High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients.

Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition. The application of a computational method called PARADIGM to a large dataset of cancer patients' longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.

An Overview of Microcrystal Electron Diffraction (MicroED).

The bedrock of drug discovery and a key tool for understanding cellular function and drug mechanisms of action is the structure determination of chemical compounds, peptides, and proteins. The development of new structure characterization tools, particularly those that fill critical gaps in existing methods, presents important steps forward for structural biology and drug discovery. The emergence of microcrystal electron diffraction (MicroED) expands the application of cryo-electron microscopy to include samples ranging from small molecules and membrane proteins to even large protein complexes using crystals that are one-billionth the size of those required for X-ray crystallography. This review outlines the conception, achievements, and exciting future trajectories for MicroED, an important addition to the existing biophysical toolkit.

An Inflection Point in High-Throughput Proteomics with Orbitrap Astral: Analysis of Biofluids, Cells, and Tissues.

This Technical Note presents a comprehensive proteomics workflow for the new combination of Orbitrap and Astral mass analyzers across biofluids, cells, and tissues. Central to our workflow is the integration of Adaptive Focused Acoustics (AFA) technology for cells and tissue lysis to ensure robust and reproducible sample preparation in a high-throughput manner. Furthermore, we automated the detergent-compatible single-pot, solid-phase-enhanced sample Preparation (SP3) method for protein digestion. The synergy of these advanced methodologies facilitates a robust and high-throughput approach for cell and tissue analysis, an important consideration in translational research. This work disseminates our platform workflow, analyzes the effectiveness, demonstrates the reproducibility of the results, and highlights the potential of these technologies in biomarker discovery and disease pathology. For cells and tissues (heart, liver, lung, and intestine) proteomics analysis by data-independent acquisition mode, identifications exceeding 10,000 proteins can be achieved with a 24 min active gradient. In 200 ng injections of HeLa digest across multiple gradients, an average of more than 80% of proteins have a CV less than 20%, and a 45 min run covers ∼90% of the expressed proteome. This complete workflow allows for large swaths of the proteome to be identified and is compatible with diverse sample types.

Astrocyte diversity in the ferret cerebrum revealed with astrocyte-specific genetic manipulation.

Astrocytes in the cerebrum play important roles such as the regulation of synaptic functions, homeostasis, water transport, and the blood-brain barrier. It has been proposed that astrocytes in the cerebrum acquired diversity and developed functionally during evolution. Here, we show that like human astrocytes, ferret astrocytes in the cerebrum exhibit various morphological subtypes which mice do not have. We found that layer 1 of the ferret cerebrum contained not only protoplasmic astrocytes but also pial interlaminar astrocytes and subpial interlaminar astrocytes. Morphologically polarized astrocytes, which have a long unbranched process, were found in layer 6. Like human white matter, ferret white matter exhibited four subtypes of astrocytes. Furthermore, our quantification showed that ferret astrocytes had a larger territory size and a longer radius length than mouse astrocytes. Thus, our results indicate that, similar to the human cerebrum, the ferret cerebrum has a well-developed diversity of astrocytes. Ferrets should be useful for investigating the molecular and cellular mechanisms leading to astrocyte diversity, the functions of each astrocyte subtype and the involvement of different astrocyte subtypes in various neurological diseases.

Endovascular Thrombectomy Alone for Large Vessel Occlusion: A Cost-Effectiveness Evaluation Based on Meta-Analyses.

BACKGROUND: The benefit of intravenous thrombolysis with alteplase before endovascular thrombectomy (EVT) for acute ischemic stroke due to large vessel occlusion remains debated. In this study, we analyzed the cost-effectiveness of EVT alone versus intravenous alteplase before EVT in patients directly admitted to EVT-capable stroke centers from the Dutch health care payer perspective. METHODS: A decision analysis was performed using a Markov model with 15-year simulated follow-up to estimate total costs, quality-adjusted life years, and an incremental cost-effectiveness ratio of intravenous alteplase before EVT compared with EVT alone. A hypothetical cohort of 10 000 patients with large vessel occlusion aged 70 years was run in Monte Carlo simulation. Functional outcome of each treatment was derived from pooled results of 6 randomized controlled trials (RCTs). Uncertainty was assessed by probabilistic analyses, scenario analyses, and 1-way sensitivity analyses. RESULTS: Using functional outcomes obtained from 6 RCTs (intention-to-treat population), intravenous alteplase before EVT resulted in 0.05 quality-adjusted life years gained at an additional $2817 compared with EVT alone, resulting in the incremental cost-effectiveness ratio of $62 287. Probabilistic analyses showed that intravenous alteplase before EVT had a probability of 45% and 54%, respectively, of being cost-effective at the $52 500 and $84 000 thresholds. Restricting functional outcomes from our post hoc modified as-treated analysis of 6 RCTs (scenario 1), European RCTs (scenario 2), or a Dutch RCT (scenario 3), intravenous alteplase before EVT was cost-effective in 64%, 81%, and 50% of simulations at the $52 500 threshold, and 79%, 91%, and 67% of simulations at the $84 000 threshold. CONCLUSIONS: Intravenous alteplase before EVT was not cost-effective in patients with large vessel occlusion in the Netherlands at the $52 500 threshold but possibly cost-effective at the $84 000 threshold. Variable functional outcomes at 3 months based on different trial populations affected the cost-effectiveness of intravenous alteplase before EVT.

