Re-PROGRAM: The evaluation of a brief intervention program for patients with functional seizures in an outpatient hospital setting.

OBJECTIVE: Functional seizures (FS) account for 20%-25% of referrals to specialist epilepsy clinics. They are associated with major disability, increased mortality, and frequent and costly health care use. Current guidelines emphasize the importance of implementing clinical pathways to coordinate and deliver effective treatment, but there are few targeted evidence-based interventions that reliably improve patient outcomes, and treatment resources are limited. We conducted a retrospective evaluation of Re-PROGRAM, a novel, brief intervention for functional seizure patients, to assess its feasibility in an outpatient setting. METHODS: Twenty-nine patients with FS undertook Re-PROGRAM between August 2020 and January 2022 at the Alfred Hospital Functional Seizures Clinic, Melbourne, Australia. The intervention comprised five 60-90-min consecutive weekly appointments via telehealth, where psychologists engaged patients in a structured program of seizure management skills, lifestyle modification, and behavioral activation strategies. Following the intervention, patient feedback was collected in routine clinical follow-up as well as with a 24-item self-report pre-/postintervention comparison questionnaire. RESULTS: All 29 patients who enrolled in Re-PROGRAM completed the scheduled sessions. Of those who returned the postintervention questionnaire (n = 16), 15 reported a reduction in seizure frequency. Four patients were lost to follow-up. Of the remaining nine, eight reported seizure frequency reduction during clinical follow-up. Qualitative analysis of the feedback revealed the majority of patients reported reduced seizure duration, intensity, and bothersomeness, and patients felt improvements in their sense of control over seizures, confidence to use seizure control strategies, assertive communication, problem solving, coping skills, relationships with others, and their day-to-day functioning. SIGNIFICANCE: This retrospective evaluation demonstrates the feasibility and acceptability of Re-PROGRAM as a brief intervention for individuals diagnosed with FS delivered in a clinical outpatient setting and warrants further investigation in larger scale, randomized controlled studies.

"What are your seizures telling you?": A therapeutic tool for functional seizures.

BACKGROUND: Understanding illness representations is considered important for improving health outcomes, yet how people with functional seizures reflect on the possible psychological function of their seizures has not been studied. METHODS: A semi-structured interview comprising open and closed questions was administered to 99 participants with a documented diagnosis of functional seizures. One item, 'What do you think your functional seizure symptoms are telling you?" sought to explore how individuals reflect on the possible function of their seizures. Qualitative analysis using NVivo comprised thematic content analysis of responses to the question, and pattern analysis, to determine association with diagnosis acceptance, and openness to a possible psychological aetiology. RESULTS: Most patients (88 %) readily interpreted their seizures in response to this question. We identified one major theme, with the majority of participants interpreting seizure symptoms as an enforced hiatus. Two minor themes were identified: personal growth and contempt. Subthemes were identified within both the enforced hiatus (stop, slow down, relax) and personal growth (self-care, self-development, acceptance) themes. Individuals who did not accept the diagnosis of functional seizures referenced seizures with contempt towards the self or answered, 'don't know'. Respondents who did not know also tended to reject a psychological basis for their seizures in contrast to those who discussed themes of enforced hiatus, personal growth, and contempt. CONCLUSIONS: Responses provide valuable insight into how individuals reflect on their condition in a non-acute setting. Themes can serve as a foundation for future therapeutic discussions and patient-centred communication strategies to build a mutual understanding of the potential function of physical symptoms regardless of whether a psychological basis for them is accepted or not. What is already known on this topic: Outcomes for functional seizures are generally poor and often attributed to patients rejecting psychiatric care or not accepting the diagnosis. WHAT THIS STUDY ADDS: This study is the first to explore patient conceptualisations of the possible function of their functional seizures as a therapeutic tool for understanding the condition. How this study might affect research, practice, or policy: Findings may provide a basis for improved clinician-patient relationships, treatment engagement, and more targeted interventions for people with functional seizures.

Breathing control training for functional seizures: A multi-site, open-label pilot study.

