An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.

Age- and ethnic-driven molecular and clinical disparity of East Asian breast cancers.

BACKGROUND: Breast cancer (BC) is a complex disease with profound genomic aberrations. However, the underlying molecular disparity influenced by age and ethnicity remains elusive. METHODS: In this study, we aimed to investigate the molecular properties of 843 primary and metastatic BC patients enrolled in the K-MASTER program. By categorizing patients into two distinct age subgroups, we explored their unique molecular properties. Additionally, we leveraged large-scale genomic data from the TCGA and MSK-IMPACT studies to examine the ethnic-driven molecular and clinical disparities. RESULTS: We observed a high prevalence of PI3KCA mutations in K-MASTER HER2 + tumors, particularly in older patients. Moreover, we identified increased mutation rates in DNA damage response molecules, including ARID1A, MSH6, and MLH1. The K-MASTER patients were mainly comprised of triple-negative breast cancer (TNBC) and HER2-positive tumors, while the TCGA and MSK-IMPACT cohorts exhibited a predominance of hormone receptor-positive (HR +) subtype tumors. Importantly, GATA3 mutations were less frequently observed in East Asian patients, which correlated with poor clinical outcomes. In addition to characterizing the molecular disparities, we developed a gradient-boosting multivariable model to identify a new molecular signature that could predict the therapeutic response to platinum-based chemotherapy. CONCLUSIONS: Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.

Cumulative Blood Pressure Load and Incident CKD.

RATIONALE & OBJECTIVE: The association of long-term cumulative blood pressure (BP) loads with the risk of incident chronic kidney disease (CKD) remains a matter of debate. This study investigated this association among healthy Korean adults with normal kidney function. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We analyzed 5,221 participants without CKD in the Korean Genome and Epidemiology Study. Cumulative systolic and diastolic BP (SBP and DBP) loads were calculated as the ratios of the areas under the curve (AUC) for SBP≥120mm Hg or≥80mm Hg for DBP divided by the AUC for all SBP or DBP measurements during the exposure period. These AUCs were categorized into 4 groups: group 0 (reference), cumulative BP load of 0 and groups 1-3, tertiles of cumulative BP loads. OUTCOME: Primary end point was incident CKD defined as a composite of an estimated glomerular filtration rate (eGFR) below 60mL/min/1.73m2 or proteinuria greater than 1+on dipstick examination for at least 2 consecutive measurements≥90 days apart. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression to estimate the independent association of cumulative BP loads with incident CKD. RESULTS: Higher cumulative SBP and DBP loads were associated with an increased risk of incident CKD (HR, 1.23 [95% CI, 1.12-1.35] for SBP; and HR, 1.14 [95% CI, 1.04-1.26] for DBP loads for each 1.0-unit greater load). Compared with SBP group 0, groups 2 and 3 were associated with 1.94- and 1.89-fold greater risk of incident CKD. Compared with DBP group 0, groups 2 and 3 were associated with 1.42- and 1.54-fold greater risks. These associations of high cumulative BP loads with an increased risk of incident CKD remained consistent even in the subgroups not taking antihypertensive agents or without prior hypertension diagnosis. LIMITATIONS: The assessment of CKD outcomes relied on eGFR and spot urine tests. CONCLUSIONS: These findings highlight the association between high cumulative SBP and DBP loads and the occurrence of CKD, even in individuals with normal BP levels. PLAIN-LANGUAGE SUMMARY: Although hypertension is a major risk factor for chronic kidney disease (CKD), most studies have focused on single-point blood pressure (BP) measurements. To explore the association between long-term cumulative BP load and the development of CKD, 5,221 Korean adults with normal kidney function were included in this study. Cumulative systolic BP and diastolic BP load both exhibited a significant association with an increased risk of incident CKD. Notably, the association of cumulative BP loads with elevated risk of incident CKD was evident also in individuals who were not taking antihypertensive agents or who had no previous history of hypertension. These findings underscore the importance of managing long-term exposure to high BP, even in individuals with normal BP levels.

Plasma Levels of Polyunsaturated Fatty Acids and Adverse Kidney Outcomes.

