Does arthroscopic or open washout in native knee septic arthritis result in superior post-operative function? A systematic review and meta-analysis of randomised controlled trials and observational studies.

AIMS: Septic arthritis (SA) of the native knee joint is associated with significant morbidity. This review compared post-operative functional outcomes (patient-reported outcome measures (PROMs) and range of movement (ROM)) following arthroscopic washout (AW) and open washout (OW) amongst adult patients with SA of the native knee. The need for further operative intervention was also considered. METHODS: Electronic databases of PubMed, MEDLINE, Embase, Cochrane, Web of Science and Scopus were searched between 16 February 2023 and 18 March 2023. Randomised controlled trials (RCTs) and comparative observational analytic studies comparing function (reflected in PROMs or ROM) at latest follow-up following AW and OW were included. A narrative summary was provided concerning post-operative PROMs. Pooled estimates for mean ROM and re-operation rates were conducted using the random-effects model. The risk of bias was assessed using the Cochrane risk-of-bias assessment tool-2 for RCTs and the Risk of Bias in Non-Randomized Studies of Interventions tool for observational analytic studies. RESULTS: Of 2580 retrieved citations, 7 articles (1 RCT and 6 cohort studies) met the inclusion criteria. Of these, five had some concerns/moderate risk of bias, and two had serious risk. There was a slight tendency for superior mean PROMs following AW compared with OW, but due to small effect sizes, this was unlikely clinically relevant. Additionally, the use of four different PROMs scales made direct comparisons impossible. AW was associated with superior ROM (mean difference 20.18° (95% CI 14.35, 26.02; p < 0.00001)), whilst there was a tendency for lower re-operation requirements following AW (OR 0.64, 95% CI 0.26, 1.57, p = 0.44). CONCLUSIONS: AW was associated with equivalent to superior post-operative function and lower requirement for further intervention compared with OW. Results need to be interpreted cautiously, taking into consideration the methodological and clinical heterogeneity of the included studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2022, CRD42022364062.

Modelling the dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after cardiac surgery.

Major surgery and critical illness produce a potentially life-threatening systemic inflammatory response. The hypothalamic-pituitary-adrenal (HPA) axis is one of the key physiological systems that counterbalances this systemic inflammation through changes in adrenocorticotrophic hormone (ACTH) and cortisol. These hormones normally exhibit highly correlated ultradian pulsatility with an amplitude modulated by circadian processes. However, these dynamics are disrupted by major surgery and critical illness. In this work, we characterize the inflammatory, ACTH and cortisol responses of patients undergoing cardiac surgery and show that the HPA axis response can be classified into one of three phenotypes: single-pulse, two-pulse and multiple-pulse dynamics. We develop a mathematical model of cortisol secretion and metabolism that predicts the physiological mechanisms responsible for these different phenotypes. We show that the effects of inflammatory mediators are important only in the single-pulse pattern in which normal pulsatility is lost-suggesting that this phenotype could be indicative of the greatest inflammatory response. Investigating whether and how these phenotypes are correlated with clinical outcomes will be critical to patient prognosis and designing interventions to improve recovery.

A Facile Method for the Non-Covalent Amine Functionalization of Carbon-Based Surfaces for Use in Biosensor Development.

Affinity biosensors based on graphene field-effect transistor (GFET) or resistor designs require the utilization of graphene's exceptional electrical properties. Therefore, it is critical when designing these sensors, that the electrical properties of graphene are maintained throughout the functionalization process. To that end, non-covalent functionalization may be preferred over covalent modification. Drop-cast 1,5-diaminonaphthalene (DAN) was investigated as a quick and simple method for the non-covalent amine functionalization of carbon-based surfaces such as graphene, for use in biosensor development. In this work, multiple graphene surfaces were functionalized with DAN via a drop-cast method, leading to amine moieties, available for subsequent attachment to receptor molecules. Successful modification of graphene with DAN via a drop-cast method was confirmed using X-ray photoelectron spectroscopy (XPS), Raman spectroscopy and real-time resistance measurements. Successful attachment of receptor molecules also confirmed using the aforementioned techniques. Furthermore, an investigation into the effect of sequential wash steps which are required in biosensor manufacture, on the presence of the DAN layer, confirmed that the functional layer was not removed, even after multiple solvent exposures. Drop-cast DAN is thus, a viable fast and robust method for the amine functionalization of graphene surfaces for use in biosensor development.

Dynamic Pituitary-Adrenal Interactions in the Critically Ill after Cardiac Surgery.

