Enlarged pituitary gland volume: a possible state rather than trait marker of psychotic disorders.

BACKGROUND: Enlarged pituitary gland volume could be a marker of psychotic disorders. However, previous studies report conflicting results. To better understand the role of the pituitary gland in psychosis, we examined a large transdiagnostic sample of individuals with psychotic disorders. METHODS: The study included 751 participants (174 with schizophrenia, 114 with schizoaffective disorder, 167 with psychotic bipolar disorder, and 296 healthy controls) across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Structural magnetic resonance images were obtained, and pituitary gland volumes were measured using the MAGeT brain algorithm. Linear mixed models examined between-group differences with controls and among patient subgroups based on diagnosis, as well as how pituitary volumes were associated with symptom severity, cognitive function, antipsychotic dose, and illness duration. RESULTS: Mean pituitary gland volume did not significantly differ between patients and controls. No significant effect of diagnosis was observed. Larger pituitary gland volume was associated with greater symptom severity (F = 13.61, p = 0.0002), lower cognitive function (F = 4.76, p = 0.03), and higher antipsychotic dose (F = 5.20, p = 0.02). Illness duration was not significantly associated with pituitary gland volume. When all variables were considered, only symptom severity significantly predicted pituitary gland volume (F = 7.54, p = 0.006). CONCLUSIONS: Although pituitary volumes were not increased in psychotic disorders, larger size may be a marker associated with more severe symptoms in the progression of psychosis. This finding helps clarify previous inconsistent reports and highlights the need for further research into pituitary gland-related factors in individuals with psychosis.

Lateral extra-articular tenodesis does not enhance ACL graft healing, however, does reduce graft tunnel widening.

PURPOSE: The study hypothesized that the addition of lateral extra-articular tenodesis (LEAT) in anterior cruciate ligament reconstruction (ACLR) had a significant effect on ACL graft healing. METHODS: A total of 80 patients were divided into two cohorts matched for gender, age, body mass index, time from surgery to post-operative MRI and graft diameter. Forty patients underwent ACL reconstruction alone, while 40 underwent ACLR in addition to LEAT. Patients underwent a magnetic resonance imaging scan at 12 months post-surgery; tunnel apertures were measured using multiplanar reformation, graft healing was assessed using signal-to-noise quotient (SNQ) in three regions of interest and finally graft maturity and integration were classified using the Howell and Ge scale, respectively. In addition, clinical evaluation and patient-reported outcome measures were collected. RESULTS: The mean femoral tunnel widening at 12 months post-surgery was 39.8 ± 14.0% in the ACLR + LEAT group and 55.2 ± 12.7% in the ACLR alone group (p < 0.05). The mean tibial tunnel widening was 29.3 ± 12.7% in the ACLR + LEAT group and 44.4 ± 12.1% in the ACLR group (p < 0.05). The mean adjusted graft SNQ was 9.0 ± 14.9 in the ACLR + LEAT group and 9.5 ± 11.4 in the ACLR group (n.s.). CONCLUSION: At 1 year post-operatively, we noted significantly less femoral and tibial tunnel widening in the ACLR + LEAT group. LEAT did not result in a statistically significant effect on graft healing. LEVEL OF EVIDENCE: Level III.

Deep psychophysiological phenotyping of adolescents and adults with 22q11.2 deletion syndrome: a multilevel approach to defining core disease processes.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders. Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. METHODS: Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity. To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. DISCUSSION: Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes. Our manuscript describes our ongoing study's protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.

Enzymatic C-H activation of aromatic compounds through CO2 fixation.

The direct C-H carboxylation of aromatic compounds is an attractive route to the corresponding carboxylic acids, but remains challenging under mild conditions. It has been proposed that the first step in anaerobic microbial degradation of recalcitrant aromatic compounds is a UbiD-mediated carboxylation. In this study, we use the UbiD enzyme ferulic acid decarboxylase (Fdc) in combination with a carboxylic acid reductase to create aromatic degradation-inspired cascade reactions, leading to efficient functionalization of styrene through CO2 fixation. We reveal that rational structure-guided laboratory evolution can expand the substrate scope of Fdc, resulting in activity on a range of mono- and bicyclic aromatic compounds through a single mutation. Selected variants demonstrated 150-fold improvement in the conversion of coumarillic acid to benzofuran + CO2 and unlocked reactivity towards naphthoic acid. Our data demonstrate that UbiD-mediated C-H activation is a versatile tool for the transformation of aryl/alkene compounds and CO2 into commodity chemicals.

