Extracorporeal Membrane Oxygenation in Amniotic Fluid Embolism: A Systematic Review of Case Reports.

Amniotic fluid embolism (AFE) is an obstetric complication that can result in acute circulatory failure during and after labor. The effectiveness of extracorporeal membrane oxygenation (ECMO) in AFE patients has not been established, especially in the context of coagulopathy. This review aims to evaluate the efficacy of ECMO support in AFE patients. We conducted a systematic review of case reports following the Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality assessment was performed using a standardized tool. Out of 141 studies screened, 33 studies included 79 AFE patients. The median age was 34 years, and the median gestational age was 37.5 weeks. The majority of AFE cases occurred during cesarean section delivery (55.2%), followed by labor before fetal delivery (26.7%). Extracorporeal membrane oxygenation configurations included venoarterial ECMO (81.3%) and extracorporeal cardiopulmonary resuscitation (CPR, 10.7%). The maternal survival rate was 72%, with 21.2% experiencing minor neurological sequelae and 5.8% having major neurological sequelae. Rescue ECMO to support circulation has demonstrated both safety and efficacy in managing AFE. We suggest early activation of local or mobile ECMO as soon as an AFE diagnosis is established. Further studies are needed to assess the benefits and implications of early ECMO support in AFE patients.

Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA).

BACKGROUND: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. METHODS: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). RESULTS: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02). CONCLUSIONS: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes.

Adoption of environmental management accounting in Vietnamese enterprises: An empirical analysis of influencing determinants.

Along with the process of rapid economic development and integration, Vietnam is facing serious environmental problems, largely caused by manufacturing enterprises. Environmental management accounting (EMA) is a strong management tool to improve an organization's financial and environmental performance, hence supporting businesses for sustainability. This study focused on examining the factors that influence the firms' intention to adopt EMA in Vietnam. The study used the theory of planned behavior and the technology acceptance model to develop an empirical model and hypotheses. Research data was collected through a survey of 330 businesses in 4 provinces in the North region. We analyzed the data using descriptive statistics, Anova test, Cronbach' s Alpha analysis, Exploratory factor analysis, and regression. The results showed that there are 6 significant factors driving EMA applying intention including environmental attitude, perceived benefits of EMA, subjective norms, coercion and social pressure, perceived control and barrier, and policy mix condition, in which coercion and social pressure was the strongest influencing factor. From there, the study makes some implication for government and business sectors aimed at encouraging the implementation of EMA in Vietnam.

Z-number based fuzzy MCDM models for analyzing non-traditional security threats to finance supply chains: A case study from Vietnam.

Non-traditional security (NTS) threats have a vast and profound impact on many aspects of economic, political, social, and many other areas, especially supply chain finance (SCF), particularly in countries like Vietnam, which potentially affects the economic efficiency of businesses' supply chain financial, thereby affecting the general economy of the country and the world. In order to prevent and minimize the negative impacts caused by NTS threats to SCF, this study was conducted to identify NTS threats affecting SCF in Vietnam, at the same time calculate the weight of the impact level and find out the cause and effect relationship between them. Solution strategies are also proposed and ranked, thereby serving as a reference basis for relevant parties to choose appropriate response solutions. Due to the multi-criteria nature of NTS threats, the multiple criteria decision-making (MCDM) method is used in combination with the Z-number concept and Fuzzy set theory to approach the problem of certainty and increase the accuracy of study. The NTS threats are first identified through a literature review and then validated for suitability using the DELPHI technique (DELPHI). Suitable threats will be determined by relationship, weighted by Decision Making Trial And Evaluation Laboratory (DEMATEL) method. Proposed strategies are ranked using the Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) method. The results indicate that there are 19 NTS factors affecting SCF in Vietnam, and the global economic downturn, pandemic and health crisis, financial crisis and cybersecurity risk are the four root cause factors with the most decisive influence. Businesses and concerns need to prioritize addressing these four threats because they not only have a strong impact but also entail many other threats. The two strategies considered to be the most effective are a sustainable practice and a risk-hedging strategy. Businesses, governments, and stakeholders also should pay attention to the macroeconomic environment, technology, and environment and build sustainable businesses, regularly monitoring economic fluctuations and creating plans to prevent risks.

Place of high-flow nasal oxygen in nonoperating room anesthesia.