There are no well-validated treatments for functional seizures. While specialist psychotherapy is usually recommended, the evidence for its benefit is qualified, and it can be difficult to obtain. Given the association between hyperventilation and functional seizures we explored an alternative modality, breathing control training, in a multi-site open label pilot trial. Participants with functional seizures over the age of 16 received an hour of breathing training from a respiratory physiotherapist, with a half-hour booster session a month later. Seizure frequency and Nijmegen scores (a measure of hyperventilation) were reported at baseline and follow-up, 3-4 months later. Eighteen subjects were recruited, and 10 completed follow-up. Seven of these 10 had improved seizure frequency, and 3 did not (Wilcoxon signed rank test, p = 0.09), with seizure frequency correlating with Nijmegen score (Spearman's rank correlation = 0.75, p = 0.034). The intervention was well tolerated, with no adverse events reported. These preliminary results support a potentially new approach to treating functional seizures that should prove cost-effective and acceptable, though require confirmation by a randomised controlled trial.

Childhood trauma in patients with epileptic vs nonepileptic seizures.

OBJECTIVE: Childhood trauma has been implicated as a risk factor for the etiology of psychogenic nonepileptic seizures (PNES). Relatively little attention has been paid to whether profiles of specific trauma types differ between patients with epilepsy and PNES. Investigating childhood trauma profiles in these patient groups may identify psychological vulnerabilities that predispose to developing PNES, and aid early diagnoses, prevention, and treatment. METHODS: Data were collected from two cohorts (nRetrospective  = 203; nProspective  = 209) admitted to video-electroencephalography (EEG) monitoring units in Melbourne Australia. The differences in Childhood Trauma Questionnaire domain score between patient groups were investigated using standardized effect sizes and general linear mixed-effects models (GLMMs). Receiver-operating characteristic curves were used to investigate classification accuracy. RESULTS: In the retrospective cohort, patients diagnosed with PNES reported greater childhood emotional abuse, emotional neglect, physical abuse, sexual abuse, and physical neglect relative to patients with epilepsy. These differences were replicated in the prospective cohort, except for physical abuse. GLMMs revealed significant main effects for group in both cohorts, but no evidence for any group by domain interactions. Reported sexual abuse showed the best screening performance of PNES, although no psychometric scores were adequate as isolated measures. SIGNIFICANCE: Patients with PNES report a greater frequency of childhood trauma than patients with epilepsy. This effect appears to hold across all trauma types, with no strong evidence emerging for a particular trauma type that is more prevalent in PNES. From a practical perspective, inquiry regarding a history of sexual abuse shows the most promise as a screening measure.

Expression of the far-red D1 protein or introduction of conserved far-red D1 residues into Synechocystis sp. PCC 6803 impairs Photosystem II.

The wavelengths of light harvested in oxygenic photosynthesis are ~400-700 nm. Some cyanobacteria respond to far-red light exposure via a process called far-red light photoacclimation which enables absorption of light at wavelengths >700 nm and its use to support photosynthesis. Far-red-light-induced changes include up-regulation of alternative copies of multiple proteins of Photosystem II (PS II). This includes an alternative copy of the D1 protein, D1FR . Here, we show that D1FR introduced into Synechocystis sp. PCC 6803 (hereafter Synechocystis 6803) can be incorporated into PS II centres that evolve oxygen at low rates but cannot support photoautotrophic growth. Using mutagenesis to modify the psbA2 gene of Synechocystis 6803, we modified residues in helices A, B, and C to be characteristic of D1FR residues. Modification of the Synechocystis 6803 helix A to resemble the D1FR helix A, with modifications in the region of the bound ß-carotene (CarD1 ) and the accessory chlorophyll, ChlZD1 , produced a strain with a similar phenotype to the D1FR strain. In contrast, the D1FR changes in helices B and C had minor impacts on photoautotrophy but impacted the function of PS II, possibly through a change in the equilibrium for electron sharing between the primary and secondary plastoquinone electron acceptors QA and QB in favour of QA - . The addition of combinations of residue changes in helix C indicates compensating effects may occur and highlight the need to experimentally determine the impact of multiple residue changes.

Improving the treatment of functional seizures through a public specialist outpatient clinic.