Integrated Sensors for Soft Medical Robotics.

Minimally invasive procedures assisted by soft robots for surgery, diagnostics, and drug delivery have unprecedented benefits over traditional solutions from both patient and surgeon perspectives. However, the translation of such technology into commercialization remains challenging. The lack of perception abilities is one of the obstructive factors paramount for a safe, accurate and efficient robot-assisted intervention. Integrating different types of miniature sensors onto robotic end-effectors is a promising trend to compensate for the perceptual deficiencies in soft robots. For example, haptic feedback with force sensors helps surgeons to control the interaction force at the tool-tissue interface, impedance sensing of tissue electrical properties can be used for tumor detection. The last decade has witnessed significant progress in the development of multimodal sensors built on the advancement in engineering, material science and scalable micromachining technologies. This review article provides a snapshot on common types of integrated sensors for soft medical robots. It covers various sensing mechanisms, examples for practical and clinical applications, standard manufacturing processes, as well as insights on emerging engineering routes for the fabrication of novel and high-performing sensing devices.

Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant.

Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.

Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

Evaluation of a multimodal ctDNA-based assay for detection of aggressive cancers lacking standard screening tests.

Aim: Cancers lacking standard screening (LSS) options account for approximately 70% of cancer-related deaths due to late-stage diagnosis. Circulating tumor DNA (ctDNA) is a promising biomarker for multi-cancer early detection. We previously developed SPOT-MAS, a multimodal ctDNA-based assay analyzing methylation and fragmentomic profiles, effective in detecting common cancers (breast, colorectal, liver, lung and gastric). This study extends the analysis to five LSS cancers: endometrial, esophageal, head and neck, ovarian and pancreatic.Methods: SPOT-MAS was applied to profile cfDNA methylation and fragmentomic patterns in 739 healthy individuals and 135 LSS cancer patients.Results: We identified 347 differentially methylated regions and observed genome-wide hypomethylation across all five LSS cancers. Esophageal and head and neck cancers showed an enrichment of short cfDNA fragments (<150 bp). Eleven 4-mer end motifs were consistently altered in cfDNA fragments across all LSS cancers. Many significant signatures were consistent with previous observations in common cancers. Notably, SPOT-MAS achieved 96.2% specificity and 74.8% overall sensitivity, with a lower sensitivity of 60.7% in early-stage cancers.Conclusion: This proof-of-concept study demonstrates that SPOT-MAS a non-invasive test trained on five common cancer types, could detect a number of LSS cancer cases, potentially complementing existing screening programs.

Many cancers do not have standard tests, so they are often found too late, which leads to about 70% of cancer deaths. We've created a blood test that can help find cancer early. This test has already worked well for common cancers like breast and lung cancer, and now we're testing it on five harder-to-detect cancers: endometrial, esophageal, head and neck, ovarian and pancreatic cancers. In our study, we tested our blood test on 739 healthy people and 135 patients with these difficult cancers. Our method correctly identified healthy people 96.2% of the time and found cancer cases 74.8% of the time. This new test could help with screening for types of cancer that do not have good tests right now.

Cryogenic focus measurement system for a wide-field infrared space telescope.

We describe a technique for measuring focus errors in a cryogenic, wide-field, near-infrared space telescope. The measurements are made with a collimator looking through a large vacuum window, with a reflective cold filter to reduce the background thermal infrared loading on the detectors and optics. The vacuum window and cold filter introduce a wavefront error that we characterize using an autocollimating microscope. For the 200 mm diameter aperture f/3 space telescope SPHEREx, we achieve a focus position measurement with a ∼15µm systematic and a ∼5µm statistical error.

