Is the Human Touch Always Therapeutic? Patient Stimulation and Spreading Depolarization after Acute Neurological Injuries.

Touch and other types of patient stimulation are necessary in critical care and generally presumed to be beneficial. Recent pre-clinical studies as well as randomized trials assessing early mobilization have challenged the safety of such routine practices in patients with acute neurological injury such as stroke. We sought to determine whether patient stimulation could result in spreading depolarization (SD), a dramatic pathophysiological event that likely contributes to metabolic stress and ischemic expansion in such patients. Patients undergoing surgical intervention for severe acute neurological injuries (stroke, aneurysm rupture, or trauma) were prospectively consented and enrolled in an observational study monitoring SD with implanted subdural electrodes. Subjects also underwent simultaneous video recordings (from continuous EEG monitoring) to assess for physical touch and other forms of patient stimulation (such as suctioning and positioning). The association of patient stimulation with subsequent SD was assessed. Increased frequency of patient stimulation was associated with increased risk of SD (OR = 4.39 [95%CI = 1.71-11.24]). The overall risk of SD was also increased in the 60 min following patient stimulation compared to times with no stimulation (OR = 1.19 [95%CI = 1.13-1.26]), though not all subjects demonstrated this effect individually. Positioning of the subject was the subtype of stimulation with the strongest overall effect on SD (OR = 4.92 [95%CI = 3.74-6.47]). We conclude that in patients with some acute neurological injuries, touch and other patient stimulation can induce SD (PS-SD), potentially increasing the risk of metabolic and ischemic stress. PS-SD may represent an underlying mechanism for observed increased risk of early mobilization in such patients.

Understanding the Benefit of Magnetic Resonance-guided Adaptive Radiotherapy in Rectal Cancer Patients: a Single-centre Study.

AIMS: Neoadjuvant chemoradiotherapy followed by surgery is the mainstay of treatment for patients with rectal cancer. Standard clinical target volume (CTV) to planning target volume (PTV) margins of 10 mm are used to accommodate inter- and intrafraction motion of target. Treating on magnetic resonance-integrated linear accelerators (MR-linacs) allows for online manual recontouring and adaptation (MRgART) enabling the reduction of PTV margins. The aim of this study was to investigate motion of the primary CTV (CTVA; gross tumour volume and macroscopic nodes with 10 mm expansion to cover microscopic disease) in order to develop a simultaneous integrated boost protocol for use on MR-linacs. MATERIALS AND METHODS: Patients suitable for neoadjuvant chemoradiotherapy were recruited for treatment on MR-linac using a two-phase technique; only the five phase 1 fractions on MR-linac were used for analysis. Intrafraction motion of CTVA was measured between pre-treatment and post-treatment MRI scans. In MRgART, isotropically expanded pre-treatment PTV margins from 1 to 10 mm were rigidly propagated to post-treatment MRI to determine overlap with 95% of CTVA. The PTV margin was considered acceptable if overlap was >95% in 90% of fractions. To understand the benefit of MRgART, the same methodology was repeated using a reference computed tomography planning scan for pre-treatment imaging. RESULTS: In total, nine patients were recruited between January 2018 and December 2020 with T3a-T4, N0-N2, M0 disease. Forty-five fractions were analysed in total. The median motion across all planes was 0 mm, demonstrating minimal intrafraction motion. A PTV margin of 3 and 5mm was found to be acceptable in 96 and 98% of fractions, respectively. When comparing to the computed tomography reference scan, the analysis found that PTV margins to 5 and 10 mm only acceptably covered 51 and 76% of fractions, respectively. CONCLUSION: PTV margins can be reduced to 3-5 mm in MRgART for rectal cancer treatment on MR-linac within an simultaneous integrated boost protocol.

MRI-guided adaptive radiotherapy for prostate cancer: When do we need to account for intra-fraction motion?

A shift of the daily plan can mitigate target position changes that occur between daily MR acquisition and treatment for MR-linac radiotherapy, but increases the session time. We demonstrated that our workflow strategy and decision-making process, to determine whether a subsequent shift is necessary, is appropriate.

Spreading Depolarization as a Therapeutic Target in Severe Ischemic Stroke: Physiological and Pharmacological Strategies.