OBJECTIVES: We performed an audit of the first 12 months of clinical operations to assess the feasibility of a newly established public outpatient clinic for the assessment and treatment of functional (psychogenic nonepileptic) seizures (FS). METHOD: Clinical notes for the first 12 months of the FSclinic weresystematicallyreviewed with data compiled onreferral pathways, clinic attendance, clinical features, treatments, and outcomes. RESULTS: Of eighty-two new FS patients referred to the clinic, over 90% attended. Patients were diagnosed with FS after comprehensive epileptological and neuropsychiatric review, mostly with typical seizure-like episodes captured during video-EEG monitoring, and most accepted the diagnosis. Most had FS at least weekly, with little sense of control and significant impairment. The majority of individuals had significant psychiatric and medical comorbidity. Predisposing, precipitating, and perpetuating factors were readily identified in >90% of cases. Of 52 patients with follow-up data within12 months, 88% were either stable or improved in terms of the control of their FS. CONCLUSION: The Alfred functional seizure clinic model, the first dedicated public outpatient clinic for FS in Australia, provides a feasible and potentially effective treatment pathway for this underserved and disabled patient group.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.

Surfaces Containing Sharp Nanostructures Enhance Antibiotic Efficacy.

The ever-increasing rate of medical device implantations is met by a proportionately high burden of implant-associated infections. To mitigate this threat, much research has been directed toward the development of antibacterial surface modifications by various means. One recent approach involves surfaces containing sharp nanostructures capable of killing bacteria upon contact. Herein, we report that the mechanical interaction between Staphylococcus aureus and such surface nanostructures leads to a sensitization of the pathogen to the glycopeptide antibiotic vancomycin. We demonstrate that this is due to cell wall damage and impeded bacterial defenses against reactive oxygen species. The results of this study promise to be impactful in the clinic, as a combination of nanostructured antibacterial surfaces and antibiotics commonly used in hospitals may improve antimicrobial therapy strategies, helping clinicians to prevent and treat implant-associated infections using reduced antibiotic concentrations instead of relying on invasive revision surgeries with often poor outcomes.

Multidimensional psychopathological profile differences between patients with psychogenic nonepileptic seizures and epileptic seizure disorders.

OBJECTIVE: Early differential diagnosis of psychogenic nonepileptic seizures (PNES) and epileptic seizures (ES) remains difficult. Self-reported psychopathology is often elevated in patients with PNES, although relatively few studies have examined multiple measures of psychopathology simultaneously. This study aimed to identify differences in multidimensional psychopathology profiles between PNES and ES patient groups. METHOD: This was a retrospective case-control study involving patients admitted for video-EEG monitoring (VEM) over a two-year period. Clinicodemographic variables and psychometric measures of depression, anxiety, dissociation, childhood trauma, maladaptive personality traits, and cognition were recorded. Diagnosis of PNES or ES was determined by multidisciplinary assessment and consensus opinion. General linear mixed models (GLMMs) were used to investigate profile differences between diagnostic groups across psychometric measures. A general psychopathology factor was then computed using principal components analysis (PCA) and differences between groups in this 'p' factor were investigated. RESULTS: 261 patients (77 % with ES and 23 % with PNES) were included in the study. The PNES group endorsed greater symptomatology with GLMM demonstrating a significant main effect of group (η2p = 0.05) and group by measure interaction (η2p = 0.03). Simple effects analysis indicated that the PNES group had particularly elevated scores for childhood trauma (ß = 0.78), dissociation (ß = 0.70), and depression (ß = 0.60). There was a high correlation between psychopathology measures, with a single p factor generated to explain 60 % variance in the psychometric scores. The p factor was elevated in the PNES group (ß = 0.61). ROC curve analysis indicated that these psychometric measures had limited usefulness when considered individually (AUC range = 0.63-0.69). CONCLUSION: Multidimensional psychopathological profile differences exist between patients with PNES and ES. Patients with PNES report more psychopathology overall, with particular elevations in childhood trauma, dissociation, and depression. Although not suitable to be used as a standalone screening tool to differentiate PNES and ES, understanding of these profiles at a construct level might help triage patients and guide further psychiatric examination and enquiry.

A Novel Nanostructured Surface on Titanium Implants Increases Osseointegration in a Sheep Model.