PURPOSE OF REVIEW: This article aims to assess the utility of high-flow nasal oxygen (HFNO) therapy in nonoperating room anesthesia (NORA) settings. RECENT FINDINGS: The number of procedural interventions under deep sedation in NORA is still increasing. Administration of oxygen is recommended to prevent hypoxemia and is usually delivered with standard oxygen through nasal cannula or a face mask. HFNO is a simple alternative with a high warmed humidified flow (ranging from 30 to 70 l/min) with a precise fraction inspired of oxygen (ranging from 21 to 100%). Compared to standard oxygen, HFNO has demonstrated efficacy in reducing the incidence of hypoxemia and the need for airway maneuvers. Research on HFNO has primarily focused on its application in gastrointestinal endoscopy procedures. Yet, it has also shown promising results in various other procedural interventions including bronchoscopy, cardiology, and endovascular procedures. However, the adoption of HFNO prompted considerations regarding cost-effectiveness and environmental impact. SUMMARY: HFNO emerges as a compelling alternative to conventional oxygen delivery methods for preventing hypoxemia during procedural interventions in NORA. However, its utilization should be reserved for patients at moderate-to-high risk to mitigate the impact of cost and environmental factors.

Simple and Rapid Method of Microwell Array Fabrication for Drug Testing on 3D Cancer Spheroids.

Three-dimensional (3D) cell culture systems are becoming increasingly popular due to their ability to mimic the complex process of angiogenesis in cancer, providing more accurate and physiologically relevant data than traditional two-dimensional (2D) cell culture systems. Microwell systems are particularly useful in this context as they provide a microenvironment that more closely resembles the in vivo environment than traditional microwells. Poly(ethylene glycol) (PEG) microwells are particularly advantageous due to their bio-inertness and the ability to tailor their material characteristics depending on the PEG molecular weight. Although there are several methods available for microwell fabrication, most of them are time-consuming and expensive. The current study utilizes a low-cost laser etching technique on poly(methyl methacrylate) materials followed by molding with PDMS to produce microwells. The optimal conditions for making concave microwells are an engraving parameter speed of 600 mm/s, power of 20%, and a design diameter of the microwell of 0.4 mm. The artificial tumor achieved its full size after 7 days of cell growth in a microwell system, and the cells developed drugs through a live/dead assay test. The results of the drug testing revealed that the IC50 value of zerumbone-loaded liposomes in HepG2 was 4.53 pM, which is greater than the IC50 value of zerumbone. The HepG2 cancer sphere's 3D platform for medication testing revealed that zerumbone-loaded liposomes were very effective at high doses. These findings generally imply that zerumbone-loaded liposomes have the capacity to target the liver and maintain medication delivery.

Role of Metastasis-Directed Therapy in Genitourinary Cancers.

OPINION STATEMENT: The treatment of oligometastatic genitourinary cancers is a rapidly advancing field with ablative radiotherapy as one of the critical treatment components. The oligometastatic disease state, which can be defined as 1-5 metastatic sites with a controlled primary, represents a distinct clinical state where comprehensive ablative local therapies may provide improved outcomes. Enhanced imaging has increased the number of patients identified with oligometastatic disease. Evidence for improved outcomes with metastasis-directed therapy (MDT) in oligometastatic genitourinary cancers is increasing, and previously published outcome data continues to mature with an increasing body of prospective data to inform the role of MDT in histology-specific settings or in the context of systemic therapy. In select patients, MDT can offer benefits beyond improved local control and allow for time off of systemic therapy, prolonged time until next therapy, or even the hope of cure. However, treatment decisions for locally ablative therapy must be balanced with consideration towards safety. There are exciting advances in technologies to target and adapt treatment in real-time which have expanded options for safer delivery and dose escalation to metastatic targets near critical organs at risk. The role of systemic therapies in conjunction with MDT and incorporation of tumor genetic information to further refine prognostication and treatment decision-making in the oligometastatic setting is actively being investigated. These developments highlight the evolving field of treatment of oligometastatic disease. Future prospective studies combining MDT with enhanced imaging and integrating MDT with evolving systemic therapies will enable the optimal selection of patients most likely to benefit from this "all-or-none" approach and reveal settings in which a combination of therapies could result in synergistic outcomes.