Systems analysis of the effect of hydrogen sulfide on the growth of Methylococcus capsulatus Bath.

Methanotrophs are bacteria capable on growing on methane as their sole carbon source. They may provide a promising route for upgrading natural gas into more valuable fuels and chemicals. However, natural gas may contain significant quantities of hydrogen sulfide. Little is known about how hydrogen sulfide affects the growth and physiology of methanotrophs aside from a few studies showing that it is inhibitory. This study investigated how hydrogen sulfide affects the growth and physiology of the model methanotroph, Methylococcus capsulatus Bath. Growth studies demonstrated that hydrogen sulfide inhibits the growth of M. capsulatus Bath when the concentration exceeds 0.5% (v/v). To better understand how hydrogen sulfide is inhibiting the growth of M. capsulatus Bath, transcription and metabolite concentrations were profiled using RNA sequencing and gas chromatography-mass spectrometry, respectively. Our analysis of the differentially expressed genes and changes in metabolite concentrations suggests that hydrogen sulfide inhibits cellular respiration. The cells respond to sulfide stress in part by increasing the rate of sulfide oxidation and by increasing the expression of sulfide quinone reductase and a putative persulfide dioxygenase. In addition, they reduce the expression of the native calcium-dependent methanol dehydrogenase and increase the expression of XoxF, a lanthanide-dependent methanol dehydrogenase. While the reason of this switch in unknown, XoxF has previously been shown to be induced by lanthanides or nitric oxide in methanotrophs. Collectively, these results further our understanding of how methanotrophs respond to sulfide stress and may aid in the engineering of strains resistant to hydrogen sulfide. KEY POINTS: • Hydrogen sulfide inhibits growth of Methylococcus capsulatus Bath • Sulfide stress inhibits cellular respiration • Sulfide stress induces XoxF, a lanthanide-dependent methanol dehydrogenase.

Low percentage of surgeons meet the minimum recommended unicompartmental knee arthroplasty usage thresholds: Analysis of 3037 Surgeons from Three National Joint Registries.

PURPOSE: The reported usage of UKA is around 10% in the UK, Australian and New Zealand joint registries. However, some authors recommend that a higher UKA usage of 20%, or a minimum 12 UKA cases per year, would reduce revision rates. The purpose of this study was to analyze the percentage of surgeons performing the recommended thresholds in these 3 registries. METHODS: Data from the UK, Australian and New Zealand registry databases was utilized from the time period since their respective introduction until 2017. All primary TKA and UKA performed for the diagnosis of osteoarthritis by surgeons with more than 100 recorded knee arthroplasties in their respective registry were included. The results between the registries were compared and a pooled analysis was performed. The number of surgeons meeting the recommended caseload of > 20% UKA yearly or 12 UKA cases yearly was calculated. RESULTS: We identified 3037 knee surgeons performing 1,556,440 knee arthroplasties, of which 131,575 were UKA (8.45%). Over 50% of knee surgeons in each registry had a proportion of less than 5% UKA of their knee replacement procedures. After pooling of data, median surgeon UKA usage was 2.0% (IQR 0-9.1%). The percentage of surgeons meeting the proposed caseload criteria was highest in New Zealand, 16.3%, followed by the UK at 12.4% and Australia 11.3% (p = 0.28). CONCLUSION: More than 50% of knee surgeons in UK, Australian and New Zealand joint registries perform less than 5% of UKA yearly. The majority of experienced knee surgeons are not meeting the recommended minimum thresholds, which might indicate that the recommended thresholds are not feasible for the vast majority of knee surgeons. The reasons behind this require further research. LEVEL OF EVIDENCE: Level III retrospective registry study.

One-Stage Sequential Bilateral Total Knee Arthroplasty: An Effective Treatment for Advanced Bilateral Knee Osteoarthritis Providing High Patient Satisfaction.

