Navigated Intraoperative Ultrasound Offers Effective and Efficient Real-Time Analysis of Intracranial Tumor Resection and Brain Shift.

BACKGROUND AND OBJECTIVES: Neuronavigation is a fundamental tool in the resection of intracranial tumors. However, it is limited by its calibration to preoperative neuroimaging, which loses accuracy intraoperatively after brain shift. Therefore, surgeons rely on anatomic landmarks or tools like intraoperative MRI to assess the extent of tumor resection (EOR) and update neuronavigation. Recent studies demonstrate that intraoperative ultrasound (iUS) provides point-of-care imaging without the cost or resource utilization of an intraoperative MRI, and advances in neuronavigation-guided iUS provide an opportunity for real-time imaging overlaid with neuronavigation to account for brain shift. We assessed the feasibility, efficacy, and benefits of navigated iUS to assess the EOR and restore stereotactic accuracy in neuronavigation after brain shift. METHODS: This prospective single-center study included patients presenting with intracranial tumors (gliomas, metastasis) to an academic medical center. Navigated iUS images were acquired preresection, midresection, and postresection. The EOR was determined by the surgeon intraoperatively and compared with the postoperative MRI report by an independent neuroradiologist. Outcome measures included time to perform the iUS sweep, time to process ultrasound images, and EOR predicted by the surgeon intraoperatively compared with the postoperative MRI. RESULTS: This study included 40 patients consisting of gliomas (n = 18 high-grade gliomas, n = 4 low-grade gliomas, n = 4 recurrent) and metastasis (n = 18). Navigated ultrasound sweeps were performed in all patients (n = 83) with a median time to perform of 5.5 seconds and a median image processing time of 29.9 seconds. There was 95% concordance between the surgeon's and neuroradiologist's determination of EOR using navigated iUS and postoperative MRI, respectively. The sensitivity was 100%, and the specificity was 94%. CONCLUSION: Navigated iUS was successfully used for EOR determination in glioma and metastasis resection. Incorporating navigated iUS into the surgical workflow is safe and efficient and provides a real-time assessment of EOR while accounting for brain shift in intracranial tumor surgeries.

International Hackathon as a Tool to Augment Education, Collaboration, and Innovation in Global Neurosurgery.

BACKGROUND AND OBJECTIVES: Health care providers' exposure to global surgical disparities is limited in current nursing and/or medical school curricula. For instance, global health is often associated with infectious diseases or maternal health without acknowledging the growing need for surgical care in low- and middle-income countries (LMICs). We propose an international virtual hackathon based on neurosurgical patient cases in under-resourced settings as an educational tool to bring awareness to global surgical disparities and develop relationships among trainees in different countries. METHODS: Participants were recruited through email listservs, a social media campaign, and prize offerings. A 3-day virtual hackathon event was administered, which included workshops, mentorship, keynote panels, and pitch presentations to judges. Participants were presented with real patient cases and directed to solve a barrier to their care. Surveys assessed participants' backgrounds and event experience. The hackathon was executed through Zoom at Harvard Innovation Lab in Boston, MA, on March 25 to 27, 2022. Participants included medical students, with additional participants from business, engineering, or current health care workers. RESULTS: Three hundred seven applications were submitted for 100 spots. Participants included medical students, physicians, nurses, engineers, entrepreneurs, and undergraduates representing 25 countries and 82 cities. Fifty-one participants previously met a neurosurgeon, while 39 previously met a global health expert, with no difference between LMIC and high-income countries' respondents. Teams spent an average of 2.75 hours working with mentors, and 88% of postevent respondents said the event was "very" or "extremely conducive" to networking. Projects fell into 4 categories: access, language barriers, education and training, and resources. The winning team, which was interdisciplinary and international, developed an application that analyzes patient anatomy while performing physical therapy to facilitate remote care and clinical decision-making. CONCLUSION: An international virtual hackathon can be an educational tool to increase innovative ideas to address surgical disparities in LMICs and establish early collaborative relationships with medical trainees from different countries.

International Hackathon as a Tool to Augment Education, Collaboration, and Innovation in Global Neurosurgery.