Adherence and acceptability of multiple micronutrient supplementation during pregnancy: Study protocol for a cluster-randomized non-inferiority trial in Cambodia.

BACKGROUND: Iron and folic acid (IFA) supplements are currently provided to Cambodian women during pregnancy. However, recent research has found benefits of a multiple micronutrient supplement (MMS) over just IFA alone on several outcomes of perinatal and infant health. The Ministry of Health in Cambodia has proposed a transition from IFA to MMS but to effectively guide this transition requires implementation research on the acceptability and adherence to MMS (over IFA). METHODS: This non-inferiority trial aims to assess the adherence and acceptability of IFA (60 mg elemental iron and 400 µg folic acid) compared to MMS (standard UNIMMAP formulation including 15 micronutrients) during antenatal care in Cambodia. A prospective cohort of 1545 pregnant women will be assigned to one of three trial arms: (1) IFA for 90 days [IFA-90]; (2) MMS for 180 days with two distributions of 90-count tablet bottles [MMS-90]; or (3) MMS for 180 days with one 180-count tablet bottle [MMS-180]. Each arm will enroll 515 women across 48 health centers (clusters) in Kampong Thom Province in Cambodia. The primary outcome is the non-inferiority of adherence rates of MMS-180 compared to IFA-90, as assessed by tablet counts. Mixed-effects logistic and linear regression models will be used to estimate the difference in the adherence rate between the two groups, with an 'a priori' determined non-inferiority margin of 15%. Acceptability of MMS and IFA will be measured using a quantitative survey conducted with enrolled pregnant women at 30-day, 90-day, and 180-day time-points. DISCUSSION: Findings from this study will guide an effective and feasible MMS scale-up strategy for Cambodia. Additionally, the findings will be shared globally with other stakeholders planning to scale up MMS in other countries. TRIAL REGISTRATION: NCT05867836 ( ClinicalTrials.gov , registered May 18, 2023).

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy. OBJECTIVE: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC. DESIGN, SETTING, AND PARTICIPANTS: Here, a multicenter, international retrospective cohort of omCSPC as defined by conventional imaging was reported. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical progression-free survival (bPFS), distant progression-free survival (dPFS), and combined biochemical or distant progression-free survival (cPFS) were evaluated with Kaplan-Meier and multivariable Cox proportional hazard regression models. RESULTS AND LIMITATIONS: A total of 263 patients were included, 105 with MDT + ADT and 158 with MDT alone. The majority of patients had metachronous disease (90.5%). Five-year bPFS, dPFS, and cPFS were, respectively, 24%, 41%, and 19% in patients treated with MDT + ADT and 11% (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.36-0.64), 29% (HR 0.56, 95% CI 0.40-0.78), and 9% (HR 0.50, 95% CI 0.38-0.67) in patients treated with MDT alone. On a multivariable analysis adjusting for pretreatment variables, the use of ADT was associated with improved bPFS (HR 0.43, p < 0.001), dPFS (HR 0.45, p = 0.002), and cPFS (HR 0.44, p < 0.001). CONCLUSIONS: In this large multi-institutional report, the addition of concurrent ADT to MDT appears to improve time to prostate-specific antigen progression and distant recurrence, noting that about 10% patients had durable control with MDT alone. Ongoing phase 3 studies will help further define treatment options for omCSPC. PATIENT SUMMARY: Here, we report a large retrospective review evaluating the outcomes of metastasis-directed therapy with or without a limited course of androgen deprivation for patients with oligometastatic castration-sensitive prostate cancer. This international multi-institutional review demonstrates that the addition of androgen deprivation therapy to metastasis-directed therapy (MDT) improves progression-free survival. While a proportion of patients appear to have long-term disease control with MDT alone, further work in biomarker discovery is required to better identify which patients would be appropriate for de-escalated therapy.

A Prospective Study Assessing the Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Oligometastatic Bone Metastases.