RATIONALE & OBJECTIVE: Many studies have reported polyunsaturated fatty acids (PUFA) as significant predictors of cardiovascular disease, but little is known about the relationship between PUFA levels and chronic kidney disease (CKD). This study explored this relationship among individuals with and without CKD. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 73,419 participants without CKD (cohort 1) and 6,735 participants with CKD (cohort 2) in the UK Biobank Study, with PUFA levels measured between 2007 and 2010. EXPOSURE: Percentage of plasma PUFA, omega-3 fatty acid (FA), omega-6 FA, docosahexaenoic acid (DHA), and linoleic acid relative to total FA. OUTCOME: Incident CKD for cohort 1 and incident kidney failure requiring replacement therapy (KFRT) for cohort 2. ANALYTICAL APPROACH: Cox proportional hazards regression analyses, including a cause-specific competing risk model. RESULTS: In cohort 1, individuals with higher quartiles of plasma PUFA levels had healthier lifestyles and fewer comorbidities. During 841,007 person-years of follow-up (median 11.9 years), incident CKD occurred in 4.5% of participants (incidence rate, 39.1 per 10,000 person-years). For incident CKD in cohort 1, the adjusted cause-specific hazard ratios for quartiles 2, 3, and 4 were 0.83 (95% CI, 0.75-0.92), 0.85 (95% CI, 0.76-0.96), 0.71 (95% CI, 0.62-0.82), respectively, compared with quartile 1. This inverse relationship was consistently observed for all PUFA types. In cohort 2, although total PUFA levels were not associated with KFRT, higher PUFA subtype levels of DHA were associated with a lower risk of KFRT. LIMITATIONS: Observational design and limited generalizability to individuals with higher disease severity; no data on eicosapentaenoic acid. CONCLUSIONS: Among individuals without CKD, higher plasma PUFA levels and all 4 PUFA components were associated with a lower risk of incident CKD. In individuals with CKD, only the omega-3 component of PUFA, DHA, was associated with a lower risk of KFRT. PLAIN-LANGUAGE SUMMARY: Low amounts of polyunsaturated fatty acids (PUFA) in the blood are suspected of increasing the chances of heart disease, but it is not known whether the PUFA relates to kidney disease occurrence. In a large group without kidney disease in the United Kingdom, people with higher levels of PUFA in their blood tended to have a lower risk of developing kidney disease compared to those with lower PUFA levels. This relationship was consistently observed for all PUFA types. However, in the group with kidney disease, only higher levels of docosahexaenoic acid, a subtype of PUFAs, were associated with a lower risk of developing severe kidney problems that required kidney replacement therapy. These findings suggest that higher levels of PUFA, found in certain healthy fats, might protect against the development of kidney disease in the general population. As kidney function declines, only the docosahexaenoic acid, a subtype of PUFA, appears to be associated with preserved kidney function.

Impact of Blood Pressure on Allograft Function and Survival in Kidney Transplant Recipients.

The optimal target blood pressure for kidney transplant (KT) patients remains unclear. We included 808 KT patients from the KNOW-KT as a discovery set, and 1,294 KT patients from the KOTRY as a validation set. The main exposures were baseline systolic blood pressure (SBP) at 1 year after KT and time-varying SBP. Patients were classified into five groups: SBP <110; 110-119; 120-129; 130-139; and ≥140 mmHg. SBP trajectories were classified into decreasing, stable, and increasing groups. Primary outcome was composite kidney outcome of ≥50% decrease in eGFR or death-censored graft loss. Compared with the 110-119 mmHg group, both the lowest (adjusted hazard ratio [aHR], 2.43) and the highest SBP (aHR, 2.25) were associated with a higher risk of composite kidney outcome. In time-varying model, also the lowest (aHR, 3.02) and the highest SBP (aHR, 3.60) were associated with a higher risk. In the trajectory model, an increasing SBP trajectory was associated with a higher risk than a stable SBP trajectory (aHR, 2.26). This associations were consistent in the validation set. In conclusion, SBP ≥140 mmHg and an increasing SBP trajectory were associated with a higher risk of allograft dysfunction and failure in KT patients.

Risk factors and chlorhexidine dressings in external ventricular drainage: a retrospective analysis on infection rates.