BACKGROUND AND OBJECTIVES: Health care providers' exposure to global surgical disparities is limited in current nursing and/or medical school curricula. For instance, global health is often associated with infectious diseases or maternal health without acknowledging the growing need for surgical care in low- and middle-income countries (LMICs). We propose an international virtual hackathon based on neurosurgical patient cases in under-resourced settings as an educational tool to bring awareness to global surgical disparities and develop relationships among trainees in different countries. METHODS: Participants were recruited through email listservs, a social media campaign, and prize offerings. A 3-day virtual hackathon event was administered, which included workshops, mentorship, keynote panels, and pitch presentations to judges. Participants were presented with real patient cases and directed to solve a barrier to their care. Surveys assessed participants' backgrounds and event experience. The hackathon was executed through Zoom at Harvard Innovation Lab in Boston, MA, on March 25 to 27, 2022. Participants included medical students, with additional participants from business, engineering, or current health care workers. RESULTS: Three hundred seven applications were submitted for 100 spots. Participants included medical students, physicians, nurses, engineers, entrepreneurs, and undergraduates representing 25 countries and 82 cities. Fifty-one participants previously met a neurosurgeon, while 39 previously met a global health expert, with no difference between LMIC and high-income countries' respondents. Teams spent an average of 2.75 hours working with mentors, and 88% of postevent respondents said the event was "very" or "extremely conducive" to networking. Projects fell into 4 categories: access, language barriers, education and training, and resources. The winning team, which was interdisciplinary and international, developed an application that analyzes patient anatomy while performing physical therapy to facilitate remote care and clinical decision-making. CONCLUSION: An international virtual hackathon can be an educational tool to increase innovative ideas to address surgical disparities in LMICs and establish early collaborative relationships with medical trainees from different countries.

Navigated Simultaneous Lateral Minimally Invasive Tubular and Posterior Mini-Open Access for Removal and Revision of Triangular Sacroiliac Joint Implants: A Technical Note.

BACKGROUND: Sacroiliac joint (SIJ) fusion, to treat back pain caused by SIJ dysfunction, can employ open or minimally invasive surgery (MIS) techniques and either cylindrical (screw-shaped) or triangular (wedge-shaped) implants. Fusion nonunion sometimes explains recurrent SIJ pain following fusion and occasionally requires hardware revision. MIS revision minimizes patient pain, infection, and disability, but due to the triangular implant size and form factor, implant removal can present challenges for MIS access during the explantation and achieving good bony purchase for reinstrumentation. Here, we report a prone single-position lateral MIS/posterior mini-open procedure for triangular-implant SIJ fusion revision. METHODS: The patient is a 72-year-old female who underwent right SIJ fusion for lower back and leg pain sustained after a fall 2 years prior but experienced recurrent pain over the subsequent 2 years, with imaging findings of right SIJ peri-hardware lucencies and diagnostic injections confirming persistent right-sided sacroiliitis. RESULTS: The patient underwent hardware removal using the lateral MIS incision with table-mounted tubular access and image-guided navigation to maintain exposure, plus simultaneous reinstrumentation using a navigated S2-alar-iliac screw and iliac bolt construct with connecting rod through the posterior mini-open incision made for the navigation reference frame spinous process clamp. CONCLUSIONS: The use of navigation and MIS access can significantly decrease the complexity of lateral hardware removal, and mini-open navigated screw-and-rod constructs offer reinstrumentation options accessible to surgeons unfamiliar with specialized posterior SIJ systems.

Neurological Surgery Residency Programs in the United States: A National Cross-Sectional Survey.