Purpose: Stereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone because of its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess the efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. Methods and Materials: In this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at Brigham and Women's Hospital/Dana Farber Cancer Center and Beth Israel Deaconess Medical Center between December 2016 and May 2019. SBRT dose and fractionation regimen were not protocol mandated. Local progression-free survival, progression-free survival, prostatic specific antigen progression, and overall survival were reported. Treatment-related toxicity was also reported. Results: A total of 98 patients and 126 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (27.0%, 34/126), 30 Gy in 5 fractions (16.7%, 21/126), or 30/35 Gy in 5 fractions (16.7%, 21/126). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume and higher dose to the gross tumor volume. Four patients (4.1%, 4/98) experienced local progression at 1 site for each patient (3.2%, 4/126). Among the entire cohort, 2-year local progression-free survival (including death without local progression) was 84.8%, 2-year progression-free survival (including deaths as well as local, distant, and prostatic specific antigen progression) was 47.5%, and 2-year overall survival was 87.3%. Twenty-six patients (26.5%, 26/98) developed treatment-related toxicities. Conclusions: Our study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

Clinical Outcomes Among Patients Treated With Stereotactic Body Radiation Therapy to Femur Metastases for Oligometastatic Disease Control or Reirradiation: Results From a Large Single-Institution Experience.

Purpose: There are limited data regarding outcomes after stereotactic body radiation therapy (SBRT) for femur metastases, which was an exclusion criteria for the Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers (SABR-COMET) trial. We aimed to characterize clinical outcomes from a large single institution experience. Methods and Materials: Forty-eight patients with 53 lesions were consecutively treated with femur SBRT from May 2017 to June 2022. The Kaplan-Meier method and Cox proportional hazard models were used to characterize time-to-event endpoints and associations between baseline factors and clinical outcomes, respectively. Local control and locoregional control were defined as the absence of tumor progression within the radiation treatment field or within the treated femur, respectively. Results: Most patients had Eastern Cooperative Oncology Group performance status 0 to 1 (90%), prostate (52%) or breast/lung (17%) cancer, and 1 to 3 lesions (100%), including 29 proximal and 5 distal. Fifty-seven percent of the lesions were treated with concurrent systemic therapy. Median planning target volume was 49.1 cc (range, 6.6-387 cc). Planning target volume V100 (%) was 99% (range, 90-100). Fractionation included 18 to 20 Gy/1F, 27 to 30 Gy/3F, and 28.5-40 Gy/5F. Forty-two percent had Mirels score ≥7 and most (94%) did not have extraosseous extension. Acute toxicities included grade 1 fatigue (15%), pain flare (7.5%), nausea (3.8%), and decreased blood counts (1.9%). Late toxicities included fracture (1.9%) at 1.5 years and osteonecrosis (4%) from dose of 40 Gy in 5F and 30 Gy in 5F (after prior 30 Gy/10F). One patient (2%) required fixation postradiation for progressive pain. With median follow-up 19.4 months, 1- and 2-year rates of local control were 94% and 89%, locoregional control was 83% and 67%, progression-free survival were 56% and 25%, and overall survival were 91% and 73%. Fifty percent of local regional recurrence events occurred within 5 cm of gross tumor volume. Conclusions: Femur SBRT for oligometastatic disease control in well-selected patients was associated with good outcomes with minimal rates of acute and late toxicity. Patterns of local regional recurrence warrant consideration of larger elective volume coverage. Additional prospective study is needed.

RNA therapeutics for disorders of excretory system.

The excretory system is responsible for removing wastes from the human body, which plays a crucial role in our lives. Current treatments for diseases related to this system have shown several limitations; therefore, there is a rising need for novel methods. In this circumstance, RNA-based therapeutics have rapidly emerged as new and promising candidates. In fact, to date, a handful of potential drugs have passed the development step and entered the clinical pipeline. Among them, one drug received FDA approval to enter the global market, which is Oxlumo (Lumasiran) for the treatment of primary hyperoxaluria type 1. For other excretory diseases, such as paroxysmal nocturnal hemoglobinuria, urothelial cancer or renal cancer, RNA-based candidates are also being tested under clinical trials. Currently, the most potential types of RNA therapeutics to treat disorders of the excretory system are those based on small interfering RNA (siRNA), antisense oligonucleotides (ASO) and messenger RNA (mRNA), Among them, siRNA therapeutics seem to be the most promising, including Oxlumo and two other developing drug candidates. This chapter will provide a general overview on the application of RNA therapeutics in disorders of the excretory system.

Targeted micro-fiber arrays for measuring and manipulating localized multi-scale neural dynamics over large, deep brain volumes during behavior.