This retrospective study endeavors to scrutinize risk factors associated with infections resulting from external ventricular drainage (EVD) and to assess the effectiveness of chlorhexidine dressing in mitigating infection rates. Conducted from January 2018 to July 2023, this single-center study encompassed 108 EVD patients. Comprehensive data on demographics, comorbidities, surgical procedures, and the utilization of chlorhexidine dressing were meticulously compiled. The primary endpoint was the incidence of EVD-associated infections based on CDC criteria. Infection rates attributable to EVD were 24.32% without and 20.59% with chlorhexidine dressing. Notably, diabetes mellitus emerged as the solitary significant infection risk factor (p < 0.01). Although the application of chlorhexidine dressing suggested a propensity for diminishing infection rates, statistical significance remained elusive. No notable disparities were discerned in variables such as catheter type, procedural location, and underlying diseases. Diabetes mellitus has been identified as a significant risk factor for EVD-associated infections. While the utilization of chlorhexidine dressing exhibited a potential reduction in infection rates, the lack of statistical significance underscores the imperative for further research, encompassing more expansive randomized trials, to comprehensively evaluate the safety and efficacy of chlorhexidine dressings in preventing EVD-associated infections.

Effectiveness of electrocardiogram interpretation education program using mixed learning methods and webpage.

AIM: This study was conducted to develop an electrocardiogram education program that incorporates an HTML webpage and blended learning methods to enhance electrocardiogram interpretation skills. Through continual and efficient education, the program aims to assist nurses in providing appropriate care and treatment to patients. DESIGN: Pre-post design study. METHODS: We developed an electrocardiogram interpretation HTML webpage based on an electrocardiogram interpretation algorithm and implemented an 18-week (2023.5.15 ~ 2023.9.22) electrocardiogram education program, which included daily 5-minute training sessions. Twenty-seven ward nurses were provided with the URL ( https://ecgweb.github.io/ECGwebEN ) to the electrocardiogram interpretation HTML webpage and shared one electrocardiogram case daily for self-interpretation. Electrocardiogram interpretation performance and confidence were evaluated through questionnaires at three phases: before the program, after 6 weeks of basic electrocardiogram and arrhythmia education, and after 12 weeks of application of the electrocardiogram interpretation HTML webpage and case-based lecture education. The statistical tests used were repeated-measures ANOVA or the Wilcoxon signed-rank test. RESULTS: The average score for electrocardiogram interpretation performance before the electrocardiogram education program was 11.89(SD = 3.50), after 6 weeks of basic electrocardiogram and arrhythmia education it was 14.15(SD = 3.68), and after 12 weeks of application of the electrocardiogram interpretation HTML webpage and case-based lecture education, it was 15.56(SD = 3.04). This shows that electrocardiogram interpretation performance significantly improved over time (p < .001). Additionally, post-hoc analysis revealed significant differences in electrocardiogram interpretation performance at each stage, i.e., before, during, and after the application of an electrocardiogram education program. Furthermore, the electrocardiogram interpretation confidence questionnaire score (pre-Median 18, IQR = 5; post-Median 23, IQR = 3) was improved significantly after the completion of the 18-week education program (p < .001). CONCLUSIONS: Based on the results of this study, we believe that an electrocardiogram education program using HTML webpage, and a blended teaching method would be very beneficial for maintaining and improving electrocardiogram interpretation skills of clinical nurses. Such a program can help nurses interpret electrocardiograms more effectively and assist them in making important decisions in patient care.

OsLRR-RLP2 Gene Regulates Immunity to Magnaporthe oryzae in Japonica Rice.

Rice is an important cereal crop worldwide, the growth of which is affected by rice blast disease, caused by the fungal pathogen Magnaporthe oryzae. As climate change increases the diversity of pathogens, the disease resistance genes (R genes) in plants must be identified. The major blast-resistance genes have been identified in indica rice varieties; therefore, japonica rice varieties with R genes now need to be identified. Because leucine-rich repeat (LRR) domain proteins possess R-gene properties, we used bioinformatics analysis to identify the rice candidate LRR domain receptor-like proteins (OsLRR-RLPs). OsLRR-RLP2, which contains six LRR domains, showed differences in the DNA sequence, containing 43 single-nucleotide polymorphisms (SNPs) in indica and japonica subpopulations. The results of the M. oryzae inoculation analysis indicated that indica varieties with partial deletion of OsLRR-RLP2 showed susceptibility, whereas japonica varieties with intact OsLRR-RLP2 showed resistance. The oslrr-rlp2 mutant, generated using clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), showed increased pathogen susceptibility, whereas plants overexpressing this gene showed pathogen resistance. These results indicate that OsLRR-RLP2 confers resistance to rice, and OsLRR-RLP2 may be useful for breeding resistant cultivars.

Association of Plant Protein Intake With Risk of Incident CKD: A UK Biobank Study.