BACKGROUND AND OBJECTIVES: The Accreditation Council for Graduate Medical Education has approved 117 neurological surgery residency programs which develop and educate neurosurgical trainees. We present the current landscape of neurosurgical training in the United States by examining multiple aspects of neurological surgery residencies in the 2022-2023 academic year and investigate the impact of program structure on resident academic productivity. METHODS: Demographic data were collected from publicly available websites and reports from the National Resident Match Program. A 34-question survey was circulated by e-mail to program directors to assess multiple features of neurological surgery residency programs, including curricular structure, fellowship availability, recent program changes, graduation requirements, and resources supporting career development. Mean resident productivity by program was collected from the literature. RESULTS: Across all 117 programs, there was a median of 2.0 (range 1.0-4.0) resident positions per year and 1.0 (range 0.0-2.0) research/elective years. Programs offered a median of 1.0 (range 0.0-7.0) Committee on Advanced Subspecialty Training-accredited fellowships, with endovascular fellowships being most frequently offered (53.8%). The survey response rate was 75/117 (64.1%). Of survey respondents, the median number of clinical sites was 3.0 (range 1.0-6.0). Almost half of programs surveyed (46.7%) reported funding mechanisms for residents, including R25, T32, and other in-house grants. Residents received a median academic stipend of $1000 (range $0-$10 000) per year. Nearly all programs (93.3%) supported wellness activities for residents, which most frequently occurred quarterly (46.7%). Annual academic stipend size was the only significant predictor of resident academic productivity (R 2 = 0.17, P = .002). CONCLUSION: Neurological surgery residency programs successfully train the next generation of neurosurgeons focusing on education, clinical training, case numbers, and milestones. These programs offer trainees the chance to tailor their career trajectories within residency, creating a rewarding and personalized experience that aligns with their career aspirations.

From dawn till dusk: Time-adaptive bayesian optimization for neurostimulation.

Stimulation optimization has garnered considerable interest in recent years in order to efficiently parametrize neuromodulation-based therapies. To date, efforts focused on automatically identifying settings from parameter spaces that do not change over time. A limitation of these approaches, however, is that they lack consideration for time dependent factors that may influence therapy outcomes. Disease progression and biological rhythmicity are two sources of variation that may influence optimal stimulation settings over time. To account for this, we present a novel time-varying Bayesian optimization (TV-BayesOpt) for tracking the optimum parameter set for neuromodulation therapy. We evaluate the performance of TV-BayesOpt for tracking gradual and periodic slow variations over time. The algorithm was investigated within the context of a computational model of phase-locked deep brain stimulation for treating oscillopathies representative of common movement disorders such as Parkinson's disease and Essential Tremor. When the optimal stimulation settings changed due to gradual and periodic sources, TV-BayesOpt outperformed standard time-invariant techniques and was able to identify the appropriate stimulation setting. Through incorporation of both a gradual "forgetting" and periodic covariance functions, the algorithm maintained robust performance when a priori knowledge differed from observed variations. This algorithm presents a broad framework that can be leveraged for the treatment of a range of neurological and psychiatric conditions and can be used to track variations in optimal stimulation settings such as amplitude, pulse-width, frequency and phase for invasive and non-invasive neuromodulation strategies.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 µg/mL, range 0.05-0.4; RTX: 0.03 µg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Time to Care: Analysis of Time Differences and Outcomes in the Management of Pediatric Traumatic Brain Injury for a High-Income and Lower-Middle-Income Country.

BACKGROUND: Pediatric cranial trauma is the leading cause of acquired death and disability in children worldwide. However, trauma resources vary widely among countries. We sought to compare management and timely access to care between a level 1 U.S. pediatric trauma center and a tertiary referral hospital in a lower-middle-income country to assess whether system and resource differences influence care and outcomes. METHODS: We compared data from 214 pediatric head trauma admissions to Philippine General Hospital (Manila) with 136 children from the TRACK-TBI pediatrics study cohort at Massachusetts General Hospital (MGH). Admitted MGH patients were compared with the Philippine cohort regarding demographics; mechanism of injury; times to neurosurgical consult, imaging, and surgery; in-hospital mortality; and length of hospitalization. RESULTS: Age (9 years), gender distribution (67% male), and presenting Glasgow Coma Scale scores were similar (P = 0.10) between sites. More children had intracranial injury in the Philippine cohort (73% vs. 60%; n = 319) and more underwent neurosurgery (27% vs. 4%). Times to consult, imaging, and surgery were longer in the Philippines (12.3 vs. 6.5, 12.0 vs. 2.8, and 45.4 vs. 5.6 hours, respectively). In-hospital mortality across all admissions was similar between cohorts (3% vs. 0%; P = 0.09), but significantly higher in the most severe Philippines cases (31% vs. 0%, P=0.04). Length of stay was longer (5 vs. 2 days; P < 0.001) in the Philippine cohort. CONCLUSIONS: High-income country status correlated with faster care, shorter hospitalizations, and better outcomes among severe cases. Prompt care through sophisticated trauma system implementation may improve pediatric health in resource-limited settings.