BACKGROUND: The mortality and risks of bilateral total knee arthroplasty (BTKA) have been reported to be far greater than in unilateral total knee arthroplasty (UTKA). This study aimed to determine whether this remains the case using contemporary anesthetic and surgical techniques for one-stage single anesthetic sequential BTKA. METHODS: Two cohorts of 394 patients were created by propensity matching for gender, age, body mass index, American Society of Anesthesiologists grade, and Veterans Rand-12 health survey scores. Primary outcome was morbidity and mortality, with satisfaction measures using patient-reported outcome measures. RESULTS: The mortality rate was low with one case after BTKA. Major complications were also low; however, a pulmonary embolism rate of 2% in BTKA patients was significantly higher than 0.3% after UTKA (P < .05), and associated with an American Society of Anesthesiologists grade ≥3. The rate of minor complications between the 2 cohorts was comparable (P = .95). Blood transfusions were uncommon and not significantly different between cohorts (2.5% vs 1.3%, P = .3). BTKA patients stayed in hospital a mean 1.3 days longer with greater rehabilitation requirements. At final follow-up, patient satisfaction was high with all patient-reported outcome measures significantly improved and comparable between cohorts. CONCLUSION: BTKA is safe and effective in the majority of patients. Transfusion rates were far lower than historically reported and major complications were rare after both UTKA and BTKA. A significant increase in the rate of pulmonary embolism after BTKA was observed, especially in high risk patients. At minimum 1-year postoperatively, cohorts had the same significant clinical improvement and high level of satisfaction.

Correlation of tibial component size and rotation with outcomes after total knee arthroplasty.

INTRODUCTION: Tibial component design and positioning contribute more to patient satisfaction than previously realized. A surgeon needs to decide on the size and rotation, bearing in mind that coverage should be as high as possible, whilst malrotation and overhang should be avoided. No study investigates the impact of each of these components on clinical outcomes in a single cohort. MATERIALS AND METHODS: This is a retrospective analysis of 1-year postoperative outcomes measured with the Knee Injury and Osteoarthritis Outcome (KOOS) Score, as well as a previously validated rotational CT protocol. Coverage, rotation from Insall's axis, and overhang of an asymmetric tibial baseplate were measured, and positive and negative correlations to clinical outcomes were calculated. RESULTS: A total of 499 knees were analyzed. Patient average age was 68.4 years. Rotation within 7° internal and 5° external from Insall's axis was a "safe zone". Mean coverage was 76%. A total of 429 knees (94%) had a coverage of at least 70% and 102 knees (22%) greater than 80%. Overhang was detected in 23% of the cohort. Increased coverage was correlated to increased KOOS score and overhang correlated with a decreased KOOS score (p = 0.008). CONCLUSIONS: This study demonstrates the individual role of three aspects of tibial component implantation properties in postoperative pain and short-term functional outcomes. Upsizing to the point of overhang with rotational tolerance of 7° internal and 3° external to Insall's axis demonstrates best patient reported outcomes. Overhang decreases the clinical outcome by the same margin as loss of 16% of coverage.

The role of conserved residues in Fdc decarboxylase in prenylated flavin mononucleotide oxidative maturation, cofactor isomerization, and catalysis.

The UbiD family of reversible decarboxylases act on aromatic, heteroaromatic, and unsaturated aliphatic acids and utilize a prenylated flavin mononucleotide (prFMN) as cofactor, bound adjacent to a conserved Glu-Arg-Glu/Asp ionic network in the enzyme's active site. It is proposed that UbiD activation requires oxidative maturation of the cofactor, for which two distinct isomers, prFMNketimine and prFMNiminium, have been observed. It also has been suggested that only the prFMNiminium form is relevant to catalysis, which requires transient cycloaddition between substrate and cofactor. Using Aspergillus niger Fdc1 as a model system, we reveal that isomerization of prFMNiminium to prFMNketimine is a light-dependent process that is largely independent of the Glu277-Arg173-Glu282 network and accompanied by irreversible loss of activity. On the other hand, efficient catalysis was highly dependent on an intact Glu-Arg-Glu network, as only Glu → Asp substitutions retain activity. Surprisingly, oxidative maturation to form the prFMNiminium species is severely affected only for the R173A variant. In summary, the unusual irreversible isomerization of prFMN is light-dependent and probably proceeds via high-energy intermediates but is independent of the Glu-Arg-Glu network. Our results from mutagenesis, crystallographic, spectroscopic, and kinetic experiments indicate a clear role for the Glu-Arg-Glu network in both catalysis and oxidative maturation.