RATIONALE & OBJECTIVE: Data suggest that various dietary interventions slow kidney disease progression and improve clinical outcomes for those with chronic kidney disease (CKD). However, the association between plant protein intake and incident CKD has been uncertain. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 117,809 participants who completed at least 1 dietary questionnaire and had an estimated glomerular filtration rate (eGFR) ≥ 60mL/min/1.73m2, a urinary albumin-creatinine ratio (UACR)<30mg/g, and no history of CKD. EXPOSURE: Daily plant protein intake in g/kg/day. OUTCOME: Incident CKD based on the International Classification of Diseases, 10th Revision (ICD-10) or the Office of Population Censuses and Surveys Classification of Interventions and Procedures, version 4 (OPCS-4) codes. ANALYTICAL APPROACH: A cause-specific proportional hazards analysis incorporating competing risks that treated death occurring before incident CKD as a competing event. RESULTS: During a median follow-up period of 9.9 years, incident CKD occurred in 3,745 participants (3.2%; incidence rate, 3.2 per 1,000 person-years). In a multivariable model, the adjusted hazard ratio (AHR) for the second, third, and highest quartiles of plant protein intake was 0.90 (95% CI, 0.82-0.99), 0.83 (95% CI, 0.75-0.92), and 0.82 (95% CI, 0.73-0.93), respectively, compared with the lowest quartile. Modeled as a continuous variable, the AHR per 0.1g/kg/day plant protein intake increase was 0.96 (95% CI, 0.93-0.99). This beneficial association was also consistent in secondary analyses for which CKD was defined based on codes or 2 consecutive measures of eGFR<60mL/min/1.73m2 or UACR>30mg/g. Various sensitivity analyses demonstrated consistent findings. LIMITATIONS: Potential incomplete dietary assessments; limited generalizability due to the characteristics of participants in the UK Biobank Study. CONCLUSIONS: In this large, prospective cohort study, greater dietary plant protein intake was associated with a lower risk of incident CKD. Further interventional studies demonstrating the kidney-protective benefits of plant protein intake are warranted. PLAIN-LANGUAGE SUMMARY: Plant-based diets confer various health benefits, including lowering the risk of cardiovascular disease and certain cancers. However, the relationship between plant protein intake and the risk of chronic kidney disease (CKD) remains unclear. Our study investigated the association between plant protein intake and the development of CKD. Using the UK Biobank Study data, we found that participants with a higher plant protein intake had a lower risk of developing CKD. Our finding suggests that a higher dietary intake of plant-based protein may be beneficial for kidney health and provides insight into dietary interventions to prevent CKD in primary care settings.

Insomnia in patients on incident maintenance dialysis and the risk of major acute cardio-cerebrovascular events and all-cause mortality.

BACKGROUND AND HYPOTHESIS: Insomnia is a known risk factor for cardio-cerebrovascular disease in the general population; however, its effect on cardio-cerebrovascular outcomes in end-stage kidney disease patients is unclear. Therefore, this study aimed to investigate the association between cardio-cerebrovascular outcomes and insomnia in patients who initiated maintenance dialysis. METHODS: This study used nationwide Korean health insurance claims data to analyze 79 420 patients who initiated maintenance dialysis from January 2009 to December 2017. Insomnia was defined using claim codes and sleep medication prescription data. Patients were categorized according to the presence of insomnia before and after dialysis initiation: a) no insomnia, b) insomnia before dialysis only (improved insomnia), c) insomnia after dialysis only (developed insomnia), and d) insomnia in both periods (persistent insomnia). The primary and secondary outcomes were major adverse cardiac and cerebrovascular events (MACCE) and all-cause mortality, respectively. The outcome risks were estimated by Cox regression models with inverse probability of treatment weighting. RESULTS: The mean age was 61.4 ± 13.4 years, and 39.7% were women. During the transition period from pre-dialysis to maintenance dialysis, 13.2% experienced insomnia. The insomnia groups showed significantly higher risks for MACCE (weighted hazard ratios [95% confidence intervals]: developed insomnia, 1.26 [1.25-1.28]; improved insomnia, 1.31 [1.29-1.33]; persistent insomnia, 1.39 [1.37-1.41]) and higher all-cause mortality risks than the no insomnia group. The insomnia related cardio-cerebrovascular disease risk elevation was more prominent in younger and male patients. CONCLUSIONS: Insomnia may increase cardio-cerebrovascular disease and all-cause mortality risk among end-stage kidney disease patients who initiate maintenance dialysis.

Lactate oxidase/catalase-displaying nanoparticles efficiently consume lactate in the tumor microenvironment to effectively suppress tumor growth.