The Association of Oxygen Delivery and Transfusion on Cardiopulmonary Bypass with Acute Kidney Injury.

OBJECTIVES: To estimate whether the association of transfusion and acute kidney injury (AKI) has a threshold of oxygen delivery below which transfusion is beneficial but above which it is harmful. DESIGN: Retrospective study SETTING: Cardiovascular operating room and intensive care unit PARTICIPANTS: Patients undergoing cardiac surgery with continuous oxygen delivery monitoring during cardiopulmonary bypass INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Logistic regression was used to estimate the associations between oxygen delivery (mean, cumulative deficit, and bands of oxygen delivery), transfusion, and their interaction and AKI. A subgroup analysis of transfused and nontransfused patients with exact matching on cumulative oxygen deficit and time on bypass with adjustment for propensity to receive a transfusion using logistic regression. Nine hundred ninety-one of 4,203 patients developed AKI within 7 days. After adjustment for confounders, lower mean oxygen delivery (odds ratio [OR], 0.968; 95% confidence interval [CI], 0.949-0.988; p = 0.002) and transfusions (OR, 1.442; 95% CI, 1.077, 1.932; p = 0.014) were associated with increased odds of AKI by 7 days. As oxygen delivery decreased, the risk of AKI increased, with the slope of the OR steeper at <160 mL/m2/min. In the subgroup analysis, matched transfused patients were more likely than matched nontransfused patients to develop AKI (45% [n = 145] v 31% [n = 101]; p < 0.001). However, after propensity score adjustment, the difference was nonsignificant (OR, 1.181; 95% CI, 0.796-1.752; p = 0.406). CONCLUSIONS: We found a nonlinear relationship between oxygen delivery and AKI. We found no level of oxygen delivery at which transfusion was associated with a decreased risk of AKI.

Antioxidant potentials of extracts from different parts of Clinacanthus nutans (Burm. f.) Lindau.

The research aimed to explore the antioxidant potential of extracts from different parts of Clinacanthus nutans growing in Vietnam, a member of the Acanthaceae family. The plant's roots, stem and leaves were extracted using 96% ethanol. The antioxidant actions of these extracts were evaluated by DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay on thin-layer plates and 96 well plates. The extract with the most potent activity was applied for distribution extraction with solvents with different polarities, including dichloromethane, ethyl acetate and water. Dry column vacuum chromatography was utilized to obtain the most antioxidant-potent extract fractions. The stem extract had the lowest IC50 value of 6.85µg/mL, showing the most potent antioxidant activity. The ethyl acetate fraction from the stem extract expressed the lowest IC50 value of 9.67µg/mL. Meanwhile, fraction 5, separated from the ethyl acetate fraction of the stem extract, had the lowest IC50 value of 9.89µg/mL. In conclusion, the extracts from different parts of Clinacanthus nutans all expressed antioxidant action at different levels, in which the stem extract, the ethyl acetate fraction and fraction 5 from the ethyl acetate fraction displayed the most effective actions. These findings highlight the promising potential of Clinacanthus nutans in treating oxidative stress-associated diseases, inspiring further research and exploration in this area.

mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine.

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mechanistic target of rapamycin complex 1 activity but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient.

Facile de Novo Sequencing of Tetrazine-Cyclized Peptides through UV-Induced Ring-Opening and Cleavage from the Solid Phase.

While most FDA-approved peptide drugs are cyclic, the robust cyclization chemistry of peptides and the deconvolution of cyclic peptide sequences by using tandem mass spectrometry render cyclic peptide drug discovery difficult. Here we present the successful design of cyclic peptides on solid phase that addresses both of these problems. We demonstrate that this peptide cyclization method using dichloro-s-tetrazine on solid phase allows successful cyclization of a panel of random peptide sequences with various charges and hydrophobicities. The cyclic peptides can be linearized and cleaved from the solid phase by simple UV light irradiation, and we demonstrate that accurate sequence information can be obtained for the UV-cleaved linearized peptides by using tandem mass spectrometry. The tetrazine linker used in the cyclic peptides can further be explored for inverse electron-demand Diels-Alder (IEDDA) reactions for screening or bioconjugation applications in the future.

Impact of pre-existing type 2 diabetes with and without cardiovascular disease on patients with COVID-19.