BACKGROUND: A nanostructured titanium surface that promotes antimicrobial activity and osseointegration would provide the opportunity to create medical implants that can prevent orthopaedic infection and improve bone integration. Although nanostructured surfaces can exhibit antimicrobial activity, it is not known whether these surfaces are safe and conducive to osseointegration. QUESTIONS/PURPOSES: Using a sheep animal model, we sought to determine whether the bony integration of medical-grade, titanium, porous-coated implants with a unique nanostructured surface modification (alkaline heat treatment [AHT]) previously shown to kill bacteria was better than that for a clinically accepted control surface of porous-coated titanium covered with hydroxyapatite (PCHA) after 12 weeks in vivo. The null hypothesis was that there would be no difference between implants with respect to the primary outcomes: interfacial shear strength and percent intersection surface (the percentage of implant surface with bone contact, as defined by a micro-CT protocol), and the secondary outcomes: stiffness, peak load, energy to failure, and micro-CT (bone volume/total volume [BV/TV], trabecular thickness [Tb.Th], and trabecular number [Tb.N]) and histomorphometric (bone-implant contact [BIC]) parameters. METHODS: Implants of each material (alkaline heat-treated and hydroxyapatite-coated titanium) were surgically inserted into femoral and tibial metaphyseal cancellous bone (16 per implant type; interference fit) and in tibial cortices at three diaphyseal locations (24 per implant type; line-to-line fit) in eight skeletally mature sheep. At 12 weeks postoperatively, bones were excised to assess osseointegration of AHT and PCHA implants via biomechanical push-through tests, micro-CT, and histomorphometry. Bone composition and remodeling patterns in adult sheep are similar to that of humans, and this model enables comparison of implants with ex vivo outcomes that are not permissible with humans. Comparisons of primary and secondary outcomes were undertaken with linear mixed-effects models that were developed for the cortical and cancellous groups separately and that included a random effect of animals, covariates to adjust for preoperative bodyweight, and implant location (left/right limb, femoral/tibial cancellous, cortical diaphyseal region, and medial/lateral cortex) as appropriate. Significance was set at an alpha of 0.05. RESULTS: The estimated marginal mean interfacial shear strength for cancellous bone, adjusted for covariates, was 1.6 MPa greater for AHT implants (9.3 MPa) than for PCHA implants (7.7 MPa) (95% CI 0.5 to 2.8; p = 0.006). Similarly, the estimated marginal mean interfacial shear strength for cortical bone, adjusted for covariates, was 6.6 MPa greater for AHT implants (25.5 MPa) than for PCHA implants (18.9 MPa) (95% CI 5.0 to 8.1; p < 0.001). No difference in the implant-bone percent intersection surface was detected for cancellous sites (cancellous AHT 55.1% and PCHA 58.7%; adjusted difference of estimated marginal mean -3.6% [95% CI -8.1% to 0.9%]; p = 0.11). In cortical bone, the estimated marginal mean percent intersection surface at the medial site, adjusted for covariates, was 11.8% higher for AHT implants (58.1%) than for PCHA (46.2% [95% CI 7.1% to 16.6%]; p < 0.001) and was not different at the lateral site (AHT 75.8% and PCHA 74.9%; adjusted difference of estimated marginal mean 0.9% [95% CI -3.8% to 5.7%]; p = 0.70). CONCLUSION: These data suggest there is stronger integration of bone on the AHT surface than on the PCHA surface at 12 weeks postimplantation in this sheep model. CLINICAL RELEVANCE: Given that the AHT implants formed a more robust interface with cortical and cancellous bone than the PCHA implants, a clinical noninferiority study using hip stems with identical geometries can now be performed to compare the same surfaces used in this study. The results of this preclinical study provide an ethical baseline to proceed with such a clinical study given the potential of the alkaline heat-treated surface to reduce periprosthetic joint infection and enhance implant osseointegration.

Clinical predictors of discordance between screening tests and psychiatric assessment for depressive and anxiety disorders among patients being evaluated for seizure disorders.