CONTEXT: Patients with critical illness are thought to be at risk of adrenal insufficiency. There are no models of dynamic hypothalamic-pituitary-adrenal (HPA) axis function in this group of patients and thus current methods of diagnosis are based on aggregated, static models. OBJECTIVE: To characterize the secretory dynamics of the HPA axis in the critically ill (CI) after cardiac surgery. DESIGN: Mathematical modeling of cohorts. SETTING: Cardiac critical care unit. PATIENTS: 20 male patients CI at least 48 hours after cardiac surgery and 19 healthy (H) male volunteers. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Measures of hormone secretory dynamics were generated from serum adrenocorticotrophic hormone (ACTH) sampled every hour and total cortisol every 10 min for 24 h. RESULTS: All CI patients had pulsatile ACTH and cortisol profiles. CI patients had similar ACTH secretion (1036.4 [737.6] pg/mL/24 h) compared to the H volunteers (1502.3 [1152.2] pg/mL/24 h; P = .20), but increased cortisol secretion (CI: 14 447.0 [5709.3] vs H: 5915.5 [1686.7)] nmol/L/24 h; P < .0001). This increase in cortisol was due to nonpulsatile (CI: 9253.4 [3348.8] vs H: 960 [589.0] nmol/L/24 h, P < .0001), rather than pulsatile cortisol secretion (CI: 5193.1 [3018.5] vs H: 4955.1 [1753.6] nmol/L/24 h; P = .43). Seven (35%) of the 20 CI patients had cortisol pulse nadirs below the current international guideline threshold for critical illness-related corticosteroid insufficiency, but an overall secretion that would not be considered deficient. CONCLUSIONS: This study supports the premise that current tests of HPA axis function are unhelpful in the diagnosis of adrenal insufficiency in the CI. The reduced ACTH and increase in nonpulsatile cortisol secretion imply that the secretion of cortisol is driven by factors outside the HPA axis in critical illness.

A randomized controlled trial of arthroscopic capsular release versus hydrodilatation in the treatment of primary frozen shoulder.

BACKGROUND: Arthroscopic capsular release (ACR) and hydrodilatation (HD) have been developed for the management of frozen shoulder refractory to conservative treatment. To date no randomized trial has directly compared the efficacy of both interventions. The aim of this trial was to determine whether the Oxford Shoulder Score (OSS) differs between patients with frozen shoulder randomized to treatment with ACR or HD. METHODS: Patients presenting with severe idiopathic frozen shoulder deemed suitable for surgical intervention by a consultant shoulder surgeon were randomized to ACR or HD. The primary outcome measure was OSS at 6 months, with secondary outcomes measures of the EuroQol-5D visual analog scale, external rotation, complications, and crossover rate also recorded. RESULTS: Between June 2013 and December 2016, 50 patients were randomized to HD or ACR. The average age of the HD and ACR cohorts was 55.2 and 52.6 years, respectively (P = .36). At 6 months after the intervention, 20 patients were available for follow-up in the HD cohort and 19 in the ACR cohort. Both groups demonstrated significant improvements in OSS from baseline, but the OSS was significantly higher in the ACR cohort than the HD cohort (43.8 vs. 38.5, P = .023). The OSS was noted to improve rapidly after the intervention, with 75% of improvement in OSS noted at 6 weeks after surgery in both groups. CONCLUSIONS: Patients randomized to ACR reported a significantly higher OSS at 6 months than those randomized to HD. Both groups, however, showed a significant improvement.

Investigation into the effects of surface stripping ZnO nanosheets.

ZnO nanosheets are polycrystalline nanostructures that are used in devices including solar cells and gas sensors. However, for efficient and reproducible device operation and contact behaviour the conductivity characteristics must be controlled and surface contaminants removed. Here we use low doses of argon bombardment to remove surface contamination and make reproducible lower resistance contacts. Higher doses strip the surface of the nanosheets altering the contact type from near-ohmic to rectifying by removing the donor-type defects, which photoluminescence shows to be concentrated in the near-surface. Controlled doses of argon treatments allow nanosheets to be customised for device formation.

A randomized controlled trial of a manual-based psychosocial group intervention for young people with epilepsy [PIE].

We conducted an exploratory RCT to examine feasibility and preliminary efficacy for a manual-based psychosocial group intervention aimed at improving epilepsy knowledge, self-management skills, and quality of life in young people with epilepsy. METHOD: Eighty-three participants (33:50m/f; age range 12-17years) were randomized to either the treatment or control group in seven tertiary paediatric neuroscience centres in the UK, using a wait-list control design. Participants were excluded if they reported suicidal ideation and/or scored above the cut off on mental health screening measures, or if they had a learning disability or other neurological disorder. The intervention consisted of six weekly 2-hour sessions using guided discussion, group exercises and role-plays facilitated by an epilepsy nurse and a clinical psychologist. RESULTS: At three month follow up the treatment group (n=40) was compared with a wait-list control group (n=43) on a range of standardized measures. There was a significant increase in epilepsy knowledge in the treatment group (p=0.02). Participants receiving the intervention were also significantly more confident in speaking to others about their epilepsy (p=0.04). Quality of life measures did not show significant change. Participants reported the greatest value of attending the group was: Learning about their epilepsy (46%); Learning to cope with difficult feelings (29%); and Meeting others with epilepsy (22%). Caregiver and facilitator feedback was positive, and 92% of participants would recommend the group to others. CONCLUSION: This brief psychosocial group intervention was effective in increasing participants' knowledge of epilepsy and improved confidence in discussing their epilepsy with others. We discuss the qualitative feedback, feasibility, strengths and limitations of the PIE trial.