When do bursts matter in the primary motor cortex? Investigating changes in the intermittencies of beta rhythms associated with movement states.

Brain activity exhibits significant temporal structure that is not well captured in the power spectrum. Recently, attention has shifted to characterising the properties of intermittencies in rhythmic neural activity (i.e. bursts), yet the mechanisms that regulate them are unknown. Here, we present evidence from electrocorticography recordings made over the motor cortex to show that the statistics of bursts, such as duration or amplitude, in the beta frequency (14-30 Hz) band, significantly aid the classification of motor states such as rest, movement preparation, execution, and imagery. These features reflect nonlinearities not detectable in the power spectrum, with states increasing in nonlinearity from movement execution to preparation to rest. Further, we show using a computational model of the cortical microcircuit, constrained to account for burst features, that modulations of laminar specific inhibitory interneurons are responsible for the temporal organisation of activity. Finally, we show that the temporal characteristics of spontaneous activity can be used to infer the balance of cortical integration between incoming sensory information and endogenous activity. Critically, we contribute to the understanding of how transient brain rhythms may underwrite cortical processing, which in turn, could inform novel approaches for brain state classification, and modulation with novel brain-computer interfaces.

The predominant stride-frequency for routine swimming in catsharks (Scyliorhinus canicula) generates high power at high efficiency in the red musculature.

Videos of free swimming of catsharks (Scyliorhinus canicula) were analysed to give values of swimming speed (units: FL (fish lengths) s-1), stride-length (forward movement in the direction of travel per cycle of body undulation (units: FL) and stride-frequency (units: s-1). Most of the swims (139 of 163, 85%) were at speeds less than 0.545 FL s-1 and were categorized as slow. The rest (24/163, 15%) were categorized as fast. Stride-lengths and stride-frequencies could be evaluated for 115 of the slow swims and 16 of the fast swims. We discuss the fast swim results, but there were so few fast swims that no firm conclusions could be made. As swim speed increased during slow swims, there was a strong increase stride-length [slope 0.965, P < 0.0001)] and a small increase in stride-frequency. Most stride-frequencies (70/115, 61%) were in the range 0.68-0.88 s-1. Previous experiments on red muscle isolated of catshark showed that in this range of frequencies of sinusoidal movement, high power was produced at high efficiency (Curtin and Woledge b). Lower frequencies gave less power and at higher frequencies the efficiency of energy conversion was lower. Thus, we conclude that during routine swimming catsharks choose a swimming speed that optimizes red muscle performance in terms of power and efficiency.

A Novel Stereospecific Bioluminescent Assay for Detection of Endogenous d-Cysteine.

The presence of endogenous d-stereoisomers of amino acids in mammals dispels a long-standing dogma about their existence. d-Serine and d-aspartate function as novel neurotransmitters in mammals. However, the stereoisomer with the fastest, spontaneous in vitro racemization rate, d-cysteine, has not been reported. We utilized a novel, stereospecific, bioluminescent assay to identify endogenous d-cysteine in substantial amounts in the eye, brain, and pancreas of mice. d-Cysteine is enriched in mice embryonic brains at day E9.5 (4.5 mM) and decreases progressively with development (µM levels). d-Cysteine is also present in significantly higher amounts in the human brain white matter compared with gray matter. In the luciferase assay, d-cysteine conjugates with cyano hydroxy benzothiazole in the presence of a base and reducing agent to form d-luciferin. d-Luciferin, subsequently, in the presence of firefly luciferase and ATP, emits bioluminescence proportional to the concentration of d-cysteine. The assay is stereospecific and allows the quantitative estimation of endogenous d-cysteine in tissues in addition to its specificity for d-cysteine. Future efforts aimed at bioluminescent in vivo imaging of d-cysteine may allow a more noninvasive means of its detection, thereby elucidating its function.

Stimulating at the right time to recover network states in a model of the cortico-basal ganglia-thalamic circuit.