AIM: To compare adverse outcomes among COVID-19 patients with pre-existing type 2 diabetes (T2D) only, T2D and cardiovascular disease (CVD), or neither. METHODS: This retrospective cohort study used administrative claims, laboratory and mortality data from the HealthCore Integrated Research Database. Patients with COVID-19 were identified from 3 January 2020 to 31 May 2021 and stratified by the presence of T2D and CVD. Outcomes included hospitalization, intensive care unit (ICU) admission, mortality and complications following COVID-19 infection. Propensity score matching and multivariable analyses were performed. RESULTS: A total of 321 232 COVID-19 patients were identified (21 651 T2D + CVD, 28 184 T2D only, and 271 397 neither) with a mean (SD) follow-up of 5.4 (3.0) months. After matching, 6 967 patients were identified for each group, and residual baseline differences remained. Adjusted analyses showed that COVID-19 patients with T2D + CVD were 59% more probable to be hospitalized, 74% more probable to be admitted to the ICU, and had a 26% higher mortality risk than those with neither. COVID-19 patients with T2D only were 28% and 32% more probable to be admitted to the hospital and ICU than those with neither, respectively. Among all T2D + CVD patients, acute respiratory distress syndrome (31%) and acute kidney disease (24%) were observed. CONCLUSION: Our study highlights the incrementally poorer outcomes associated with pre-existing T2D + CVD in COVID-19 patients compared with those without T2D/CVD and suggests consideration of a more optimal management approach in these patients.

Investigating STEAP2 as a potential therapeutic target for the treatment of aggressive prostate cancer.

The expression of six transmembrane epithelial antigen of the prostate (STEAP2) is increased in prostate cancer when compared to normal tissue, suggesting a role for STEAP2 in disease progression. This study aimed to determine whether targeting STEAP2 with an anti-STEAP2 polyclonal antibody (pAb) or CRISPR/Cas9 knockout influenced aggressive prostate cancer traits. Gene expression analysis of the STEAP gene family was performed in a panel of prostate cancer cell lines; C4-2B, DU145, LNCaP and PC3. The highest increases in STEAP2 gene expression were observed in C4-2B and LNCaP cells (p<0.001 and p<0.0001 respectively) when compared to normal prostate epithelial PNT2 cells. These cell lines were treated with an anti-STEAP2 pAb and their viability assessed. CRISPR/Cas9 technology was used to knockout STEAP2 from C4-2B and LNCaP cells and viability, proliferation, migration and invasion assessed. When exposed to an anti-STEAP2 pAb, cell viability significantly decreased (p<0.05). When STEAP2 was knocked out, cell viability and proliferation was significantly decreased when compared to wild-type cells (p<0.001). The migratory and invasive potential of knockout cells were also decreased. These data suggest that STEAP2 has a functional role in driving aggressive prostate cancer traits and could provide a novel therapeutic target for the treatment of prostate cancer.

Mixed pollutants adsorption potential of Eichhornia crassipes biochar on Manihot esculenta processing industry effluents.

The starch is one of the most essential food stuff and serves as a raw material for number of food products for the welfare of human. During the production process enormous volume of effluents are being released into the environment. In this regard, this study was performed to evaluate the physicochemical traits of Manihot esculenta processing effluent and possible sustainable approach to treat this issue using Eichhornia crassipes based biochar. The standard physicochemical properties analysis revealed that the most the parameters (EC was recorded as 4143.17 ± 67.12 mhom-1, TDS: 5825.62 ± 72.14 mg L-1, TS: 7489.21 ± 165.24 mg L-1, DO: 2.12 ± 0.21 mg L-1, BOD 2673.74 ± 153.53 mg L-1, COD: 6672.66 ± 131.21 mg L-1, and so on) were beyond the permissible limits and which can facilitate eutrophication. Notably, the DO level was considerably poor and thus can support the eutrophication. The trouble causing E. crassipes biomass was used as raw material for biochar preparation through pyrolysis process. The temperature ranging from 250 to 350 °C with residence time of 20-60 min were found as suitable temperature to provide high yield (56-33%). Furthermore, 10 g L-1 concentration of biochar showed maximum pollutant adsorption than other concentrations (5 g L-1 and 15 g L-1) from 1 L of effluent. The suitable temperature required to remediate the pollutants from the effluent by biochar was found as 45 °C and 35 °C at 10 g L-1 concentration. These results conclude that at such optimized condition, the E. crassipes effectively adsorbed most of the pollutants from the M. esculenta processing effluent. Furthermore, such pollutants adsorption pattern on biochar was confirmed by SEM analysis.

