landscapes of increasing gradients, where the natural variability in participants' step frequency provided cost changes of 3.6% (shallow), 7.2% (intermediate), and 10.2% (steep). Participants did not spontaneously initiate adaptation in response to any of the gradients. Using metronome-guided walking-a previously established protocol for eliciting initiation of adaptation-participants next experienced a step frequency with a lower cost. Participants then adapted by -1.41 ± 0.81 (P = 0.007) normalized units away from their originally preferred step frequency obtaining cost savings of 4.80% ± 3.12%. That participants would adapt under some conditions, but not in response to steeper cost gradients, suggests that the nervous system does not solely rely on the gradient of energetic cost to initiate adaptation in novel situations.NEW & NOTEWORTHY People can adapt to novel conditions but often require cues to initiate the adaptation. Using a mechatronic system to reshape energetic cost gradients during treadmill walking, we tested whether the nervous system can use information present in the cost gradient to spontaneously initiate adaptation. We found that our participants did not spontaneously initiate adaptation even in the steepest gradient. The nervous system does not rely solely on the cost gradient when initiating adaptation.

Design of an anthropomorphic PET phantom with elastic lungs and respiration modeling.

PURPOSE: Respiratory motion during positron emission tomography (PET) scans can be a major detriment to image quality in oncological imaging. The impact of motion on lesion quantification and detectability can be assessed using phantoms with realistic anatomy representation and motion modeling. In this work, we develop an anthropomorphic phantom for PET imaging that combines anatomic fidelity and a realistic breathing mechanism with deformable lungs. METHODS: We start from a previously developed anatomically accurate but static phantom of a human torso, and add elastic lungs with a highly controllable actuation mechanism which replicates the physics of breathing. The space outside the lungs is filled with a radioactive water solution. To maintain anatomical accuracy and realistic gamma ray attenuation in the torso, all motion mechanisms and actuators are positioned outside of the phantom compartment. The actuation mechanism can produce custom respiratory waveforms with breathing rates up to 25 breaths per minute and tidal volumes up to 1200 mL. RESULTS: Several tests were performed to validate the performance of the phantom assembly, in which the phantom was filled with water and given respiratory waveforms to execute. All parts demonstrated expected performance. Force requirements were not exceeded and no leaks were detected, although continued use of the phantom is required to evaluate wear. The motion of the lungs was determined to be within a reasonable realistic range. CONCLUSIONS: The full mechanical design is described in this paper, as well as a software application with graphical user interface which was developed to plan and visualize respiratory patterns. Both are available online as open source files. The developed phantom will facilitate future work in evaluating the impact of respiratory motion on lesion quantification and detectability in clinical practice.

The Use of Postoperative Antibiotics Following Endoscopic Sinus Surgery for Chronic Rhinosinusitis: A Systematic Review and Meta-analysis.

BACKGROUND: Endoscopic sinus surgery is performed for medically recalcitrant chronic rhinosinusitis. There is no universally accepted strategy regarding post-operative antibiotics despite the high rates of usage worldwide. The aim of this study was to analyse patient-reported and objective outcomes behind antibiotic use following endoscopic sinus surgery. METHODS: A search of electronic databases was performed. Eligible randomised controlled trials (RCTs) and observational trials were included. The primary outcome was patient reported outcome measures. Secondary outcomes were local infections, endoscopy scores and adverse events. Meta-analysis was performed. RESULTS: Of 1045 publications identified, 7 were included in the qualitative synthesis and 5 RCTs were included in meta-analysis. Antibiotic regimens varied between studies in terms of antibiotic selection, timing commenced and duration of use. Meta-analysis suggested no significant difference between placebo and antibiotics in patient reported outcome measures (standardised mean difference (SMD) -0.215, 95% confidence interval (CI) -0.637 to 0.207) or endoscopic scores (SMD -2.86, 95% CI -0.846 to 0.273). There was no consistent definition in reporting of infection; therefore, this outcome cannot be comprehensively considered. No severe adverse events were attributable to antibiotics. CONCLUSIONS: From the studies analysed, there is no level 1 evidence to suggest that antibiotics improved patient outcomes following sinus surgery. However, there was significant heterogeneity in outcome measures and no clear data exists regarding the effects of antibiotics on postoperative infections. The available evidence at present is not enough to make a recommendation in either direction. Further designed larger RCTs are required to investigate these questions in more detail.

Catechol Containing Polyelectrolyte Complex Nanoparticles as Local Drug Delivery System for Bortezomib at Bone Substitute Materials.