The aggressive proliferation of tumor cells often requires increased glucose uptake and excessive anaerobic glycolysis, leading to the massive production and secretion of lactate to form a unique tumor microenvironment (TME). Therefore, regulating appropriate lactate levels in the TME would be a promising approach to control tumor cell proliferation and immune suppression. To effectively consume lactate in the TME, lactate oxidase (LOX) and catalase (CAT) were displayed onto Aquifex aeolicus lumazine synthase protein nanoparticles (AaLS) to form either AaLS/LOX or AaLS/LOX/CAT. These complexes successfully consumed lactate produced by CT26 murine colon carcinoma cells under both normoxic and hypoxic conditions. Specifically, AaLS/LOX generated a large amount of H2O2 with complete lactate consumption to induce drastic necrotic cell death regardless of culture condition. However, AaLS/LOX/CAT generated residual H2O2, leading to necrotic cell death only under hypoxic condition similar to the TME. While the local administration of AaLS/LOX to the tumor site resulted in mice death, that of AaLS/LOX/CAT significantly suppressed tumor growth without any severe side effects. AaLS/LOX/CAT effectively consumed lactate to produce adequate amounts of H2O2 which sufficiently suppress tumor growth and adequately modulate the TME, transforming environments that are favorable to tumor suppressive neutrophils but adverse to tumor-supportive tumor-associated macrophages. Collectively, these findings showed that the modular functionalization of protein nanoparticles with multiple metabolic enzymes may offer the opportunity to develop new enzyme complex-based therapeutic tools that can modulate the TME by controlling cancer metabolism.

Effects of preparation routes on the physical and rheological properties of isosorbide-based thermoplastic polyurethanes.

Biomass-derived isosorbide (ISB) is a promising alternative to petroleum-based monomers in industrial plastics. In this study, ISB-based thermoplastic polyurethanes (ISB-TPUs) were prepared using ISB as a biomass chain extender, and the effects of the preparation route on the structural and physical properties of the resultant polymers were investigated. Prepolymer methods were more suitable for obtaining the desired molecular weights (MWs) and physical properties of ISB-TPUs than the one-shot method. The presence of the solvent and catalyst in the prepolymer step had significant effects on the structural and physical properties of the resultant polymer. Among several prepolymer conditions, the solvent- and catalyst-free methods were the most suitable for preparing commercial-level ISB-TPUs, with number- and weight-average MWs (M n and M w ) of 32,881 and 90,929 g mol-1, respectively, and a tensile modulus (E) and ultimate tensile strength (UTS) of 12.0 and 40.2 MPa, respectively. In comparison, the presence of a catalyst in the prepolymer step resulted in lower MWs and mechanical properties (81,033 g mol-1 and 18.3 MPa of M w and UTS, respectively). The co-existence of the catalyst/solvent led to a further decline in the properties of ISB-TPUs (26,506 and 10.0 MPa of M w and UTS, respectively). ISB-TPU prepared via the solvent- and catalyst-free methods exhibited remarkable elastic recovery when subjected to up to 1000% strain in mechanical cycling tests. Rheological characterization confirmed the thermo-reversible phase change (thermoplasticity) of the polymer. Supplementary Information: The online version contains supplementary material available at 10.1007/s13233-023-00125-w.

Epidemiologic outlook of therapy-related myeloid neoplasms and selection of high-risk patients: A Korean nationwide study.

BACKGROUND: Although a considerable proportion of patients with cancer receive chemotherapy (CT) or radiotherapy (RT), only a very few patients eventually develop therapy-related myeloid neoplasms (t-MNs). METHODS: To identify subsets of cancer patients who have substantially elevated risk of developing t-MNs. Incidences and risks of t-MNs after contemporary CT or RT in patients newly diagnosed major cancers during 2009-2013 were analyzed. By merging two Korean nationwide health care big data sets, patients were selected and observed on follow-up to until t-MN development or December 2019. RESULTS: Among 250,155 patients, 555 (0.22%) were diagnosed with t-MNs with a standard incidence ratio (SIR) of 3.40 (95% CI, 3.13-3.70). Patients had bone/joint cancers (SIR, 94.25; 95% CI, 50.71-137.80) and a remarkably high SIR for t-MN development. Patients receiving both CT and RT had the highest SIR (4.64; 95% CI, 4.08-5.20), followed by those receiving CT only (SIR, 3.30; 95% CI, 2.89-3.70). Contrarily, RT alone did not increase t-MN risk (SIR, 1.16; 95% CI, 0.76-1.56). More exposure to leukemogenic agents resulted in the higher t-MNs development. CONCLUSIONS: The increased risk of developing acute myeloid leukemia or myelodysplastic syndrome after CT and/or RT was confirmed and subsets with substantially elevated risk for developing t-MNs were found. Such patients would be suitable for a prospective cohort for investigating t-MN pathogenesis by time series analyses.