BACKGROUND: Spreading depolarization (SD) occurs nearly ubiquitously in malignant hemispheric stroke (MHS) and is strongly implicated in edema progression and lesion expansion. Due to this high burden of SD after infarct, it is of great interest whether SD in MHS patients can be mitigated by physiologic or pharmacologic means and whether this intervention improves clinical outcomes. Here we describe the association between physiological variables and risk of SD in MHS patients who had undergone decompressive craniectomy and present an initial case of using ketamine to target SD in MHS. METHODS: We recorded SD using subdural electrodes and time-linked with continuous physiological recordings in five subjects. We assessed physiologic variables in time bins preceding SD compared to those with no SD. RESULTS: Using multivariable logistic regression, we found that increased ETCO2 (OR 0.772, 95% CI 0.655-0.910) and DBP (OR 0.958, 95% CI 0.941-0.991) were protective against SD, while elevated temperature (OR 2.048, 95% CI 1.442-2.909) and WBC (OR 1.113, 95% CI 1.081-1.922) were associated with increased risk of SD. In a subject with recurrent SD, ketamine at a dose of 2 mg/kg/h was found to completely inhibit SD. CONCLUSION: Fluctuations in physiological variables can be associated with risk of SD after MHS. Ketamine was also found to completely inhibit SD in one subject. These data suggest that use of physiological optimization strategies and/or pharmacologic therapy could inhibit SD in MHS patients, and thereby limit edema and infarct progression. Clinical trials using individualized approaches to target this novel mechanism are warranted.

Feasibility of tumour-focused adaptive radiotherapy for bladder cancer on the MR-linac.

Bladder tumour-focused magnetic resonance image-guided adaptive radiotherapy using a 1.5 Tesla MR-linac is feasible. A full online workflow adapting to anatomy at each fraction is achievable in approximately 30 min. Intra-fraction bladder filling did not compromise target coverage with the class solution employed.

Structural similarity analysis of midfacial fractures-a feasibility study.

The structural similarity index metric is used to measure the similarity between two images. The aim here was to study the feasibility of this metric to measure the structural similarity and fracture characteristics of midfacial fractures in computed tomography (CT) datasets following radiation dose reduction, iterative reconstruction (IR) and deep learning reconstruction. Zygomaticomaxillary fractures were inflicted on four human cadaver specimen and scanned with standard and low dose CT protocols. Datasets were reconstructed using varying strengths of IR and the subsequently applying the PixelShine™ deep learning algorithm as post processing. Individual small and non-dislocated fractures were selected for the data analysis. After attenuating the osseous anatomy of interest, registration was performed to superimpose the datasets and subsequently to measure by structural image quality. Changes to the fracture characteristics were measured by comparing each fracture to the mirrored contralateral anatomy. Twelve fracture locations were included in the data analysis. The most structural image quality changes occurred with radiation dose reduction (0.980036±0.011904), whilst the effects of IR strength (0.995399±0.001059) and the deep learning algorithm (0.999996±0.000002) were small. Radiation dose reduction and IR strength tended to affect the fracture characteristics. Both the structural image quality and fracture characteristics were not affected by the use of the deep learning algorithm. In conclusion, evidence is provided for the feasibility of using the structural similarity index metric for the analysis of structural image quality and fracture characteristics.

Assessment of the availability of snakebite antivenom in health facilities in Ndola District, Zambia: a cross-sectional study.

BACKGROUND: Despite snakebite antivenom being included on the WHO list of essential medicines, many parts of the world, especially Africa, lack effective and safe antivenoms. METHODS: A descriptive, field-based, cross-sectional study was undertaken from August to November 2020 in 40 out of 71 health facilities in Ndola district. Interviews and physical inspection were conducted at each facility. RESULTS: The study revealed that only three (8%) of all the private health facilities had antivenom available at the time of the assessment. Factors significantly associated with antivenom supply included lack of central country supply (90%), lack of demand of the antivenom (55%) and no budget allocation for the antivenom (95%). CONCLUSIONS: Despite the high number of notified snakebites within Ndola district, there remains poor availability of snakebite antivenom within the district.

In situ imaging of amorphous intermediates during brucite carbonation in supercritical CO2.

Progress in understanding crystallization pathways depends on the ability to unravel relationships between intermediates and final crystalline products at the nanoscale, which is a particular challenge at elevated pressure and temperature. Here we exploit a high-pressure atomic force microscope to directly visualize brucite carbonation in water-bearing supercritical carbon dioxide (scCO2) at 90 bar and 50 °C. On introduction of water-saturated scCO2, in situ visualization revealed initial dissolution followed by nanoparticle nucleation consistent with amorphous magnesium carbonate (AMC) on the surface. This is followed by growth of nesquehonite (MgCO3·3H2O) crystallites. In situ imaging provided direct evidence that the AMC intermediate acts as a seed for crystallization of nesquehonite. In situ infrared and thermogravimetric-mass spectrometry indicate that the stoichiometry of AMC is MgCO3·xH2O (x = 0.5-1.0), while its structure is indicated to be hydromagnesite-like according to density functional theory and X-ray pair distribution function analysis. Our findings thus provide insight for understanding the stability, lifetime and role of amorphous intermediates in natural and synthetic systems.