Factors Predicting Failure Rates and Patient-Reported Outcome Measures After Arthroscopic Meniscal Repair.

PURPOSE: To identify factors that affect patient-reported outcome measures (PROMs) and failure rates after arthroscopic meniscal repair. METHODS: Embase, Embase Classic, and MEDLINE were searched on August 7, 2015, December 23, 2016, and March 11, 2018, for factors associated with PROMs and failure rates after arthroscopic meniscal repair. We excluded studies that (1) were non-English language, (2) did not use human patients, (3) were nonclinical, (4) did not analyze for factors that predicted PROMs or failure rates, and (5) were below Level IV evidence. Studies were graded into higher and lower quality using the Downs and Black scale. RESULTS: A total of 34 articles met our criteria, and 32 were graded. We identified 16 articles as higher quality. Among higher-quality studies, factors that significantly predicted reduced failure rates were concurrent anterior cruciate ligament reconstruction (ACLR) (n = 6) and reduced tear complexity (n = 4). Factors that did not significantly impact failure rates were side of repair (n = 8), sex (n = 7), time from injury to surgery (n = 7), age (n = 7), rim width (n = 6), and tear length (n = 5). Factors predicting better PROMs were time from injury to surgery of less than 3 months (n = 1), Outerbridge scores below grade 3 or 4 (n = 2), and reduced varus alignment (n = 2). Factors that did not significantly impact PROMs were equipment used (n = 3) and concurrent ACLR (n = 1). CONCLUSIONS: Factors affecting failure rates and PROMs after arthroscopic meniscal repair were identified. However, more and higher-quality studies supported concurrent ACLR and less complex tears as predictors of lower failure rates. PROMs were negatively affected by a longer time from injury to surgery, higher Outerbridge scores, and greater varus alignment before surgery. LEVEL OF EVIDENCE: Level IV, systematic review of Level II to IV studies.

Clinical and Statistical Validation of a Probabilistic Prediction Tool of Total Knee Arthroplasty Outcome.

BACKGROUND: Predicting patients at risk of a poor outcome would be useful in patient selection for total knee arthroplasty (TKA). Existing models to predict outcome have seen limited functional implementation. This study aims to validate a model and shared decision-making tool for both clinical utility and predictive accuracy. METHODS: A Bayesian belief network statistical model was developed using data from the Osteoarthritis Initiative. A consecutive series of consultations for osteoarthritis before and after introduction of the tool was used to evaluate the clinical impact of the tool. A data audit of postoperative outcomes of TKA patients exposed to the tool was used to evaluate the accuracy of predictions. RESULTS: The tool changed consultation outcomes and identified patients at risk of limited improvement. After introduction of the tool, patients booked for surgery reported worse Knee Osteoarthritis and Injury Outcome Score pain scores (difference, 15.2; P < .001) than those not booked, with no significant difference prior. There was a 27% chance of not improving if predicted at risk, and a 1.4% chance if predicted to improve. This gives a risk ratio of 19× (P < .001) for patients not improving if predicted at risk. CONCLUSION: For a prediction tool to be clinically useful, it needs to provide a better understanding of the likely clinical outcome of an intervention than existed without its use when the clinical decisions are made. The tool presented here has the potential to direct patients to surgical or nonsurgical pathways on a patient-specific basis, ensuring patients who will benefit most from TKA surgery are selected.

Catalytic Determinants of Alkene Production by the Cytochrome P450 Peroxygenase OleTJE.