The proteasome inhibitor bortezomib (BZM) is one of the most potent anti-cancer drugs in the therapy of multiple myeloma. In this study, an adhesive drug delivery system (DDS) for BZM was developed. Therefore, we extended the present DDS concept of polyelectrolyte complex (PEC) nanoparticle (NP) based on electrostatic interactions between charged drug and polyelectrolyte (PEL) to a DDS concept involving covalent bonding between PEL and uncharged drugs. For this purpose, 3,4-dihydroxyphenyl acetic acid (DOPAC) was polymerized via an oxidatively induced coupling reaction. This novel chemo-reactive polyanion PDOPAC is able to temporarily bind boronic acid groups of BZM via its catechol groups, through esterification. PDOPAC was admixed to poly(l-glutamic acid) (PLG) and poly(l-lysine) (PLL) forming a redispersible PEC NP system after centrifugation, which is advantageous for further colloid and BZM loading processing. It was found that the loading capacity (LC) strongly depends on the PDOPAC and catechol content in the PEC NP. Furthermore, the type of loading and the net charge of the PEC NP affect LC and the residual content (RC) after release. Release experiments of PDOPAC/PEC coatings were performed at medically relevant bone substitute materials (calcium phosphate cement and titanium niobium alloy) whereby the DDS worked independently of the surface properties. Additionally, in contrast to electrostatically based drug loading the release behavior of covalently bound, uncharged BZM is independent of the ionic strength (salt content) in the release medium.

The Outcomes of Nonoperative Management of Patients With Hip and Knee Osteoarthritis Triaged to a Physiotherapy-Led Clinic at Minimum 5-Year Follow-Up and Factors Associated With Progression to Surgery.

BACKGROUND: The purpose of this study is to determine outcomes of a nonoperative treatment service for hip and knee osteoarthritis (OA), the "Joint Clinic," at minimum 5-year follow-up, and investigate factors that may influence progression to joint replacement surgery. METHODS: This is an observational cohort study of 337 patients with hip (n = 151, 45%) or knee OA (n = 186, 55%) seen at the Joint Clinic, at 5-7 years of follow-up. Kaplan-Meier survival curves were used to determine survivorship of the affected joint and Cox regression used to determine factors associated with time to surgery. RESULTS: At mean 6-year follow up, 188 (56%) patients had undergone or were awaiting total joint arthroplasty, 127 (38%) were still being managed nonoperatively, and 22 (7%) had died without having surgery. Patients with hip OA were more likely to have required surgery (111/151, 74%) than patients with knee OA (77/186, 41%) (chi-square = 33.6, P < .001). The 7-year surgery-free survival for hip OA was 23.7% and knee OA 55.9% (P < .001). Factors associated with increased likelihood of surgery were joint affected (hip, hazard ratio [HR] 2.80), Kellgren-Lawrence (KL) grade (KL 3, HR 2.02; KL 4, 4.79), and Oxford Hip/Knee Score (HR 1.34 for each 5 points worse at baseline). CONCLUSION: More than 50% of the patients referred to secondary care with mild-moderate knee OA may not need surgery at 7 years. Patients with hip OA and those with severe radiographic changes are more likely to require surgery and should not be delayed if there is not an adequate response to conservative measures.

Spatial distribution of interictal spikes fluctuates over time and localizes seizure onset.

The location of interictal spikes is used to aid surgical planning in patients with medically refractory epilepsy; however, their spatial and temporal dynamics are poorly understood. In this study, we analysed the spatial distribution of interictal spikes over time in 20 adult and paediatric patients (12 females, mean age = 34.5 years, range = 5-58) who underwent intracranial EEG evaluation for epilepsy surgery. Interictal spikes were detected in the 24 h surrounding each seizure and spikes were clustered based on spatial location. The temporal dynamics of spike spatial distribution were calculated for each patient and the effects of sleep and seizures on these dynamics were evaluated. Finally, spike location was assessed in relation to seizure onset location. We found that spike spatial distribution fluctuated significantly over time in 14/20 patients (with a significant aggregate effect across patients, Fisher's method: P < 0.001). A median of 12 sequential hours were required to capture 80% of the variability in spike spatial distribution. Sleep and postictal state affected the spike spatial distribution in 8/20 and 4/20 patients, respectively, with a significant aggregate effect (Fisher's method: P < 0.001 for each). There was no evidence of pre-ictal change in the spike spatial distribution for any patient or in aggregate (Fisher's method: P = 0.99). The electrode with the highest spike frequency and the electrode with the largest area of downstream spike propagation both localized the seizure onset zone better than predicted by chance (Wilcoxon signed-rank test: P = 0.005 and P = 0.002, respectively). In conclusion, spikes localize seizure onset. However, temporal fluctuations in spike spatial distribution, particularly in relation to sleep and post-ictal state, can confound localization. An adequate duration of intracranial recording-ideally at least 12 sequential hours-capturing both sleep and wakefulness should be obtained to sufficiently sample the interictal network.