Neural population dynamics relevant to behavior vary over multiple spatial and temporal scales across three-dimensional volumes. Current optical approaches lack the spatial coverage and resolution necessary to measure and manipulate naturally occurring patterns of large-scale, distributed dynamics within and across deep brain regions such as the striatum. We designed a new micro-fiber array approach capable of chronically measuring and optogenetically manipulating local dynamics across over 100 targeted locations simultaneously in head-fixed and freely moving mice, enabling the investigation of cell-type- and neurotransmitter-specific signals over arbitrary 3D volumes at a spatial resolution and coverage previously inaccessible. We applied this method to resolve rapid dopamine release dynamics across the striatum, revealing distinct, modality-specific spatiotemporal patterns in response to salient sensory stimuli extending over millimeters of tissue. Targeted optogenetics enabled flexible control of neural signaling on multiple spatial scales, better matching endogenous signaling patterns, and the spatial localization of behavioral function across large circuits.

Electrocardiographic and genetic characteristics in first degree relatives of hypertrophic cardiomyopathy probands: A descriptive cross-sectional study from Vietnam.

Objectives: In order to study the phenotype-genotype relationship and to better understand the early consequences of the mutation, we would report the spectrum of electrocardiographic and genetic features in the relatives of hypertrophic cardiomyopathy (HCM) patients. Methods: Participants underwent a comprehensive clinical assessment, electrocardiography, standardized and echocardiography and genetic testing. In probands, next-generation sequencing was performed using the gene panel associated with HCM, while in relatives, Sanger sequencing was used to screen for mutations identified in their individual probands. Results: A total of 84 participants were included in this study. The interventricular septal and posterior wall thickness was highest in the G+/LVH+ group, followed by the G+/LVH- group, and was lowest in G-/LVH- group. Compared to the normal control group, the pathologic Q wave was statistically more prevalent in the G+/LVH- group. The prevalence of repolarization abnormalities and major abnormalities was highest in the G+/LVH+ group, followed by the G+/LVH- group, and lowest in G-/LVH- group. Conclusion: Our results suggested that sarcomere mutations have early consequences on myocardial biology. These findings suggest the possibility of implementing a mutation carrier detection model within families affected by HCM, where ECG could play a central role when combined with other relevant clinical factors. Longitudinal studies on a cohort of G+/LVH- patients are required.

Risk factors for poor performance in finger cuff non-invasive monitoring of arterial pressure: A prospective multicenter study.

BACKGROUND: Compared to the invasive technique, non-invasive monitoring of arterial pressure favors easier and faster implementation while potentially sacrificing some reliability. This may be particularly true for the Clearsight™ system (Edwards Lifesciences), which enables continuous monitoring. We evaluated the risk factors for its poor performance. METHODS: Patients with an arterial catheter and stable mean arterial pressure (MAP) over a 5-min period were included. Six pairs of invasive and Clearsight measurements of MAP were collected and the bias between the two techniques was calculated. Poor performance of the Clearsight™ system was defined as either a failure to measure and display MAP or displaying an erroneous MAP (individual bias > 5 mmHg). Fingertip perfusion was assessed using the plethysmographic perfusion index (PI) and the capillary refill time (CRT). RESULTS: Among 152 ICU patients (MAP of 81 ± 14 mmHg, norepinephrine in 78 [51%]), 78 (51%) experienced a poor performance of the Clearsight™ system: failure to display MAP in 19 (13%) patients, and erroneous value displayed in 59 (44%). In multivariate analysis, PI ≤ 0.85% (adjusted odds ratio [aOR] = 2.94 [95% confidence interval (95%CI):1.34;6.45]), CRT > 4 s (aOR = 5.28 [95%CI 1.39;20.05]), and the presence of hand edema (aOR = 2.06 [95%CI 1.01;4.21]) were associated with a higher likelihood of poor performance. Cardiac arrhythmia (aOR = 1.39 [95%CI 0.64;3.02]) and other tested variables were not associated with poor performance. CONCLUSIONS: Half of the included patients exhibited poor Clearsight™ system performance. Our results caution against using finger cuff arterial pressure monitoring in patients with low PI (≤0.85%), protracted CRT (>4 s), or hand edema. REGISTRATION: ClinicalTrials.gov, NCT04269382, Dr. G. Muller, February 13, 2020. https://classic. CLINICALTRIALS: gov/ct2/show/NCT04269382.