The Jeotgalicoccus sp. peroxygenase cytochrome P450 OleTJE (CYP152L1) is a hydrogen peroxide-driven oxidase that catalyzes oxidative decarboxylation of fatty acids, producing terminal alkenes with applications as fine chemicals and biofuels. Understanding mechanisms that favor decarboxylation over fatty acid hydroxylation in OleTJE could enable protein engineering to improve catalysis or to introduce decarboxylation activity into P450s with different substrate preferences. In this manuscript, we have focused on OleTJE active site residues Phe79, His85, and Arg245 to interrogate their roles in substrate binding and catalytic activity. His85 is a potential proton donor to reactive iron-oxo species during substrate decarboxylation. The H85Q mutant substitutes a glutamine found in several peroxygenases that favor fatty acid hydroxylation. H85Q OleTJE still favors alkene production, suggesting alternative protonation mechanisms. However, the mutant undergoes only minor substrate binding-induced heme iron spin state shift toward high spin by comparison with WT OleTJE, indicating the key role of His85 in this process. Phe79 interacts with His85, and Phe79 mutants showed diminished affinity for shorter chain (C10-C16) fatty acids and weak substrate-induced high spin conversion. F79A OleTJE is least affected in substrate oxidation, whereas the F79W/Y mutants exhibit lower stability and cysteine thiolate protonation on reduction. Finally, Arg245 is crucial for binding the substrate carboxylate, and R245E/L mutations severely compromise activity and heme content, although alkene products are formed from some substrates, including stearic acid (C18:0). The results identify crucial roles for the active site amino acid trio in determining OleTJE catalytic efficiency in alkene production and in regulating protein stability, heme iron coordination, and spin state.

Outcomes of Primary Total Knee Arthroplasty in Patients With Parkinson's Disease.

BACKGROUND: Parkinson's disease is a degenerative disorder causing rigidity, bradykinesia, and tremor of the motor system. There is significant paucity of evidence regarding whether total knee arthroplasty (TKA) is of benefit in patients with both Parkinson's disease and osteoarthritis. We aimed to compare outcomes and complications of TKA between patients with Parkinson's disease and those without. METHODS: A cohort of 43 knees from 35 patients with Parkinson's disease who received a primary TKA between January 2004 and December 2015 were retrospectively extracted from a private clinical database held by 2 surgeons and compared to an age and gender-matched control group of 50 knees from 41 patients. TKAs were performed by 2 surgeons at 1 tertiary private hospital.The indication for TKA in both groups was osteoarthritis. Difference between preoperative and 1-year range of movement (ROM) and 12-point Oxford Knee Score (OKS) was assessed using Student's unpaired t-test. Postoperative complications and revision procedures were also recorded during the follow-up period. The minimal clinically important difference for OKS at 1-year follow-up, defined as improvement of ≥6, was also assessed. RESULTS: In the Parkinson's group, mean ROM improvement was 14° (100° preoperatively to 114° at 12 months), compared to 12° in the control group (102°-114°, respectively). Mean OKS improvement was 15 in the Parkinson's group (23 preoperatively to 38 at 12 months) compared to 17 in the control group (23 and 40, respectively.) No significant difference was identified between the 2 groups for either ROM (P = .96) or OKS (P = .45.) All Parkinson's patients achieved the minimal clinically important difference at 1-year follow-up. There were no mortalities during the study follow-up period and no significant difference in complication rates between the 2 groups (P = .41). CONCLUSION: Parkinson's disease was not associated with poorer functional outcomes or increased complications compared to controls in our study. We suggest that Parkinson's disease is not an absolute contraindication to TKA.

Gait adaptations following multiple-ligament knee reconstruction occur with altered knee kinematics during level walking.

PURPOSE: The biomechanical behaviour of the knee following multiple-ligament reconstruction (MLKR) may play a role in the pathogenesis of post-traumatic osteoarthritis. The aim of this study was to compare three-dimensional knee kinematics and gait characteristics of MLKR patients to healthy controls during level walking. METHODS: Three-dimensional optoelectronic motion capture during overground walking was performed on 16 patients with MLKR and a group of healthy controls matched individually to each patient for age, gender, height and weight. Three-dimensional knee angles were extracted from the weight acceptance and propulsion sub-phases of gait. Statistical analysis was performed using group-aggregated data, as well as for each patient-control pair using a single-case approach. RESULTS: Although group analysis detected few differences, single-case analysis revealed significant differences for a proportion of patients for all dependent variables during weight acceptance and propulsion sub-phases of stance. These kinematic differences occurred in the context of reduced gait velocity, step length and cadence, as well as increased time spent in double support. CONCLUSION: Patients with MLKR display abnormalities in knee kinematics during gait at an average of 4.5 years after surgery. The pattern of kinematic abnormalities appears individual specific and may not be related to differences in spatiotemporal gait characteristics. The current findings describe detailed functional outcomes of MLKR reconstruction at average medium-term follow-up that provide improved prognostic information for clinicians to counsel patients with these types of injuries.