A convolutional neural network for segmentation of yeast cells without manual training annotations.

MOTIVATION: Single-cell time-lapse microscopy is a ubiquitous tool for studying the dynamics of complex cellular processes. While imaging can be automated to generate very large volumes of data, the processing of the resulting movies to extract high-quality single-cell information remains a challenging task. The development of software tools that automatically identify and track cells is essential for realizing the full potential of time-lapse microscopy data. Convolutional neural networks (CNNs) are ideally suited for such applications, but require great amounts of manually annotated data for training, a time-consuming and tedious process. RESULTS: We developed a new approach to CNN training for yeast cell segmentation based on synthetic data and present (i) a software tool for the generation of synthetic images mimicking brightfield images of budding yeast cells and (ii) a convolutional neural network (Mask R-CNN) for yeast segmentation that was trained on a fully synthetic dataset. The Mask R-CNN performed excellently on segmenting actual microscopy images of budding yeast cells, and a density-based spatial clustering algorithm (DBSCAN) was able to track the detected cells across the frames of microscopy movies. Our synthetic data creation tool completely bypassed the laborious generation of manually annotated training datasets, and can be easily adjusted to produce images with many different features. The incorporation of synthetic data creation into the development pipeline of CNN-based tools for budding yeast microscopy is a critical step toward the generation of more powerful, widely applicable and user-friendly image processing tools for this microorganism. AVAILABILITY AND IMPLEMENTATION: The synthetic data generation code can be found at https://github.com/prhbrt/synthetic-yeast-cells. The Mask R-CNN as well as the tuning and benchmarking scripts can be found at https://github.com/ymzayek/yeastcells-detection-maskrcnn. We also provide Google Colab scripts that reproduce all the results of this work. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Synergistic Coupling of CO2 and H2O during Expansion of Clays in Supercritical CO2-CH4 Fluid Mixtures.

We used IR and XRD, with supporting theoretical calculations, to investigate the swelling behavior of Na+-, NH4+-, and Cs+-montmorillonites (SWy-2) in supercritical fluid mixtures of H2O, CO2, and CH4. Building on our prior work with Na-clay that demonstrated that H2O facilitated CO2 intercalation at relatively low RH, here we show that increasing CO2/CH4 ratios promote H2O intercalation and swelling of the Na-clay at progressively lower RH. In contrast to the Na-clay, CO2 intercalated and expanded the Cs-clay even in the absence of H2O, while increasing fluid CO2/CH4 ratios inhibited H2O intercalation. The NH4-clay displayed intermediate behavior. By comparing changes in the HOH bending vibration of H2O intercalated in the Cs-, NH4-, and Na-clays, we posit that CO2 facilitated expansion of the Na-clay by participating in outer-sphere solvation of Na+ and by disrupting the H-bond network of intercalated H2O. In no case did the pure CH4 fluid induce expansion. Our experimental data can benchmark modeling studies aimed at predicting clay expansion in humidified fluids with varying ratios of CO2 and CH4 in real reservoir systems with implications for enhanced hydrocarbon recovery and CO2 storage in subsurface environments.

An Orally Bioavailable (Mice) Prodrug of Glutathione.

L-Cysteine-glutathione mixed disulfide (CySSG), a prodrug of glutathione (GSH), was found to be orally bioavailable in mice, and protected mice against a toxic dose of acetaminophen. If oral bioavailability can also be demonstrated in humans, a wide range of applicability for CySSG can be envisioned.

Iterative reconstruction and deep learning algorithms for enabling low-dose computed tomography in midfacial trauma.

OBJECTIVES: The objective of this study was to quantitatively assess the image quality of Advanced Modeled Iterative Reconstruction (ADMIRE) and the PixelShine (PS) deep learning algorithm for the optimization of low-dose computed tomography protocols in midfacial trauma. STUDY DESIGN: Six fresh frozen human cadaver head specimens were scanned by computed tomography using both standard and low-dose scan protocols. Three iterative reconstruction strengths were applied to reconstruct bone and soft tissue data sets and these were subsequently applied to the PS algorithm. Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were calculated for each data set by using the image noise measurements of 10 consecutive image slices from a standardized region of interest template. RESULTS: The low-dose scan protocol resulted in a 61.7% decrease in the radiation dose. Radiation dose reduction significantly reduced, and iterative reconstruction and the deep learning algorithm significantly improved, the CNR for bone and soft tissue data sets. The algorithms improved image quality after substantial dose reduction. The greatest improvement in SNRs and CNRs was found using the iterative reconstruction algorithm. CONCLUSION: Both the ADMIRE and PS algorithms significantly improved image quality after substantial radiation dose reduction.