Prospective Evaluation of the Clinical Benefits of a Novel Tattoo-less Workflow for Nonspine Bone Stereotactic Body Radiation Therapy: Integrating Surface-Guidance With Triggered Imaging Reduces Treatment Time and Eliminates the Need for Tattoos.

PURPOSE: Oligometastatic disease has expanded the indications for nonspine bone stereotactic body radiation therapy (NSB SBRT). We investigated whether optical surface monitoring systems (OSMS) could enable tattoo-less setup and substitute for 2-dimensional/3-dimensional or cone beam computed tomography (CBCT)-based mid-imaging in NSB SBRT. METHODS AND MATERIALS: OSMS was incorporated in parallel with an existing workflow using pretreatment CBCT and 2-dimensional/3-dimensional kV/kV mid-imaging beginning November 2019. The ability of OSMS to detect out-of-tolerance (>2 mm/>2°) and commanded couch shifts was analyzed. A workflow incorporating OSMS reference captures, CBCT for pretreatment verification, and OSMS/triggered imaging (TI) for intrafraction monitoring was developed for rib/sternum SBRT beginning November 2021 and all NSB SBRT beginning February 2022. Treatment time and CBCT-related radiation dose between the OSMS and the non-OSMS intrafraction monitoring group was analyzed pre- and post-OSMS/TI workflow adoption. All fractions were analyzed through statistical process control with use of an XmR chart of treatment time per quarter from February 2019 to February 2023. Special cause rules were based on Institute for Healthcare Improvement criteria. RESULTS: From February 2019 to February 2023, 1993 NSB SBRT fractions were delivered, including 234 rib, 109 sternum, 214 ilium, and 682 multisite. Over 20 commanded shifts, OSMS could detect 2-mm shifts to within 0.4 mm 67% of the time and 0.8 mm 95% of the time. All NSB SBRT sites showed significant reductions in treatment time, including the greatest improvement in rib total treatment (21.6-13.4 minutes; P = 1.16 × 10-17) and beam time (7.9-3.2 minutes; P = 7.32 × 10-27). Significant reductions in CBCT-related radiation were also observed for several NSB sites. These process improvements were associated with OSMS adoption. CONCLUSIONS: Adoption of a novel NSB SBRT workflow incorporating OSMS/TI for bone intrafraction motion monitoring reduced treatment time and CBCT-related radiation exposure while also allowing for more continuous intrafraction motion monitoring for NSB SBRT. OSMS/TI enabled the transition to a tattoo-less workflow.

Non-Labeled, Stable Labeled, or Radiolabelled Approaches for Provision of Intravenous Pharmacokinetics in Humans: A Discussion Piece.

A review of the use of microdoses and isotopic microtracers for clinical intravenous pharmacokinetic (i.v. PK) data provision is presented. The extent of application of the varied approaches available and the relative merits of each are highlighted with the aim of assisting practitioners in making informed decisions on the most scientifically appropriate design to adopt for any given new drug in development. It is envisaged that significant efficiencies will be realized as i.v. PK data in humans becomes more routinely available for suitable assets in early development, than has been the case prior to the last decade.

Widening the therapeutic window for central and ultra-central thoracic oligometastatic disease with stereotactic MR-guided adaptive radiation therapy (SMART).

BACKGROUND/PURPOSE: Central/ultra-central thoracic tumors are challenging to treat with stereotactic radiotherapy due potential high-grade toxicity. Stereotactic MR-guided adaptive radiation therapy (SMART) may improve the therapeutic window through motion control with breath-hold gating and real-time MR-imaging as well as the option for daily online adaptive replanning to account for changes in target and/or organ-at-risk (OAR) location. MATERIALS/METHODS: 26 central (19 ultra-central) thoracic oligoprogressive/oligometastatic tumors treated with isotoxic (OAR constraints-driven) 5-fraction SMART (median 50 Gy, range 35-60) between 10/2019-10/2022 were reviewed. Central tumor was defined as tumor within or touching 2 cm around proximal tracheobronchial tree (PBT) or adjacent to mediastinal/pericardial pleura. Ultra-central was defined as tumor abutting the PBT, esophagus, or great vessel. Hard OAR constraints observed were ≤ 0.03 cc for PBT V40, great vessel V52.5, and esophagus V35. Local failure was defined as tumor progression/recurrence within the planning target volume. RESULTS: Tumor abutted the PBT in 31 %, esophagus in 31 %, great vessel in 65 %, and heart in 42 % of cases. 96 % of fractions were treated with reoptimized plan, necessary to meet OAR constraints (80 %) and/or target coverage (20 %). Median follow-up was 19 months (27 months among surviving patients). Local control (LC) was 96 % at 1-year and 90 % at 2-years (total 2/26 local failure). 23 % had G2 acute toxicities (esophagitis, dysphagia, anorexia, nausea) and one (4 %) had G3 acute radiation dermatitis. There were no G4-5 acute toxicities. There was no symptomatic pneumonitis and no G2 + late toxicities. CONCLUSION: Isotoxic 5-fraction SMART resulted in high rates of LC and minimal toxicity. This approach may widen the therapeutic window for high-risk oligoprogressive/oligometastatic thoracic tumors.