Synthesis of customized petroleum-replica fuel molecules by targeted modification of free fatty acid pools in Escherichia coli.

Biofuels are the most immediate, practical solution for mitigating dependence on fossil hydrocarbons, but current biofuels (alcohols and biodiesels) require significant downstream processing and are not fully compatible with modern, mass-market internal combustion engines. Rather, the ideal biofuels are structurally and chemically identical to the fossil fuels they seek to replace (i.e., aliphatic n- and iso-alkanes and -alkenes of various chain lengths). Here we report on production of such petroleum-replica hydrocarbons in Escherichia coli. The activity of the fatty acid (FA) reductase complex from Photorhabdus luminescens was coupled with aldehyde decarbonylase from Nostoc punctiforme to use free FAs as substrates for alkane biosynthesis. This combination of genes enabled rational alterations to hydrocarbon chain length (Cn) and the production of branched alkanes through upstream genetic and exogenous manipulations of the FA pool. Genetic components for targeted manipulation of the FA pool included expression of a thioesterase from Cinnamomum camphora (camphor) to alter alkane Cn and expression of the branched-chain α-keto acid dehydrogenase complex and ß-keto acyl-acyl carrier protein synthase III from Bacillus subtilis to synthesize branched (iso-) alkanes. Rather than simply reconstituting existing metabolic routes to alkane production found in nature, these results demonstrate the ability to design and implement artificial molecular pathways for the production of renewable, industrially relevant fuel molecules.

Structure and biochemical properties of the alkene producing cytochrome P450 OleTJE (CYP152L1) from the Jeotgalicoccus sp. 8456 bacterium.

The production of hydrocarbons in nature has been documented for only a limited set of organisms, with many of the molecular components underpinning these processes only recently identified. There is an obvious scope for application of these catalysts and engineered variants thereof in the future production of biofuels. Here we present biochemical characterization and crystal structures of a cytochrome P450 fatty acid peroxygenase: the terminal alkene forming OleTJE (CYP152L1) from Jeotgalicoccus sp. 8456. OleTJE is stabilized at high ionic strength, but aggregation and precipitation of OleTJE in low salt buffer can be turned to advantage for purification, because resolubilized OleTJE is fully active and extensively dissociated from lipids. OleTJE binds avidly to a range of long chain fatty acids, and structures of both ligand-free and arachidic acid-bound OleTJE reveal that the P450 active site is preformed for fatty acid binding. OleTJE heme iron has an unusually positive redox potential (-103 mV versus normal hydrogen electrode), which is not significantly affected by substrate binding, despite extensive conversion of the heme iron to a high spin ferric state. Terminal alkenes are produced from a range of saturated fatty acids (C12-C20), and stopped-flow spectroscopy indicates a rapid reaction between peroxide and fatty acid-bound OleTJE (167 s(-1) at 200 µm H2O2). Surprisingly, the active site is highly similar in structure to the related P450BSß, which catalyzes hydroxylation of fatty acids as opposed to decarboxylation. Our data provide new insights into structural and mechanistic properties of a robust P450 with potential industrial applications.

Femoral nerve blocks for acute postoperative pain after knee replacement surgery.

