Excess prevalence of preexisting chronic conditions in older adults with incident epilepsy.

OBJECTIVE: Prior studies have examined chronic conditions in older adults with prevalent epilepsy, but rarely among those with incident epilepsy. Identifying the chronic conditions with which older adults present at epilepsy incidence assists with the evaluation of disease burden in this patient population and informs coordinated care development. The aim of this study was to identify preexisting chronic conditions with excess prevalence in older adults with incident epilepsy compared to those without. METHODS: Using a random sample of 4 999 999 fee-for-service Medicare beneficiaries aged >65 years, we conducted a retrospective cohort study of epilepsy incidence in 2019. Non-Hispanic Black and Hispanic beneficiaries were oversampled. We identified preexisting chronic conditions from the 2016-2018 Medicare Beneficiary Summary Files and compared chronic condition prevalence between Medicare beneficiaries with and without incident epilepsy in 2019. We characterized variations in preexisting excess chronic condition prevalence by age, sex, and race/ethnicity, adjusting for the racial/ethnic oversampling. RESULTS: We observed excess prevalence of most preexisting chronic conditions in beneficiaries with incident epilepsy (n = 20 545, weighted n = 19 631). For stroke, for example, the adjusted prevalence rate ratio (APRR) was 4.82 (99% CI:4.60, 5.04), meaning that, compared to those without epilepsy, beneficiaries with incident epilepsy in 2019 had 4.82 times the stroke prevalence. Similarly, beneficiaries with incident epilepsy had a higher prevalence rate for preexisting neurological conditions (APRR = 3.17, 99% CI = 3.08-3.27), substance use disorders (APRR = 3.00, 99% CI = 2.81-3.19), and psychiatric disorders (APRR = 1.98, 99% CI = 1.94-2.01). For most documented chronic conditions, excess prevalence among beneficiaries with incident epilepsy in 2019 was larger for younger age groups compared to older age groups, and for Hispanic beneficiaries compared to both non-Hispanic White and non-Hispanic Black beneficiaries. SIGNIFICANCE: Compared to epilepsy-free Medicare beneficiaries, those with incident epilepsy in 2019 had a higher prevalence of most preexisting chronic conditions. Our findings highlight the importance of health promotion and prevention, multidisciplinary care, and elucidating shared pathophysiology to identify opportunities for prevention.

Understanding the Utility of Less Than Six-Month Prognosis Using Administrative Data Among U.S. Nursing Home Residents With Cancer.

Background: There is a dearth of studies evaluating the utility of reporting prognostication among nursing home (NH) residents with cancer. Objective: To study factors associated with documented less than six-month prognosis, and its relationship with end-of-life (EOL) care quality measures among residents with cancer. Methods: The Surveillance, Epidemiology, and End Results linked with Medicare, and the Minimum Data Set databases was used to identify 20,397 NH residents in the United States with breast, colorectal, lung, pancreatic, or prostate cancer who died between July 2016 and December 2018. Of these, 2205 residents (10.8%) were documented with less than six-month prognosis upon NH admission. Main outcomes were more than one hospitalization, more than one emergency department visit, and any intensive care unit admission within the last 30 days of life as aggressive EOL care markers, as well as admission to hospice, receipt of advance care planning and palliative care, and survival. Specificity and sensitivity of prognosis were assessed using six-month mortality as the outcome. Propensity score matching adjusted for selection biases, and logistic regression examined association. Results: Specificity and sensitivity of documented less than six-month prognosis for mortality were 94.2% and 13.7%, respectively. Residents with documented less than six-month prognosis had greater odds of being admitted to hospice than those without (adjusted odds ratio: 3.27, 95% confidence interval: 2.86-3.62), and lower odds to receive aggressive EOL care. Conclusion: In this cohort study, documented less than six-month prognosis was associated with less aggressive EOL care. Despite its high specificity, however, low sensitivity limits its utility to operationalize care on a larger population of residents with terminal illness.