Synchronization of neural oscillations is thought to facilitate communication in the brain. Neurodegenerative pathologies such as Parkinson's disease (PD) can result in synaptic reorganization of the motor circuit, leading to altered neuronal dynamics and impaired neural communication. Treatments for PD aim to restore network function via pharmacological means such as dopamine replacement, or by suppressing pathological oscillations with deep brain stimulation. We tested the hypothesis that brain stimulation can operate beyond a simple "reversible lesion" effect to augment network communication. Specifically, we examined the modulation of beta band (14-30 Hz) activity, a known biomarker of motor deficits and potential control signal for stimulation in Parkinson's. To do this we setup a neural mass model of population activity within the cortico-basal ganglia-thalamic (CBGT) circuit with parameters that were constrained to yield spectral features comparable to those in experimental Parkinsonism. We modulated the connectivity of two major pathways known to be disrupted in PD and constructed statistical summaries of the spectra and functional connectivity of the resulting spontaneous activity. These were then used to assess the network-wide outcomes of closed-loop stimulation delivered to motor cortex and phase locked to subthalamic beta activity. Our results demonstrate that the spatial pattern of beta synchrony is dependent upon the strength of inputs to the STN. Precisely timed stimulation has the capacity to recover network states, with stimulation phase inducing activity with distinct spectral and spatial properties. These results provide a theoretical basis for the design of the next-generation brain stimulators that aim to restore neural communication in disease.

Dynamics of cortical and corticomuscular connectivity during planning and execution of visually guided steps in humans.

The cortical mechanisms underlying the act of taking a step-including planning, execution, and modification-are not well understood. We hypothesized that oscillatory communication in a parieto-frontal and corticomuscular network is involved in the neural control of visually guided steps. We addressed this hypothesis using source reconstruction and lagged coherence analysis of electroencephalographic and electromyographic recordings during visually guided stepping and 2 control tasks that aimed to investigate processes involved in (i) preparing and taking a step and (ii) adjusting a step based on visual information. Steps were divided into planning, initiation, and execution phases. Taking a step was characterized by an upregulation of beta/gamma coherence within the parieto-frontal network during planning followed by a downregulation of alpha and beta/gamma coherence during initiation and execution. Step modification was characterized by bidirectional modulations of alpha and beta/gamma coherence in the parieto-frontal network during the phases leading up to step execution. Corticomuscular coherence did not exhibit task-related effects. We suggest that these task-related modulations indicate that the brain makes use of communication through coherence in the context of large-scale, whole-body movements, reflecting a process of flexibly fine-tuning inter-regional communication to achieve precision control during human stepping.

Reducing antibiotic treatment duration for ventilator-associated pneumonia (REGARD-VAP): a trial protocol for a randomised clinical trial.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units (ICUs). Using short-course antibiotics to treat VAP caused by Gram-negative non-fermenting bacteria has been reported to be associated with excess pneumonia recurrences. The "REducinG Antibiotic tReatment Duration for Ventilator-Associated Pneumonia" (REGARD-VAP) trial aims to provide evidence for using a set of reproducible clinical criteria to shorten antibiotic duration for individualised treatment duration of VAP. METHODS AND ANALYSIS: This is a randomised controlled hierarchical non-inferiority-superiority trial being conducted in ICUs across Nepal, Thailand and Singapore. The primary outcome is a composite endpoint of death and pneumonia recurrence at day 60. Secondary outcomes include ventilator-associated events, multidrug-resistant organism infection or colonisation, total duration of antibiotic exposure, mechanical ventilation and hospitalisation. Adult patients who satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria are enrolled. Participants are assessed daily until fever subsides for >48 hours and have stable blood pressure, then randomised to a short duration treatment strategy or a standard-of-care duration arm. Antibiotics may be stopped as early as day 3 if respiratory cultures are negative, and day 5 if respiratory cultures are positive in the short-course arm. Participants receiving standard-of-care will receive antibiotics for at least 8 days. Study participants are followed for 60 days after enrolment. An estimated 460 patients will be required to achieve 80% power to determine non-inferiority with a margin of 12%. All outcomes are compared by absolute risk differences. The conclusion of non-inferiority, and subsequently superiority, will be based on unadjusted and adjusted analyses in both the intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: The study has received approvals from the Oxford Tropical Research Ethics Committee and the respective study sites. Results will be disseminated to patients, their caregivers, physicians, the funders, the critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT03382548.