Health attacks and protection strategies during Gaza's Great March of Return: a mixed methods study using data from WHO's Surveillance System for Attacks on Healthcare.

BACKGROUND: WHO defines an attack on health care as "any act of verbal or physical violence or obstruction or threat of violence that interferes with the availability, access and delivery of curative and/or preventive health services during emergencies." Gaza's Great March of Return (GMR) began on Mar 30, 2018, with 322 Palestinians killed and 33 141 injured by December, 2019, and first-response health-care teams exposed to high levels of violence. The aims of this study were threefold: to explore the vulnerabilities of health workers to attacks during the GMR; to understand the effectiveness and comprehensiveness of systems for monitoring health attacks; and to identify potential strategies and interventions to improve protection. METHODS: WHO's Surveillance System for Attacks on Healthcare (SSA) verifies and records health attacks. We analysed SSA data for the Gaza Strip from Mar 30, 2018, to Dec 31, 2019, examining the number and type of attacks, the mechanisms of injury, and the distribution of attacks by gender, time, and location. We analysed the correlation of health worker injuries and deaths with total injuries and deaths of Palestinians during the GMR. We held interviews and focus groups with individuals working for organizations defined as partners contributing to the SSA in the Gaza Strip, to understand data comprehensiveness, the nature and impact of violence, and protection gaps and strategies. FINDINGS: During the study period, there were 567 confirmed incidents, in which three health workers were killed, 845 health workers were injured, and 129 ambulances and vehicles and 7 health facilities were damaged, including one hospital and three medical field stations. Of the total health personnel killed and injured, 166 of 848 (20%) were in the Gaza governorate, 274 (32%) were in the Khan Yunis governorate, 119 (14%) were in the middle governorate, 192 (22%) were in North governorate, and 96 (11%) were in the Rafah governorate. Of 845 injuries, 743 (88%) were in men, 45 (5%) were live ammunition injuries, 62 (7%) were rubber bullet injuries, 151 (18%) were gas canister injuries, 41 (5%) were shrapnel injuries, and 533 (64%) were gas inhalation injuries. Injuries and deaths among health workers correlated moderately (R2=0·54) with and accounted for 2% of the total. Qualitative findings highlighted the incidental and structural nature of violence, normalisation and under-reporting of attacks, the need for improved coordination of protection for health care, and gaps in the availability of protective equipment. INTERPRETATION: Health-care workers function at great personal risk. The correlation of attacks against health care with total injuries and deaths points to the need for alignment of efforts to protect health care with strategies to safeguard civilian populations, including protection of populations living under occupation and those engaged in civil demonstrations. Health-care workers identified the need for systemic measures to improve protection through training, monitoring, and coordination, and through linking of monitoring and documentation of health attacks with stronger accountability measures for prevention. FUNDING: In 2017 and 2018, WHO's Right to Health Advocacy programme received funding from the Swiss Development Cooperation and the oPt Humanitarian Fund.

Preoperative Ionized Magnesium Levels and Risk of Acute Kidney Injury After Cardiac Surgery.