BACKGROUND: Total knee replacement (TKR) is a common and often painful operation. Femoral nerve block (FNB) is frequently used for postoperative analgesia. OBJECTIVES: To evaluate the benefits and risks of FNB used as a postoperative analgesic technique relative to other analgesic techniques among adults undergoing TKR. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 1, MEDLINE, EMBASE, CINAHL, Web of Science, dissertation abstracts and reference lists of included studies. The date of the last search was 31 January 2013. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing FNB with no FNB (intravenous patient-controlled analgesia (PCA) opioid, epidural analgesia, local infiltration analgesia, and oral analgesia) in adults after TKR. We also included RCTs that compared continuous versus single-shot FNB. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection and data extraction. We undertook meta-analysis (random-effects model) and used relative risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) or standardized mean differences (SMDs) for continuous outcomes. We interpreted SMDs according to rule of thumb where 0.2 or smaller represents a small effect, 0.5 a moderate effect and 0.8 or larger, a large effect. MAIN RESULTS: We included 45 eligible RCTs (2710 participants) from 47 publications; 20 RCTs had more than two allocation groups. A total of 29 RCTs compared FNB (with or without concurrent treatments including PCA opioid) versus PCA opioid, 10 RCTs compared FNB versus epidural, five RCTs compared FNB versus local infiltration analgesia, one RCT compared FNB versus oral analgesia and four RCTs compared continuous versus single-shot FNB. Most included RCTs were rated as low or unclear risk of bias for the aspects rated in the risk of bias assessment tool, except for the aspect of blinding. We rated 14 (31%) RCTs at high risk for both participant and assessor blinding and rated eight (18%) RCTs at high risk for one blinding aspect.Pain at rest and pain on movement were less for FNB (of any type) with or without a concurrent PCA opioid compared with PCA opioid alone during the first 72 hours post operation. Pooled results demonstrated a moderate effect of FNB for pain at rest at 24 hours (19 RCTs, 1066 participants, SMD -0.72, 95% CI -0.93 to -0.51, moderate-quality evidence) and a moderate to large effect for pain on movement at 24 hours (17 RCTs, 1017 participants, SMD -0.94, 95% CI -1.32 to -0.55, moderate-quality evidence). Pain was also less in each FNB subgroup: single-shot FNB, continuous FNB and continuous FNB + sciatic block, compared with PCA. FNB also was associated with lower opioid consumption (IV morphine equivalent) at 24 hours (20 RCTs, 1156 participants, MD -14.74 mg, 95% CI -18.68 to -10.81 mg, high-quality evidence) and at 48 hours (MD -14.53 mg, 95% CI -20.03 to -9.02 mg), lower risk of nausea and/or vomiting (RR 0.47, 95% CI 0.33 to 0.68, number needed to treat for an additional harmful outcome (NNTH) four, high-quality evidence), greater knee flexion (11 RCTs, 596 participants, MD 6.48 degrees, 95% CI 4.27 to 8.69 degrees, moderate-quality evidence) and greater patient satisfaction (four RCTs, 180 participants, SMD 1.06, 95% CI 0.74 to 1.38, low-quality evidence) compared with PCA.We could not demonstrate a difference in pain between FNB (any type) and epidural analgesia in the first 72 hours post operation, including pain at 24 hours at rest (six RCTs, 328 participants, SMD -0.05, 95% CI -0.43 to 0.32, moderate-quality evidence) and on movement (six RCTs, 317 participants, SMD 0.01, 95% CI -0.21 to 0.24, high-quality evidence). No difference was noted at 24 hours for opioid consumption (five RCTs, 341 participants, MD -4.35 mg, 95% CI -9.95 to 1.26 mg, high-quality evidence) or knee flexion (six RCTs, 328 participants, MD -1.65, 95% CI -5.14 to 1.84, high-quality evidence). However, FNB demonstrated lower risk of nausea/vomiting (four RCTs, 183 participants, RR 0.63, 95% CI 0.41 to 0.97, NNTH 8, moderate-quality evidence) and higher patient satisfaction (two RCTs, 120 participants, SMD 0.60, 95% CI 0.23 to 0.97, low-quality evidence), compared with epidural analgesia.Pooled results of four studies (216 participants) comparing FNB with local infiltration analgesia detected no difference in analgesic effects between the groups at 24 hours for pain at rest (SMD 0.06, 95% CI -0.61 to 0.72, moderate-quality evidence) or pain on movement (SMD 0.38, 95% CI -0.10 to 0.86, low-quality evidence). Only one included RCT compared FNB with oral analgesia. We considered this evidence insufficient to allow judgement of the effects of FNB compared with oral analgesia.Continuous FNB provided less pain compared with single-shot FNB (four RCTs, 272 participants) at 24 hours at rest (SMD -0.62, 95% CI -1.17 to -0.07, moderate-quality evidence) and on movement (SMD -0.42, 95% CI -0.67 to -0.17, high-quality evidence). Continuous FNB also demonstrated lower opioid consumption compared with single-shot FNB at 24 hours (three RCTs, 236 participants, MD -13.81 mg, 95% CI -23.27 to -4.35 mg, moderate-quality evidence).Generally, the meta-analyses demonstrated considerable statistical heterogeneity, with type of FNB, allocation concealment and blinding of participants, personnel and outcome assessors reducing heterogeneity in the analyses. Available evidence was insufficient to allow determination of the comparative safety of the various analgesic techniques. Few RCTs reported on serious adverse effects such as neurological injury, postoperative falls or thrombotic events. AUTHORS' CONCLUSIONS: Following TKR, FNB (with or without concurrent treatments including PCA opioid) provided more effective analgesia than PCA opioid alone, similar analgesia to epidural analgesia and less nausea/vomiting compared with PCA alone or epidural analgesia. The review also found that continuous FNB provided better analgesia compared with single-shot FNB. RCTs were insufficient to allow definitive conclusions on the comparison between FNB and local infiltration analgesia or oral analgesia.