Inference of brain networks with approximate Bayesian computation - assessing face validity with an example application in Parkinsonism.

This paper describes and validates a novel framework using the Approximate Bayesian Computation (ABC) algorithm for parameter estimation and model selection in models of mesoscale brain network activity. We provide a proof of principle, first pass validation of this framework using a set of neural mass models of the cortico-basal ganglia thalamic circuit inverted upon spectral features from experimental, in vivo recordings. This optimization scheme relaxes an assumption of fixed-form posteriors (i.e. the Laplace approximation) taken in previous approaches to inverse modelling of spectral features. This enables the exploration of model dynamics beyond that approximated from local linearity assumptions and so fit to explicit, numerical solutions of the underlying non-linear system of equations. In this first paper, we establish a face validation of the optimization procedures in terms of: (i) the ability to approximate posterior densities over parameters that are plausible given the known causes of the data; (ii) the ability of the model comparison procedures to yield posterior model probabilities that can identify the model structure known to generate the data; and (iii) the robustness of these procedures to local minima in the face of different starting conditions. Finally, as an illustrative application we show (iv) that model comparison can yield plausible conclusions given the known neurobiology of the cortico-basal ganglia-thalamic circuit in Parkinsonism. These results lay the groundwork for future studies utilizing highly nonlinear or brittle models that can explain time dependant dynamics, such as oscillatory bursts, in terms of the underlying neural circuits.

Effectiveness of a sepsis programme in a resource-limited setting: a retrospective analysis of data of a prospective observational study (Ubon-sepsis).

OBJECTIVE: To evaluate the effectiveness of a Sepsis Fast Track (SFT) programme initiated at a regional referral hospital in Thailand in January 2015. DESIGN: A retrospective analysis using the data of a prospective observational study (Ubon-sepsis) from March 2013 to January 2017. SETTING: General medical wards and medical intensive care units (ICUs) of a study hospital. PARTICIPANTS: Patients with community-acquired sepsis observed under the Ubon-sepsis cohort. Sepsis was defined as modified Sequential Organ Failure Assessment (SOFA) Score ≥2. MAIN EXPOSURE: The SFT programme was a protocol to identify and initiate sepsis care on hospital admission, implemented at the study hospital in 2015. Patients in the SFT programme were admitted directly to the ICUs when available. The non-exposed group comprised of patients who received standard of care. MAIN OUTCOME: The primary outcome was 28-day mortality. The secondary outcomes were measured sepsis management interventions. RESULTS: Of 3806 sepsis patients, 903 (24%) were detected and enrolled in the SFT programme of the study hospital (SFT group) and 2903 received standard of care (non-exposed group). Patients in the SFT group had more organ dysfunction, were more likely to receive measured sepsis management and to be admitted directly to the ICU (19% vs 4%). Patients in the SFT group were more likely to survive (adjusted HR 0.72, 95% CI 0.58 to 0.88, p=0.001) adjusted for admission year, gender, age, comorbidities, modified SOFA Score and direct admission to the ICUs. CONCLUSIONS: The SFT programme is associated with improved sepsis care and lower risk of death in sepsis patients in rural Thailand, where some critical care resources are limited. The survival benefit is observed even when all patients enrolled in the programme could not be admitted directly into the ICUs. TRIAL REGISTRATION NUMBER: NCT02217592.

Programmable Transcranial Magnetic Stimulation: A Modulation Approach for the Generation of Controllable Magnetic Stimuli.