Improving the transition of patients with mental health disorders back to primary care: A protocol for a partnered, mixed-methods, stepped-wedge implementation trial.

The current study protocol regards a partnered, mixed-methods, cluster-randomized stepped wedge trial of the implementation and effectiveness of the FLOW program. FLOW (not an acronym) is a collection of resources and strategies to assist in determining which recovered or stabilized specialty mental health (SMH) patients should transition back to primary care (PC) and tools to make the transition seamless. Transitioning appropriate patients to PC can increase access and timeliness of mental health care for newly referred mental health patients. Nine sites in one US region will be randomized to one of three waves in which they will receive implementation-facilitation to implement the FLOW program. Primary outcomes will include the reach of FLOW, provider adoption of the program, effectiveness in increasing access in SMH, implementation fidelity, and maintenance over time. A mixed-methods analysis of implementation factors associated with implementation success will also be conducted, including the following as possible predictors: staffing ratios, site resources, leadership and provider support for the program, and local champion characteristics. This study's results will provide evidence for the effectiveness of FLOW in increasing access and may provide generalizable information about characteristics of sites that are likely to be successful with implementing similar programs.

Feasibility of magnetic resonance guided radiotherapy for the treatment of bladder cancer.

Whole bladder magnetic resonance image-guided radiotherapy using the 1.5 Telsa MR-linac is feasible. Full online adaptive planning workflow based on the anatomy seen at each fraction was performed. This was delivered within 45 min. Intra-fraction bladder filling did not compromise target coverage. Patients reported acceptable tolerance of treatment.

Retrospective Review of Loop Electrosurgical Excision Procedure (LEEP) Outcomes at a Tertiary Hospital in Zambia.

There is a lack of knowledge on the histologic outcomes of loop electrosurgical excision procedure (LEEP) biopsies in the diagnosis, treatment, and prevention of cervical cancer in Zambia. This study determined the outcomes of LEEP biopsies and associated factors at a tertiary hospital. We conducted a retrospective chart review of patients evaluated at a tertiary hospital cervical cancer screening centre. From the database, we identified patients who underwent LEEP between January 2015 and June 2018. We extracted demographic data, HIV data, and LEEP biopsy results. A P value less than 0.05 was considered statistically significant. 137 charts were identified, and 114 were included in the final analysis. 23 were excluded for missing histology. The mean age of participants was 36.3 ± 9.6. Histology outcomes revealed that 37% had cervicitis, while CIN 1, 2, and 3 contributed to 27%, 14%, and 3%, respectively. Squamous cell cancer was present in 8% (age groups 35-49) and was three times higher (13%) in HIV-positive compared to HIV-negative participants (3.8%). Normal histology accounted for 11%. Increasing age (P=0.029), less than tertiary education (P=0.0011), and being married (P=0.017) increased the chances of having cancer in the chi-square analysis, while single women had lower odds of having CIN 1 (OR = 0.012) in the multinomial logistic regression. There is a need for increased cervical cancer screening and training in precancer treatment and holistic consideration of other factors like age in addition to the positive VIA test in advising patients on treatment options.

Enhancing Collaborative Learning for Quality Improvement: Evidence from the Improving Clinical Flow Project, a Breakthrough Series Collaborative with Project ECHO.

BACKGROUND: This project engaged teams from Federally Qualified Health Centers (FQHCs) in a quality improvement (QI) collaborative to improve clinical flow (increase quality and efficiency of operations), using a novel combination of Breakthrough Series Collaborative tools with Project ECHO's telementoring model. This mixed methods study describes the collaborative and evaluates its success in generating improvement and developing QI capacity at participating FQHCs. METHODS: The 18-month collaborative used three in-person/virtual learning session workshops and weekly telementoring sessions with brief lectures and case-based learning. Participants engaged in QI work (for example, PDSAs [Plan-Do-Study-Act]) and tracked data for 10 care system measures to evaluate progress. These data were averaged across consistently reporting sites for standard run chart analysis. Semistructured interviews assessed the effectiveness and value of the approach for participants. RESULTS: Fifteen sites across the United States participated for one year (Cohort 1); 10 sites continued to 18 months (Cohort 2). Cohort 2 evidenced improvement for 6 measures: Patient/Family Experience, Patient Time Valued, Empanelment, Cycle Time, Colorectal Cancer Screening Rate, and Third Next Available Appointment. Progress varied across sites and measures. Participant interviews indicated value from both in-person and virtual activities, increased QI knowledge, and professional growth, as well as challenges when participants lacked time, engagement, leadership support, and consistent and committed staff. CONCLUSION: This novel collaborative structure is promising. Evidence indicates progress in building QI capacity and improving processes and patient experience across participating FQHCs. Future iterations should address barriers to improvement identified here. Additional work is needed to compare the efficacy of this approach to other collaborative modes.