Patient-specific instrumentation for total knee arthroplasty does not match the pre-operative plan as assessed by intra-operative computer-assisted navigation.

PURPOSE: The introduction of patient-specific instruments (PSI) for guiding bone cuts could increase the incidence of malalignment in primary total knee arthroplasty. The purpose of this study was to assess the agreement between one type of patient-specific instrumentation (Zimmer PSI) and the pre-operative plan with respect to bone cuts and component alignment during TKR using imageless computer navigation. METHODS: A consecutive series of 30 femoral and tibial guides were assessed in-theatre by the same surgeon using computer navigation. Following surgical exposure, the PSI cutting guides were placed on the joint surface and alignment assessed using the navigation tracker. The difference between in-theatre data and the pre-operative plan was recorded and analysed. RESULTS: The error between in-theatre measurements and pre-operative plan for the femoral and tibial components exceeded 3° for 3 and 17% of the sample, respectively, while the error for total coronal alignment exceeded 3° for 27% of the sample. CONCLUSION: The present results indicate that alignment with Zimmer PSI cutting blocks, assessed by imageless navigation, does not match the pre-operative plan in a proportion of cases. To prevent unnecessary increases in the incidence of malalignment in primary TKR, it is recommended that these devices should not be used without objective verification of alignment, either in real-time or with post-operative imaging. Further work is required to identify the source of discrepancies and validate these devices prior to routine use. LEVEL OF EVIDENCE: II.

Characterizing the Relationship between Personality Dimensions and Psychosis-Specific Clinical Characteristics.

Background: Past studies associating personality with psychosis have been limited by small nonclinical samples and a focus on general symptom burden. This study uses a large clinical sample to examine personality's relationship with psychosis-specific features and compare personality dimensions across clinically and neurobiologically defined categories of psychoses. Methods: A total of 1352 participants with schizophrenia, schizoaffective disorder, and bipolar with psychosis, as well as 623 healthy controls (HC), drawn from the Bipolar-Schizophrenia Network for Intermediate Phenotypes (BSNIP-2) study, were included. Three biomarker-derived biotypes were used to separately categorize the probands. Mean personality factors (openness, conscientiousness, extraversion, agreeableness, and neuroticism) were compared between HC and proband subgroups using independent sample t-tests. A robust linear regression was utilized to determine personality differences across biotypes and diagnostic subgroups. Associations between personality factors and cognition were determined through Pearson's correlation. A canonical correlation was run between the personality factors and general functioning, positive symptoms, and negative symptoms to delineate the relationship between personality and clinical outcomes of psychosis. Results: There were significant personality differences between the proband and HC groups across all five personality factors. Overall, the probands had higher neuroticism and lower extraversion, agreeableness, conscientiousness, and openness. Openness showed the greatest difference across the diagnostic subgroups and biotypes, and greatest correlation with cognition. Openness, agreeableness, and extraversion had the strongest associations with symptom severity. Conclusions: Individuals with psychosis have different personality profiles compared to HC. In particular, openness may be relevant in distinguishing psychosis-specific phenotypes and experiences, and associated with biological underpinnings of psychosis, including cognition. Further studies should identify potential causal factors and mediators of this relationship.