RATIONALE & OBJECTIVE: Although postoperative acute kidney injury (AKI) is a serious complication after cardiac surgery, preventive measures are limited. Despite the known association of preoperative low magnesium levels with cardiac surgery-related atrial fibrillation, the association between preoperative magnesium concentration and postoperative AKI has not been fully elucidated. This study evaluated the association between preoperative serum magnesium level and the development of AKI after cardiac surgery. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: Patients aged≥18 years who underwent cardiac surgery at 2 South Korean tertiary hospitals between 2006 and 2020 were identified from medical records. Patients with missing information, an estimated glomerular filtration rate<15mL/min/1.73m2, receiving maintenance dialysis, or a history of AKI treated by dialysis within 1 year before surgery were excluded. EXPOSURE: Preoperative serum magnesium levels. OUTCOME: Postoperative AKI within 48 hours after surgery, defined using the Acute Kidney Injury Network (AKIN) criteria, and dialysis-treated AKI within 30 days after surgery. ANALYTICAL APPROACH: Multivariable logistic regression analysis. RESULTS: Among the 9,766 patients (median age, 64.0 years; 60.1% male), postoperative AKI and dialysis-treated AKI were observed in 40.1% and 4.3% patients, respectively. Postoperative AKI was more prevalent in patients with lower serum magnesium levels (44.9%, 41.4%, 39.4%, and 34.8% in quartiles 1-4, respectively). Multivariable logistic regression analysis revealed that the odds ratios (ORs) for postoperative AKI were progressively larger across progressively lower quartiles of serum magnesium concentration (adjusted ORs of 1.53 [95% CI, 1.33-1.76], 1.29 [95% CI, 1.12-1.48], 1.15 [95% CI, 1.01-1.31] for quartiles 1-3, respectively, relative to quartile 4, P for trend<0.001). Preoperative hypomagnesemia (serum magnesium level<1.09mg/dL) was also significantly associated with AKI (adjusted OR, 1.39 [95% CI, 1.10-1.77]) and dialysis-treated AKI (adjusted OR, 1.67 [95% CI, 1.02-2.72]). LIMITATIONS: Causality could not be evaluated in this observational study. CONCLUSIONS: Lower serum magnesium levels were associated with a higher incidence of AKI in patients undergoing cardiac surgery.

Economic Impact of Donating a Kidney on Living Donors: A Korean Cohort Study.

RATIONALE & OBJECTIVE: Although existing studies have reported adverse health outcomes after kidney donation, its socioeconomic impact on living donors requires further study. STUDY DESIGN: A retrospective observational cohort study including a matched comparison group. SETTING & PARTICIPANTS: 1,285 living kidney donors from 7 tertiary hospitals between 2003 and 2016, and a matched comparison group consisting of the same number of health screening examinees with similar baseline clinical characteristics and socioeconomic status. All participants were receiving Korean national health insurance. EXPOSURE: Kidney donation as reflected in the Korean National Health Insurance System (NHIS) database. OUTCOME: Changes in household economic status estimated by Korean national health insurance fees and changes in employment status reflected in the NHIS database. ANALYTICAL APPROACH: The outcomes of the donor group and matched control group were compared annually using multivariable logistic regression analyses adjusted for clinical and demographic characteristics. RESULTS: The median ages of the donors and matched controls were 45 and 46 years, respectively; 44.6% of both groups were male. Compared to the comparison group, living donors were at higher risk of being unemployed or losing employment during the first 2 years after donation (eg, first-year loss of employment: odds ratio (OR), 2.27 [95% CI, 1.55-3.33]); however, this association did not persist. Donors also had a significantly lower odds of improvement in economic status (OR, 0.57 [95% CI, 0.47-0.71]) and a higher odds of deterioration in financial status (OR, 1.54 [95% CI, 1.23-1.93]) in the first year after transplantation and subsequently. LIMITATIONS: Unmeasured differences between donors and matched controls creating residual selection bias and confounding. CONCLUSIONS: Living kidney donors may suffer loss of employment and poor economic status after their voluntary donation. The socioeconomic impact on these donors should be considered in conjunction with the potential long-term adverse health outcomes after donation.

A risk scoring system to predict clinical events in chronic hepatitis B virus infection: A nationwide cohort study.

Many patients with chronic hepatitis B do not receive adequate follow-up. This study aimed to develop a risk score to predict clinical events in patients with chronic hepatitis B virus (HBV) infection at the population level for identifying patients at high risk to warrant regular follow-up. This study analysed population-based data from the nationwide claims database of South Korea obtained between 2005 and 2015. We identified 507,239 non-cirrhotic patients with chronic HBV infection who are not under antiviral treatment. A risk score for predicting clinical events (hepatocellular carcinoma, death or liver transplantation) was developed based on multivariable Cox proportional hazard model in a development cohort (n = 401,745) and validated in a validation cohort (n = 105,494). The cumulative incidence rates of clinical events at 5 years were 2.56% and 2.44% in the development and validation cohorts, respectively. Clinical events in asymptomatic patients with chronic HBV infection (CAP-B) score ranging from 0 to 7.5 points based on age, sex, socioeconomic status, chronic hepatitis C co-infection, diabetes mellitus, statin or antiplatelet exposure, smoking, alcohol consumption, alanine aminotransferase and gamma-glutamyltransferase had good discriminatory accuracy in both the development and validation cohorts (c-indices for 3-, 5- and 10-year risk prediction: all 0.786). The predicted and observed probabilities of clinical events were calibrated in both cohorts. A score of >3.5 points identified subjects at distinctly high risk. The CAP-B score using easily accessible variables can predict clinical events and may allow selection of patients with chronic HBV infection for priority of regular follow-up.