OBJECTIVE: This study was undertaken to identify factors that predict discordance between the screening instruments Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Generalized Anxiety Disorder scale (GAD-7), and diagnoses made by qualified psychiatrists among patients with seizure disorders. Importantly, this is not a validation study; rather, it investigates clinicodemographic predictors of discordance between screening tests and psychiatric assessment. METHODS: Adult patients admitted for inpatient video-electroencephalographic monitoring completed eight psychometric instruments, including the NDDI-E and GAD-7, and psychiatric assessment. Patients were grouped according to agreement between the screening instrument and psychiatrists' diagnoses. Screening was "discordant" if the outcome differed from the psychiatrist's diagnosis, including both false positive and false negative results. Bayesian statistical analyses were used to identify factors associated with discordance. RESULTS: A total of 411 patients met inclusion criteria; mean age was 39.6 years, and 55.5% (n = 228) were female. Depression screening was discordant in 33% of cases (n = 136/411), driven by false positives (n = 76/136, 56%) rather than false negatives (n = 60/136, 44%). Likewise, anxiety screening was discordant in one third of cases (n = 121/411, 29%) due to false positives (n = 60/121, 50%) and false negatives (n = 61/121, 50%). Seven clinical factors were predictive of discordant screening for both depression and anxiety: greater dissociative symptoms, greater patient-reported adverse events, subjective cognitive impairment, negative affect, detachment, disinhibition, and psychoticism. When the analyses were restricted to only patients with psychogenic nonepileptic seizures (PNES) or epilepsy, the rate of discordant depression screening was higher in the PNES group (n = 29, 47%) compared to the epilepsy group (n = 70, 30%, Bayes factor for the alternative hypothesis = 4.65). SIGNIFICANCE: Patients with seizure disorders who self-report a variety of psychiatric and other symptoms should be evaluated more thoroughly for depression and anxiety, regardless of screening test results, especially if they have PNES and not epilepsy. Clinical assessment by a qualified psychiatrist remains essential in diagnosing depressive and anxiety disorders among such patients.

Psychiatric and cognitive characteristics of older adults admitted to a Video-EEG monitoring (VEM) unit.

OBJECTIVE: To compare the clinical, psychiatric, and cognitive characteristics of older with younger patients presenting to a video-EEG monitoring (VEM) unit. METHOD: This was a retrospective case-control study involving patients admitted for VEM over a two-year period (from April 2018 to April 2020) at two comprehensive epilepsy units. Patients were categorized into an older (≥60 years) and a younger (<60 years) group. Younger patients were individually matched to older adults to form a matched younger group. Diagnosis was determined by a consensus opinion of epileptologists, neurologists, and neuropsychiatrists. The main diagnostic categories were epilepsy, psychogenic nonepileptic seizures (PNES), and 'other' diagnosis (non-diagnostic and other nonepileptic diagnoses). Clinical psychiatric diagnoses were obtained from neuropsychiatric reports. Objective cognitive function was measured with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG). Subjective cognitive function was assessed using the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) cognitive subscales. RESULTS: Five-hundred and thirty three patients (71 older, 462 younger) aged 16-91 years were admitted to the VEM unit during the study period. There was a diagnosis of focal epilepsy in 55% of the older group and 48% of the younger group, generalized epilepsy in 3% of the older group and 10% of the younger group, and 'other' in 32% of the older group and 19% of the younger group. Ten percent (2 males and 5 females) of the older group were diagnosed with PNES compared to 22% of the younger group (p = 0.016). A depressive disorder was diagnosed in 34% of the older group and 24% of the younger group (p = 0.20). An anxiety disorder was diagnosed in 15% of the older group and 25% of the younger group (p = 0.15). Mild neurocognitive disorder was more common in the older group (34%) compared to the matched younger group (34% vs 3%, p < 0.001). The older group had lower mean NUCOG scores compared to the matched younger group (79.49 vs 87.73, p = <0.001). There was no evidence for a relationship between mean NUCOG score and overall subjective cognitive difficulties for the older group (r = 0.03, p = 0.83). Among older adults, those diagnosed with PNES had more experiences of childhood trauma. Measures of dissociation, depression, or general anxiety did not differ between PNES and non-PNES diagnoses in the older group. CONCLUSION: Psychiatric comorbidities are common among older adults admitted for VEM. The psychological impact of epilepsy and risk factors for PNES seen in younger patients are also applicable in the older group. The older group demonstrated more cognitive impairments than the younger group, although these were usually unrecognized by individuals. Older adults admitted to VEM will benefit from psychiatric and neuropsychological input to ensure a comprehensive care approach to evaluation and management.

Adverse events related to antiepileptic drugs.