Organic gelatin-coated ZnNPs for the production of biodegradable biopolymer films.

Petroleum-based polymers have raised significant environmental concerns. It is critical to create compostable, good biocompatibility, and nontoxic polymers to replace petroleum-based polymers. Thus, this research was performed to extract the gelatin from fish waste cartilage and coated it over the surface of spherical shaped pre-synthesized ZnNPs along with a suitable plasticizer to produce the biodegradable film. The presence of gelatin on the surface of ZnNPs was first confirmed using UV-visible spectrophotometers, as well as the characteristic functional groups involved in the coating were investigated using Fourier-Transform Infrared Spectroscopy (FTIR). The morphological appearance of gelatin coated ZnNPs was ranged from 41.43 to 52.31 nm, the shape was found as platonic to pentagonal shape, and the fabricated film was observed through Scanning Electron Microscope (SEM). The thickness, density, and tensile strength of fabricated film were found to be 0.04-0.10 mm, 0.10-0.27 g/cm3, and 31.7 kPa. These results imply that the fish waste cartilage gelatin coated ZnNPs-based nanocomposite can be used for film preparation as well as a wrapper for food and pharmaceutical packaging.

How public health insurance expansion affects healthcare utilizations in middle and low-income households: an observational study from national cross-section surveys in Vietnam.

Public health insurance (PHI) has been implemented with different levels of participation in many countries, from voluntary to mandatory. In Vietnam, a law amendment made PHI compulsory nationwide in 2015 with a tolerance phase allowing people a flexible time to enroll. This study aims to examine mechanisms under which the amendment affected the enrollment, healthcare utilization, and out-of-pocket (OOP) expenditures by middle- and low-income households in this transitioning process.Using the biennial Vietnam Household Living Standard Surveys, the study applied the doubly robust difference-in-differences approach to compare outcomes in the post-amendment period from the 2016 survey with those in the pre-amendment period from the 2014 survey. The approach inheriting advantages from its predecessors, i.e., the difference-in-differences and the augmented inverse-probability weighting methods, can mitigate possible biases in policy evaluations due to the changes within the group and between groups over time in the cross-section observational study.The results showed health insurance expansion with extensive subsidies in premiums and medical coverage for persons other than the full-time employed, young children or elderly members in the family, significantly increased enrollments in the middle- and low-income groups by 9% and 8%, respectively. The number of visits for PHI-eligible services also increased, approximately 0.5 more visit per person in the middle-income and 1 more visit per person in the low-income. The amendment, however, so far did not show any significant effect on reducing OOP payments, neither for the low nor the middle-income groups. To further expand PHI coverage and financial protections, policymakers should focus on improving public health facilities, contracting PHI to more accredited private health providers, and motivating the high-income group's enrollments.

Cost-effectiveness of improvement strategies for reperfusion treatments in acute ischemic stroke: a systematic review.

BACKGROUND: Reducing delays along the acute stroke pathway significantly improves clinical outcomes for acute ischemic stroke patients eligible for reperfusion treatments. The economic impact of different strategies reducing onset to treatment (OTT) is crucial information for stakeholders in acute stroke management. This systematic review aimed to provide an overview on the cost-effectiveness of several strategies to reduce OTT. METHODS: A comprehensive literature search was conducted in EMBASE, PubMed, and Web of Science until January 2022. Studies were included if they reported 1/ stroke patients treated with intravenous thrombolysis and/or endovascular thrombectomy, 2/ full economic evaluation, and 3/ strategies to reduce OTT. The Consolidated Health Economic Evaluation Reporting Standards statement was applied to assess the reporting quality. RESULTS: Twenty studies met the inclusion criteria, of which thirteen were based on cost-utility analysis with the incremental cost-effectiveness ratio per quality-adjusted life year gained as the primary outcome. Studies were performed in twelve countries focusing on four main strategies: educational interventions, organizational models, healthcare delivery infrastructure, and workflow improvements. Sixteen studies showed that the strategies concerning educational interventions, telemedicine between hospitals, mobile stroke units, and workflow improvements, were cost-effective in different settings. The healthcare perspective was predominantly used, and the most common types of models were decision trees, Markov models and simulation models. Overall, fourteen studies were rated as having high reporting quality (79%-94%). CONCLUSIONS: A wide range of strategies aimed at reducing OTT is cost-effective in acute stroke care treatment. Existing pathways and local characteristics need to be taken along in assessing proposed improvements.