OBJECTIVE: A transcranial magnetic stimulation system with programmable stimulus pulses and patterns is presented. The stimulus pulses of the implemented system expand beyond conventional damped cosine or near-rectangular pulses and approach an arbitrary waveform. METHODS: The desired stimulus waveform shape is defined as a reference signal. This signal controls the semiconductor switches of an H-bridge inverter to generate a high-power imitation of the reference. The design uses a new paradigm for TMS, applying pulse-width modulation with a non-resonant, high-frequency switching architecture to synthesize waveforms that leverages the low-pass filtering properties of neuronal cells. The modulation technique enables control of the waveform, frequency, pattern, and intensity of the stimulus. RESULTS: A system prototype was developed to demonstrate the technique. The experimental measurements demonstrate that the system is capable of generating stimuli up to 4 kHz with peak voltage and current values of ±1000 V and ±3600 A, respectively. The maximum transferred energy measured in the experimental validation was 100.4 Joules. To characterize repetitive TMS modalities, the efficiency of generating consecutive pulse triplets and quadruplets with interstimulus intervals of 1 ms was tested and verified. CONCLUSION: The implemented TMS device can generate consecutive rectangular pulses with a predetermined time interval, widths and polarities, enables the synthesis of a wide range of magnetic stimuli. SIGNIFICANCE: New waveforms promise functional advantages over the waveforms generated by current-generation TMS systems for clinical neuroscience research.

Comparison of three commercially available ELISA assays for anti-infliximab antibodies.

Three commercially available assays for the measurement of antibodies to infliximab (ATI) are approved for clinical use in Australia: Promonitor anti-infliximab (Grifols), Lisa Tracker anti-infliximab (Theradiag) and Ridascreen anti-IFX (R-Biopharm). All are bridging ELISA assays. Measurement of ATI has been incorporated into treatment algorithms for assessing loss of response to infliximab in patients with inflammatory bowel disease, but results obtained by the three ATI assays have not been systematically compared. We performed a series of experiments to allow comparison of results between the assays. Forty-two patient samples known to be positive for ATI by the Lisa Tracker assay were run on the Promonitor assay in singlicate, of which 26 were run on the Ridascreen assay in duplicate, according to the manufacturers' instructions. The Spearman correlation coefficient for all three pairwise assay comparisons was 0.95. Results were not numerically comparable between the assays. The coefficient of variation (CV) was 2.3% for the Lisa Tracker assay, 7.6% for the Promonitor assay and 7.4% for the Ridascreen assay. The presence of infliximab interfered with all three assays in a dose dependent manner. The cut-point for loss of response to infliximab dose intensification, previously demonstrated to be 200 ng/mL on the Lisa Tracker assay, is equivalent to approximately 60 ng/mL on the Ridascreen assay and between 22.9 and 41 AU/mL on the Promonitor assay. All three assays are suitable for clinical use.

Tocilizumab for severe COVID-19 pneumonia: Case series of 5 Australian patients.

AIM: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS: Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 µg/L) were administered variable-dose tocilizumab. RESULTS: At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS: Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.

Object recognition is enabled by an experience-dependent appraisal of visual features in the brain's value system.

This paper addresses perceptual synthesis by comparing responses evoked by visual stimuli before and after they are recognized, depending on prior exposure. Using magnetoencephalography, we analyzed distributed patterns of neuronal activity - evoked by Mooney figures - before and after they were recognized as meaningful objects. Recognition induced changes were first seen at 100-120 â€‹ms, for both faces and tools. These early effects - in right inferior and middle occipital regions - were characterized by an increase in power in the absence of any changes in spatial patterns of activity. Within a later 210-230 â€‹ms window, a quite different type of recognition effect appeared. Regions of the brain's value system (insula, entorhinal cortex and cingulate of the right hemisphere for faces and right orbitofrontal cortex for tools) evinced a reorganization of their neuronal activity without an overall power increase in the region. Finally, we found that during the perception of disambiguated face stimuli, a face-specific response in the right fusiform gyrus emerged at 240-290 â€‹ms, with a much greater latency than the well-known N170m component, and, crucially, followed the recognition effect in the value system regions. These results can clarify one of the most intriguing issues of perceptual synthesis, namely, how a limited set of high-level predictions, which is required to reduce the uncertainty when resolving the ill-posed inverse problem of perception, can be available before category-specific processing in visual cortex. We suggest that a subset of local spatial features serves as partial cues for a fast re-activation of object-specific appraisal by the value system. The ensuing top-down feedback from value system to visual cortex, in particular, the fusiform gyrus enables high levels of processing to form category-specific predictions. This descending influence of the value system was more prominent for faces than for tools, the fact that reflects different dependence of these categories on value-related information.