OBJECTIVE: Adverse events (AEs) related to antiepileptic drugs (AEDs) may interfere with adequate dosing and patient adherence, leading to suboptimal seizure control, and relatedly, increased injuries, hospitalizations, and mortality. This study investigated the clinicodemographic factors associated with AEs related to AEDs as reported by the Liverpool Adverse Events Profile (LAEP), and explored the ability of LAEP to discriminate between epilepsy and psychogenic nonepileptic seizures (PNES). We hypothesized that female sex, mood disorders, AED-polytherapy, duration, and severity of epilepsy are associated with increased endorsement of AEs related to AEDs, and that endorsement of AEs related to AEDs would significantly differ between epilepsy and PNES patients. METHODS: We prospectively enrolled adult patients admitted to two inpatient video-electroencephalogram monitoring units. Clinicodemographic variables and psychometric measures of depression, anxiety, and cognitive function were recorded. Patient-reported AE endorsement was obtained using the LAEP, which was reduced to four latent domains using exploratory structural equation modeling. General linear models identified variables associated with each domain. Logistic regression determined the ability of LAEP scores to differentiate between epilepsy and PNES. RESULTS: 311 patients met inclusion criteria. Mean age was 38 years and 56% of patients were female. Network analysis demonstrated strong relationships between depression and anxiety with physical, sleep, psychiatric, and dermatological AE endorsement. Depression, female sex, and AED polytherapy were associated with greater AE endorsement. Epilepsy, compared to PNES, was associated with lower AE endorsement. Fewer prescribed AEDs and greater reported physical AE endorsement were associated with PNES diagnosis. SIGNIFICANCE: There is a strong relationship between patient-reported AEs and psychiatric symptomatology. Those with PNES paradoxically endorse greater physical AEs despite receiving fewer AEDs. Patients who endorse AEs in clinical practice should be screened for comorbid depression or anxiety and treated accordingly.

Burnout and psychological distress amongst Australian healthcare workers during the COVID-19 pandemic.

OBJECTIVE: To examine psychological distress in healthcare workers (HCWs) during the COVID-19 pandemic in April-May 2020. METHODS: A cross-sectional survey examining demographic, employment and mental health characteristics of HCWs in a large metropolitan hospital in Australia. RESULTS: HCWs showed significant symptoms of moderate-severe level depression (21%), anxiety (20%) and posttraumatic stress disorder (PTSD; 29%), associated with burnout, prior psychiatric history, profession and resilience. CONCLUSION: Despite low levels of COVID contact, moderate to high levels of psychological distress were reported. Continued monitoring and support for HCWs' mental well-being is warranted as the COVID-19 pandemic develops.

Terminally Truncated Isopenicillin N Synthase Generates a Dithioester Product: Evidence for a Thioaldehyde Intermediate during Catalysis and a New Mode of Reaction for Non-Heme Iron Oxidases.

Isopenicillin N synthase (IPNS) catalyses the four-electron oxidation of a tripeptide, l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV), to give isopenicillin N (IPN), the first-formed ß-lactam in penicillin and cephalosporin biosynthesis. IPNS catalysis is dependent upon an iron(II) cofactor and oxygen as a co-substrate. In the absence of substrate, the carbonyl oxygen of the side-chain amide of the penultimate residue, Gln330, co-ordinates to the active-site metal iron. Substrate binding ablates the interaction between Gln330 and the metal, triggering rearrangement of seven C-terminal residues, which move to take up a conformation that extends the final α-helix and encloses ACV in the active site. Mutagenesis studies are reported, which probe the role of the C-terminal and other aspects of the substrate binding pocket in IPNS. The hydrophobic nature of amino acid side-chains around the ACV binding pocket is important in catalysis. Deletion of seven C-terminal residues exposes the active site and leads to formation of a new type of thiol oxidation product. The isolated product is shown by LC-MS and NMR analyses to be the ene-thiol tautomer of a dithioester, made up from two molecules of ACV linked between the thiol sulfur of one tripeptide and the oxidised cysteinyl ß-carbon of the other. A mechanism for its formation is proposed, supported by an X-ray crystal structure, which shows the substrate ACV bound at the active site, its cysteinyl ß-carbon exposed to attack by a second molecule of substrate, adjacent. Formation of this product constitutes a new mode of reaction for IPNS and non-heme iron oxidases in general.

Cognitive relevance of the community structure of the human brain functional coactivation network.