Alzheimer disease genetic risk factor APOE e4 and cognitive abilities in 111,739 UK Biobank participants.

BACKGROUND: the apolipoprotein (APOE) e4 locus is a genetic risk factor for dementia. Carriers of the e4 allele may be more vulnerable to conditions that are independent risk factors for cognitive decline, such as cardiometabolic diseases. OBJECTIVE: we tested whether any association with APOE e4 status on cognitive ability was larger in older ages or in those with cardiometabolic diseases. SUBJECTS: UK Biobank includes over 500,000 middle- and older aged adults who have undergone detailed medical and cognitive phenotypic assessment. Around 150,000 currently have genetic data. We examined 111,739 participants with complete genetic and cognitive data. METHODS: baseline cognitive data relating to information processing speed, memory and reasoning were used. We tested for interactions with age and with the presence versus absence of type 2 diabetes (T2D), coronary artery disease (CAD) and hypertension. RESULTS: in several instances, APOE e4 dosage interacted with older age and disease presence to affect cognitive scores. When adjusted for potentially confounding variables, there was no APOE e4 effect on the outcome variables. CONCLUSIONS: future research in large independent cohorts should continue to investigate this important question, which has potential implications for aetiology related to dementia and cognitive impairment.

Moderate chemical modifications of WAY-100635 improve the selectivity for 5-HT1A versus D4 receptors.

The selectivity for 5-HT(1A) versus D(4) receptors is significantly increased when the basic side chain of WAY-100635 is replaced by a 4-phenylpiperazine (3e) or a 4-phenyl-1,2,3,6-tetrahydropyridine moiety (3i). The 4-phenyl-1,2,3,6-tetrahydropyridine compounds (3i-l) have a higher affinity for 5-HT(1A) receptors than do the corresponding unsubstituted phenylpiperazine analogues (3e-h). Compounds 3e and 3i appear to be selective for 5-HT(1A) receptors over other relevant receptors and still behave as neutral antagonists.

Synthesis and receptor profiling of Stemona alkaloid analogues reveal a potent class of sigma ligands.

Reported biological activities of Stemona natural products, such as antitussive activity, inspired the development of synthetic methods to access several alkaloids within this family and in so doing develop a general route to the core skeleta shared by the class of natural products. The chemistry was subsequently adapted to afford a series of analogue sets bearing simplified, diverse Stemona-inspired skeleta. Over 100 of these analogues were subjected to general G protein-coupled receptor profiling along with the known antitussive compound, neostenine; this led to the identification of hit compounds targeting several receptor types. The particularly rich hit subset for sigma receptors was expanded with two focused library sets, which resulted in the discovery of a fully synthetic, potent chemotype of sigma ligands. This collaborative effort combined the development of synthetic methods with extensive, flexible screening resources and exemplifies the role of natural products in bioactivity mining.

Plasma MMP-9 and MMP-2 following acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of left ventricular dysfunction.

BACKGROUND: Left ventricular dilatation and elevated plasma natriuretic peptide levels predict adverse prognosis and the development of congestive heart failure after myocardial infarction. Altered matrix metalloproteinase (MMP) activity has been implicated in the structural changes associated with development of heart failure after myocardial injury. The aims of this study were to investigate plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 concentrations following acute myocardial infarction and their relationships with measures of left ventricular function. METHODS AND RESULTS: Plasma MMP-2, MMP-9, TIMP-1, and N-terminal proBNP (N-BNP) were quantified on 5 consecutive days in 60 patients with acute myocardial infarction (39 anterior). N-BNP was measured on day 3. Echocardiographic assessment of left ventricular wall motion index and volumes was performed during admission and 6 weeks later. Plasma MMP-9 showed peaks on days 1 and 4. MMP-2 levels, similar on each day, were higher after inferior myocardial infarction. Plasma MMP-2 showed strong, inverse correlation with left ventricular volumes during and after admission. Plasma MMP-9 correlated directly with N-BNP (P=.022) and inversely with wall motion index during admission (P=.05). TIMP-1 levels were higher after anterior (1269, 870-1466 ng/mL) compared with inferior (1183, 856-1419 ng/mL, P=.05) acute myocardial infarction and fell from day 1 through 5 (P <.0005). CONCLUSION: Plasma MMP-9 concentration correlates with neurohormonal and echocardiographic measures of left ventricular dysfunction after myocardial infarction. Higher left ventricular volumes are associated with lower plasma MMP-2 concentrations. Circulating MMP concentrations may provide insights into left ventricular remodeling after acute myocardial infarction.