Trapping of a Polyketide Synthase Module after C-C Bond Formation Reveals Transient Acyl Carrier Domain Interactions.

Modular polyketide synthases (PKSs) are giant assembly lines that produce an impressive range of biologically active compounds. However, our understanding of the structural dynamics of these megasynthases, specifically the delivery of acyl carrier protein (ACP)-bound building blocks to the catalytic site of the ketosynthase (KS) domain, remains severely limited. Using a multipronged structural approach, we report details of the inter-domain interactions after C-C bond formation in a chain-branching module of the rhizoxin PKS. Mechanism-based crosslinking of an engineered module was achieved using a synthetic substrate surrogate that serves as a Michael acceptor. The crosslinked protein allowed us to identify an asymmetric state of the dimeric protein complex upon C-C bond formation by cryo-electron microscopy (cryo-EM). The possible existence of two ACP binding sites, one of them a potential "parking position" for substrate loading, was also indicated by AlphaFold2 predictions. NMR spectroscopy showed that a transient complex is formed in solution, independent of the linker domains, and photochemical crosslinking/mass spectrometry of the standalone domains allowed us to pinpoint the interdomain interaction sites. The structural insights into a branching PKS module arrested after C-C bond formation allows a better understanding of domain dynamics and provides valuable information for the rational design of modular assembly lines.

Riding high: seroprevalence of SARS-CoV-2 after 4 pandemic waves in Manitoba, Canada, April 2020-February 2022.

BACKGROUND: Canada is emerging from the largest SARS-CoV-2 Omicron wave to date, with over 3.3 million confirmed cases. Unfortunately, PCR confirmed cases illuminate only a small portion of infections in the community and underestimate true disease burden. Population based seroprevalence studies, which measure antibody levels against a virus can more accurately estimate infection rates in the community and identify geographical and epidemiological trends to inform public health responses. METHODS: The Manitoba COVID-19 Seroprevalence (MCS) study is a population-based cross-sectional study to assess the prevalence of SARS-CoV-2 antibodies across the province. Residual convenience specimens (n = 14,901) were tested for anti-SARS-CoV-2 nucleocapsid and spike IgG antibodies from April 1, 2020 to February 31, 2022. We estimated the monthly and cumulative prevalence using an exponential decay model, accounting for population demographics, sensitivity/specificity, and antibody waning. This approach generated estimates of natural infection as well as total antibody including vaccine-induced immunity within the community. FINDINGS: After four waves of the pandemic, 60.1% (95%CI-56.6-63.7) of Manitobans have generated SARS-CoV-2 antibodies due to natural exposure independent of vaccination. Geographical analysis indicates a large portion of provincial prevalence stems from increased transmission in the Northern (92.3%) and Southern (71.8%) regional health authorities. Despite the high mortality rates reported by Manitoba, infection fatality ratios (IFR) peaked at 0.67% and declined to 0.20% following the Omicron wave, indicating parity with other national and international jurisdictions. Manitoba has achieved 93.4% (95%CI- 91.5-95.1) total antibody when including vaccination. INTERPRETATION: Our data shows that more than 3 in 5 Manitobans have been infected by SARS-CoV-2 after four waves of the pandemic. This study also identifies key geographical and age specific prevalence rates that have contributed greatly to the overall severity of the pandemic in Manitoba and will inform jurisdictions considering reduction of public health measures.