Comparing the use of aggressive end-of life care among frail and non-frail patients with cancer using a claims-based frailty index.

INTRODUCTION: Despite mounting consensus that end-of-life (EOL) care for patients with cancer should focus on improving quality of life, many patients continue to receive aggressive, disease-oriented treatment until death. Within this group, patients with increased frailty may be at higher risk of adverse treatment-related outcomes. We therefore examined the relationship between degree of frailty and receipt of aggressive EOL care among Medicare-insured patients with cancer in Ohio. MATERIALS AND METHODS: From the Ohio Cancer Incidence Surveillance System (OCISS) linked with Medicare claims, we identified patients diagnosed with breast, colorectal, lung, or prostate cancer who died between 2012 and 2016. Frailty was operationalized using a validated claims-based frailty index. Six quality indicators reflecting receipt of aggressive EOL care were identified from claims: (1) any cancer-directed treatment, (2) >1 emergency department (ED) visit, (3) >1 hospital admission, (4) any intensive care unit (ICU) admission in the last 30 days of life, (5) entry to hospice in the last three days of life, and (6) in-hospital mortality. Multivariable logistic regression analysis was performed to control for demographic factors, Medicare and Medicaid dual enrollment, and cancer type and stage in the relationship between frailty and aggressive EOL care. RESULTS: Overall, 31,465 patients met selection criteria. Patients with moderate/severe frailty were less likely than non-/pre-frail patients to receive any aggressive EOL care (adjusted odds ratio [aOR] 0.92 [95% confidence interval 0.86-0.99]). This group was also less likely to undergo cancer-directed treatment in their last 30 days or to enter hospice in their last three days. Increasing frailty was associated with lower odds of admission to the ICU in the last 30 days of life (mild frailty: aOR 0.88 [0.83-0.94]; moderate/severe frailty: aOR 0.85 [0.78-0.92]) or of dying in-hospital (mild frailty: 0.85 [0.79-0.91]; moderate/severe frailty: aOR 0.74 [0.67-0.82]), but higher odds of having >1 ED visit in the last 30 days of life (mild frailty: aOR 1.43 [1.32-1.53]; moderate/severe frailty: aOR 1.61 [1.47-1.77]). DISCUSSION: These findings suggest the need for more explicit discussion of emergency care seeking for patients with cancer at the end of life.

Aggressive end-of-life care across gradients of cognitive impairment in nursing home patients with metastatic cancer.

BACKGROUND: Studies examining end-of-life (EOL) care in older cancer patients are scarce, and prior studies have not accounted for gradients of cognitive impairment (COG-I). We examine EOL care patterns across COG-I gradients, hypothesizing that greater COG-I severity is associated with lower odds of receiving aggressive EOL care. METHODS: Using data from the linked Surveillance Epidemiology and End Results (SEER) -Medicare -Minimum Data Set (MDS) 3.0, we identified patients with nursing facility stays (NFS) and who died with metastatic cancer from 2013 to 2017. Markers of aggressive EOL care were: cancer-directed treatment, intensive care unit admission, >1 emergency department visit, or >1 hospitalization in the last 30 days of life, hospice enrollment in the last 3 days of life, and in-hospital death. In addition to descriptive analysis, we conducted multivariable logistic regression analysis to evaluate the independent association between COG-I severity and receipt of aggressive EOL care. RESULTS: Of the 40,833 patients in our study population, 49.2% were cognitively intact; 24.4% had mild COG-I; 19.7% had moderate COG-I; and 6.7% had severe COG-I. The percent of patients who received aggressive EOL care was 62.6% and 74.2% among those who were cognitively intact and those with severe COG-I, respectively. Compared with cognitively intact patients, those with severe COG-I had 86% higher odds of receiving any type of aggressive EOL care (adjusted odds ratio (aOR): 1.86 (95% confidence interval: 1.70-2.04)), which were primarily associated with higher odds of in-hospital death. The odds of in-hospital death associated with severe COG-I were higher among those with short- than with long-term stays (aOR:2.58 (2.35-2.84) and aOR:1.40 (1.17-1.67), respectively). CONCLUSIONS: Contrary to our hypothesis, aggressive EOL care in older metastatic cancer patients with NFS was highest among those suffering severe COG-I. These findings can inform the development of interventions to help reduce aggressive EOL care in this patient population.