There is growing interest in the complex topology of human brain functional networks, often measured using resting-state functional MRI (fMRI). Here, we used a meta-analysis of the large primary literature that used fMRI or PET to measure task-related activation (>1,600 studies; 1985-2010). We estimated the similarity (Jaccard index) of the activation patterns across experimental tasks between each pair of 638 brain regions. This continuous coactivation matrix was used to build a weighted graph to characterize network topology. The coactivation network was modular, with occipital, central, and default-mode modules predominantly coactivated by specific cognitive domains (perception, action, and emotion, respectively). It also included a rich club of hub nodes, located in parietal and prefrontal cortex and often connected over long distances, which were coactivated by a diverse range of experimental tasks. Investigating the topological role of edges between a deactivated and an activated node, we found that such competitive interactions were most frequent between nodes in different modules or between an activated rich-club node and a deactivated peripheral node. Many aspects of the coactivation network were convergent with a connectivity network derived from resting state fMRI data (n = 27, healthy volunteers); although the connectivity network was more parsimoniously connected and differed in the anatomical locations of some hubs. We conclude that the community structure of human brain networks is relevant to cognitive function. Deactivations may play a role in flexible reconfiguration of the network according to cognitive demand, varying the integration between modules, and between the periphery and a central rich club.

Utility of the Stanford Integrated Psychosocial Assessment for Transplant in predicting outcomes before and after lung transplantation.

BACKGROUND: Optimizing donor use and achieving maximal survival following lung transplantation (LTx) require a pretransplant assessment that identifies clinical, physiological, and psychosocial patient factors associated with both poor and optimal post-LTx survival. We examined the utility of a psychosocial tool, the Stanford Integrated Psychosocial Assessment for Transplant (SIPAT), to identify patient suitability for LTx, as well as its association with clinical outcomes before and after LTx. METHODS: This was a retrospective single-center study analyzing LTx assessment clinical variables (age, gender, diagnosis, functional capacity, nutrition, renal function), with a particular focus on the utility of the SIPAT score, to predict patient suitability for LTx. The same variables were analyzed against LTx waitlist mortality, as well as post-LTx survival. RESULTS: Over an 8-year period dating from December 2012, 914 patients (male 54.4%, mean age 55.2 years) underwent LTx assessment. Patients declined for LTx (n = 152, 16.6%) were older and had reduced functional capacity, nutritional markers, and renal function but had a higher SIPAT score. Once listed for LTx, a higher SIPAT score was not associated with waitlist mortality or reduced post-LTx survival. CONCLUSIONS: The SIPAT tool measures psychosocial suitability for transplantation that can be incorporated into a standardized assessment of LTx suitability. While patients with higher SIPAT score were more likely to be declined for LTx, the SIPAT score did not predict outcome in transplanted patients. A subgroup of patients with high SIPAT scores were successfully transplanted, suggesting that unfavorable psychosocial variables are potentially modifiable with a well-resourced multidisciplinary LTx team.

Validation of the Seizure-Related Impact Assessment Scale (SERIAS): a study protocol.

INTRODUCTION: This study aims to validate the Seizure-Related Impact Assessment Scale (SERIAS). This novel patient-reported outcome measure (PROM) compares the 'trade-off' between seizures and treatment-related adverse effects, and measures epilepsy disability qualitatively and quantitively. It fills an important gap in PROMs for epilepsy clinical trials and practice. METHODS AND ANALYSIS: Adults with epileptologist-confirmed epilepsy from two Australian Epilepsy Centres are being recruited. People with functional seizures, or who are unable to self-complete English-language validated instruments are excluded. Participants providing informed consent are invited to complete questionnaires at baseline, 3 and 6 months later. SERIAS includes five questions that ask about the number of days per month that seizures or treatment-related adverse effects partially or fully impact work/home/school and family/social/non-work activities, as well as a visual analogue scale regarding epilepsy-related disability. SERIAS is completed alongside seven internationally validated instruments measuring treatment-related adverse effects, mood disorders and quality of life. Target recruitment is n=100, ensuring>50 people complete all questionnaires at all timepoints. Comprehensive psychometric analysis will be performed. Convergent validity will be investigated using bivariate correlations with relevant measures. Reliability will be investigated using Cronbach's alpha, McDonald's omega and test-retest correlation coefficients. SERIAS will be a novel PROM for epilepsy clinical trials and practice. ETHICS AND DISSEMINATION: Multisite ethics approval was granted by the Alfred Health Ethics Committee (HREC 17/23). Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12623000599673.