Kinetics and Mechanisms of ZnO to ZIF-8 Transformations in Supercritical CO2 Revealed by In†Situ X-ray Diffraction.

ZIF-8 was synthesized in supercritical carbon dioxide (scCO2 ). In situ powder X-ray diffraction, ex situ microscopy, and simulations provide an encompassing view of the formation of ZIF-8 and intermediary ZnO@ZIF-8 composites in this nontraditional solvent. Time-resolved imaging exposed divergent physicochemical reaction pathways from previous studies of the growth of anisotropic ZIF-8 core@shell structures in traditional solvents. Synthetically relevant physiochemical properties of scCO2 were integrated into classical nucleation theory, relating interfacial forces, calculated through DFTB+ based molecular dynamics (MD), with 3D nucleation outcomes. The kinetics of crystallization were examined and displayed a characteristic signature of time- and temperature-dependent mechanisms over the extent of the reaction. Lastly, it is shown that subtle factors, such as the extent of reaction and the size/shape of sacrificial templates can tailor ZIF-8 composition and size, eliciting control over hierarchical porosity in a nonconventional green solvent.

Sequestration and Elimination of Toxic Aldehydes.

It is well-known that aldehydes resulting from the in vivo oxidation of primary alcohols are toxic. Here, we experimentally demonstrate in rat models that the dipeptide cysteinylglycine (CG), formed in vivo from its oxidized product, cystinyl-bis-glycine (CbG), will sequester acetaldehyde and isoamyl aldehyde, two model aldehydes resulting from the oxidation of ethanol and isoamyl alcohol, respectively, and excrete them in urine as their respective conjugation products with CG. These data suggest that a whole series of toxic aldehydes can be sequestered and detoxified by CG and may prevent the flushing syndrome exhibited by individuals with a defective enzyme that converts acetaldehyde to acetate. The data also suggest the possibility of alleviating the hangover syndrome we believe to be caused by aldehydes, such as isoamyl aldehyde derived from short, branched-chain alcohols, present as congeners in certain alcoholic beverages. The sequestration of other toxic agents, such as cyanide, that can react with CG can also be envisioned.

A Novel Intervention for High-Need, High-Cost Medicaid Patients: a Study of ECHO Care.

BACKGROUND: A small number of high-need patients account for a disproportionate amount of Medicaid spending, yet typically engage little in outpatient care and have poor outcomes. OBJECTIVE: To address this issue, we developed ECHO (Extension for Community Health Outcomes) Care™, a complex care intervention in which outpatient intensivist teams (OITs) provided care to high-need high-cost (HNHC) Medicaid patients. Teams were supported using the ECHO model™, a continuing medical education approach that connects specialists with primary care providers for case-based mentoring to treat complex diseases. DESIGN: Using an interrupted time series analysis of Medicaid claims data, we measured healthcare utilization and expenditures before and after ECHO Care. PARTICIPANTS: ECHO Care served 770 patients in New Mexico between September 2013 and June 2016. Nearly all had a chronic mental illness, and over three-quarters had a chronic substance use disorder. INTERVENTION: ECHO Care patients received care from an OIT, which typically included a nurse practitioner or physician assistant, a registered nurse, a licensed mental health provider, and at least one community health worker. Teams focused on addressing patients' physical, behavioral, and social issues. MAIN MEASURES: We assessed the effect of ECHO Care on Medicaid costs and utilization (inpatient admissions, emergency department (ED) visits, other outpatient visits, and dispensed prescriptions. KEY RESULTS: ECHO Care was associated with significant changes in patients' use of the healthcare system. At 12 months post-enrollment, the odds of a patient having an inpatient admission and an ED visit were each reduced by approximately 50%, while outpatient visits and prescriptions increased by 23% and 8%, respectively. We found no significant change in overall Medicaid costs associated with ECHO Care. CONCLUSIONS: ECHO Care shifts healthcare utilization from inpatient to outpatient settings, which suggests decreased patient suffering and greater access to care, including more effective prevention and early intervention for chronic conditions.