Intramedullary parasite eggs, latent for three decades, mimicking acute transverse myelitis.

BACKGROUND: Intramedullary parasitic infection is extremely uncommon, and clinical presentation of Brown-Sequard syndrome is even rarer. CASE PRESENTATION: The authors report a case involving a 57-year-old woman with Brown-Sequard syndrome, in whom magnetic resonance imaging and clinical and epidemiological features were similar to those of acute transverse myelitis. Myelotomy suggested inflammation caused by latent parasite eggs in the spinal cord. Antiparasitic and steroid therapies were administered postoperatively. To the author's knowledge, this is the first report to describe a surgical experience for Taenia solium eggs in the spinal cord. CONCLUSION: Intramedullary parasitic infection is a diagnostic challenge that requires careful discrimination from other diseases. If parasite infection is suspected in a progressively deteriorating patient, myelotomy should be considered for rapid and accurate treatment.

Biocontrol of bacterial wilt in tomato with a cocktail of lytic bacteriophages.

Bacteriophages (phages) have been proposed as promising alternative pesticides against various bacterial diseases of crops. However, the efficacy of phages in managing plant bacterial diseases is variable and poorly understood in natural settings. In this study, two lytic phages, RpT1 and RpY2, were investigated for their biocontrol potential against bacterial wilt by Ralstonia pseudosolanacearum invasion in tomato plants. The two phages possess similar morphology and genome organization to those of the Autographiviridae family with a broad host range. Treatment with the two phages (alone or in combination) resulted in a significant reduction in bacterial wilt incidence. Three days post-treatment with phages, which was performed after R. pseudosolanacearum inoculation with a specified density of 108 PFU (plaque forming units)/g of soil, led to the most effective biocontrol activity compared to other treatments and a lower density of phage. A phage cocktail containing both RpT1 and RpY2 suppressed disease symptoms in agricultural soils, mimicking their ability to control diseases in natural settings. Furthermore, supplementation with specific adjuvants enhanced the biocontrol potential of both phages. The persistence of the two phages under various environmental conditions indicates their stable activity in soils. Consequently, the consistent biocontrol activity of these phages provides insights into the proper application, timing, and density of phages for effective phage therapy in bacterial wilt control in tomato. KEY POINTS: • Biocontrol potential of phages in natural settings individually and as a cocktail. • Apparent long-term persistence of phages in natural soils, various temperatures, and pH. • An effective approach for developing phages for biocontrol.

Dual-functional alginate and collagen-based injectable hydrogel for the treatment of cancer and its metastasis.

BACKGROUND: Immunotherapies have been gaining attention for the prevention of cancer recurrence and metastasis. Cancer immunotherapy can induce memory cells to target cancer-specific antigens and, thus, selectively kill cancer cells. However, there are difficulties in inducing cancer antigen-specific immunity due to limited knowledge regarding cancer antigens. In this study, we synthesized a dual-functional hydrogel to induce antigen generation and immune activation. RESULTS: To elicit a cancer self-antigen-specific immune response, we synthesized an alginate-collagen-based injectable hydrogel, called thermally responsive hydrogel (pTRG), which was incorporated with indocyanine green and the immune stimulator polyinosinic:polycytidylic acid (poly I:C). pTRG was evaluated for its anticancer and anti-metastatic effects against CT-26 carcinoma and 4T1 breast tumor in mice by combining photothermal therapy (PTT) and immunotherapy. Near-infrared (NIR) irradiation promoted temperature elevation in pTRG, consequently exerting a therapeutic effect on mouse tumors. Lung metastasis was prevented in cured CT-26 tumor-injected mice following pTRG treatment via cancer antigen-specific T cell immunity. Moreover, pTRG successfully eliminated the original tumor in 4T1 tumor-bearing mice via PTT and protected them from lung metastasis. To further evaluate the carrier function of TRGs, different types of immunotherapeutic molecules were incorporated into TRGs, which led to the effective elimination of the first CT-26 tumor and the prevention of lung metastasis. CONCLUSIONS: Our data demonstrate that TRG is a efficient material not only for treating primary tumors but also for preventing metastasis and recurrence.