Comparative effectiveness of digital mental healthcare models for adults with epilepsy: A study protocol of a randomized controlled trial.

OBJECTIVE: Mental health complaints are prevalent among people with epilepsy, yet there are major barriers that prevent access to psychological care, including high out-of-pocket costs and a lack of accessible specialized services. The purpose of the current study is to examine the comparative efficacy, acceptability, cost-effectiveness, and long-term outcomes of a digital psychological intervention when delivered under two models of care (i.e., guided vs. unguided) in supporting the mental health and functioning of adults with epilepsy. METHOD: Approximately 375 participants across Australia will be enrolled. Eligible participants will have a confirmed diagnosis of epilepsy, experience difficulties with their emotional health, be at least 18 years of age, and live in Australia. Participants will be randomized (2:2:1) to receive the Wellbeing Neuro Course, a 10-week internet-delivered program, with (i.e., guided) or without guidance by a mental health clinician (i.e., unguided), or be allocated to a treatment-as-usual waiting-list control group. Participants will complete online questionnaires at pre-, post-treatment, and 3- and 12-month follow-up and consent to have their data linked to their medical records to capture healthcare system resource use and costs. ANALYSIS: Primary outcome measures will be symptoms of depression and anxiety. A cost-utility analysis will be undertaken using the Australian healthcare system perspective and according to current economic evaluation guidelines. Resource use and costs to the healthcare system during the study period will be captured via data linkage to relevant administrative datasets in Australia. SIGNIFICANCE: The results of this trial will provide important data concerning the relative outcomes of these different models of care and will inform the integration of digital psychological interventions translation into healthcare services. ETHICS AND DISSEMINATION: The Human Research Ethics Committee of Macquarie University approved the proposed study (Reference No: 520231325151475). The results will be disseminated through peer-reviewed publication(s). ANZCTR TRIAL REGISTRATION NUMBER: ACTRN12623001327673. PLAIN LANGUAGE SUMMARY: This study seeks to find out if a 10-week online psychological treatment can improve the mental health and well-being of Australian adults with epilepsy. Around 375 participants will be randomly assigned to different groups: one will receive treatment with guidance from mental health clinician (guided group), one without guidance (unguided group), and one starting later (waiting control group). All participants will fill out the same outcome measures online. The main goal of this research is to compare these groups and assess how well the treatment works in improving mental health outcomes.

Nanoscale Titanium Surface Engineering via Low-Temperature Hydrothermal Etching for Enhanced Antimicrobial Properties.

Bioinspired nanotopography artificially fabricated on titanium surfaces offers a solution for the rising issue of postoperative infections within orthopedics. On a small scale, hydrothermal etching has proven to deliver an effective antimicrobial nanospike surface. However, translation to an industrial setting is limited by the elevated synthesis temperature (150 °C) and associated equipment requirements. Here, for the first time, we fabricate surface nanostructures using comparatively milder synthesis temperatures (75 °C), which deliver physicochemical properties and antimicrobial capability comparable to the high-temperature surface. Using a KOH etchant, the simultaneous formation of titania and titanate crystals at both temperatures produces a one-dimensional nanostructure array. Analysis indicated that the formation mechanism comprises dissolution and reprecipitation processes, identifying the deposited titanates as hydrated layered tetra-titanates (K2Ti4O9·nH2O). A proposed nanospike formation mechanism was confirmed through the identification of a core and outer shell for individual nanostructures, primarily comprised of titanates and titania, respectively. Etching conditions dictated crystalline formation, favoring a thicker titanate core for nanorods under higher synthesis temperatures and etchant concentrations. A bactericidal investigation showed the efficacy against Gram-negative bacteria for a representative low-temperature nanosurface (34.4 ± 14.4%) was comparable to the higher temperature nanosurface (34.0 ± 17.0%), illustrating the potential of low-temperature hydrothermal synthesis. Our results provide valuable insight into the applicability of low-temperature etching protocols that are more favorable in large-scale manufacturing settings.