Ibrutinib Is Associated With Increased Cardiovascular Events and Major Bleeding in Older CLL Patients.

Background: Early ibrutinib trials showed an association between ibrutinib use and risk of bleeding and atrial fibrillation (AF) in younger chronic lymphocytic leukemia (CLL) patients. Little is known about these adverse events in older CLL patients and whether increased AF rates are associated with increased stroke risk. Objectives: To compare the incidence of stroke, AF, myocardial infarction, and bleeding in CLL patients treated with ibrutinib with those who were treated without ibrutinib in a linked SEER-Medicare database. Methods: The incidence rate of each adverse event for treated and untreated patients was calculated. Among those treated, inverse probability weighted Cox proportional hazards regression models were used to calculate HRs and 95% CIs for the association between ibrutinib treatment and each adverse event. Results: Among 4,958 CLL patients, 50% were treated without ibrutinib and 6% received ibrutinib. The median age at first treatment was 77 (IQR: 73-83) years. Compared with those treated without ibrutinib, those treated with ibrutinib had a 1.91-fold increased risk of stroke (95% CI: 1.06-3.45), 3.65-fold increased risk of AF (95% CI: 2.42-5.49), a 4.92-fold increased risk of bleeding (95% CI: 3.46-7.01) and a 7.49-fold increased risk of major bleeding (95% CI: 4.32-12.99). Conclusions: In patients a decade older than those in the initial clinical trials, treatment with ibrutinib was associated with an increased risk of stroke, AF, and bleeding. The risk of major bleeding is higher than previously reported and underscores the importance of surveillance registries to identify new safety signals.

Incidence of Aggressive End-of-Life Care Among Older Adults With Metastatic Cancer Living in Nursing Homes and Community Settings.

Importance: Nearly 10% of the 1.5 million persons residing in nursing homes (NHs) have received or will receive a diagnosis of cancer. Although aggressive end-of-life (EOL) care is common among community-dwelling patients with cancer, little is known about such patterns of care among NH residents with cancer. Objective: To compare markers of aggressive EOL care between older adults with metastatic cancer who are NH residents and their community-dwelling counterparts. Design, Setting, and Participants: This cohort study used the Surveillance, Epidemiology, and End Results database linked with the Medicare database and the Minimum Data Set (including NH clinical assessment data) for deaths occurring from January 1, 2013, to December 31, 2017, among 146 329 older patients with metastatic breast, colorectal, lung, pancreas, or prostate cancer, with a lookback period in claims data through July 1, 2012. Statistical analysis was conducted between March 2021 and September 2022. Exposures: Nursing home status. Main Outcomes and Measures: Markers of aggressive EOL care were cancer-directed treatment, intensive care unit admission, more than 1 emergency department visit or more than 1 hospitalization in the last 30 days of life, hospice enrollment in the last 3 days of life, and in-hospital death. Results: The study population included 146 329 patients 66 years of age or older (mean [SD] age, 78.2 [7.3] years; 51.9% men). Aggressive EOL care was more common among NH residents than community-dwelling residents (63.6% vs 58.3%). Nursing home status was associated with 4% higher odds of receiving aggressive EOL care (adjusted odds ratio [aOR], 1.04 [95% CI, 1.02-1.07]), 6% higher odds of more than 1 hospital admission in the last 30 days of life (aOR, 1.06 [95% CI, 1.02-1.10]), and 61% higher odds of dying in the hospital (aOR, 1.61 [95% CI, 1.57-1.65]). Conversely, NH status was associated with lower odds of receiving cancer-directed treatment (aOR, 0.57 [95% CI, 0.55-0.58]), intensive care unit admission (aOR, 0.82 [95% CI, 0.79-0.84]), or enrollment in hospice in the last 3 days of life (aOR, 0.89 [95% CI, 0.86-0.92]). Conclusions and Relevance: Despite increased emphasis to reduce aggressive EOL care in the past several decades, such care remains common among older persons with metastatic cancer and is slightly more prevalent among NH residents than their community-dwelling counterparts. Multilevel interventions to decrease aggressive EOL care should target the main factors associated with its prevalence, including hospital admissions in the last 30 days of life and in-hospital death.

Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer.

Importance: Professional society guidelines recommend treating patients with metastatic colorectal cancer with targeted therapies, including epithelial growth factor receptor (EGFR) inhibitors and vascular endothelial growth factor (VEGF) inhibitors, depending on the presence or absence of certain mutations. Since most studies of first-line targeted therapies have been limited by sample size, there is a need for larger studies using data from routine clinical care. Objectives: To identify factors associated with receipt of first-line targeted therapies among patients with metastatic colorectal cancer for whom RAS or BRAF mutation data in the tumor were available and investigate whether targeted therapy is associated with survival. Design, Setting, and Participants: This cohort study used deidentified data from an electronic health record-derived database to include patients from 800 sites of patient care across the US who were diagnosed with de novo metastatic colorectal cancer between January 1, 2013, and March 31, 2020 (n = 9134). Main Outcomes and Measures: Receipt of first-line targeted therapy, categorized as ever having received EGFR inhibitors, VEGF inhibitors, or neither. The secondary outcome was overall survival. Results: The study population included 9134 patients. The median age at diagnosis was 62 years (IQR, 53-71 years), 5019 (54.9%) were male, and 5692 (62.3%) were White. The median follow-up period was 15 months. Overall, 713 patients (7.8%) received EGFR inhibitors and 5081 patients (55.6%) received VEGF inhibitors as part of their first-line treatment. Among patients with RAS wild-type (RAS-WT) tumors, 625 patients (15.5%) received EGFR inhibitors and 2053 patients (50.9%) received VEGF inhibitors. In patients with RAS mutant (RAS-Mut) tumors, 50 patients (1.1%) received EGFR inhibitors and 2682 patients (59.7%) received VEGF inhibitors; among those with BRAF-mutant (BRAF-Mut) tumors, 38 patients (6.3%) received EGFR inhibitors and 346 patients (57.2%) received VEGF inhibitors. More than one-third of the patients (36.6%) received neither EGFR inhibitors nor VEGF inhibitors. Compared with patients younger than age 40 years, those aged 80 years or older had significantly lower odds to receive targeted therapies (EGFR or VEGF inhibitors in patients with RAS-WT tumors: adjusted odds ratio [aOR], 0.53; 95% CI, 0.36-0.79; and VEGF inhibitors in patients with RAS-Mut tumors: aOR, 0.62; 95% CI, 0.42-0.90). Improved survival was associated with EGFR inhibitor therapy in patients with RAS-WT tumors (adjusted hazard ratio [aHR], 0.85; 95% CI, 0.74-0.98). Unlike in clinical trials, however, no survival benefit was noted with use of VEGF inhibitors among patients with RAS-WT (aHR, 1.00; 95% CI, 0.91-1.11) or RAS-Mut (aHR, 1.01; 95% CI, 0.93-1.10) tumors. Conclusions and Relevance: The findings of this study showed mixed results on survival benefits associated with targeted therapy. In addition, given that some of the results differed from those of randomized clinical trials, this study highlights the importance of using data originating from routine clinical care.

Pharmacokinetics derived from PET imaging of inspiring radio-enhancer platinum nanoparticles.

Personalized medicine approach in radiotherapy requires the delivery of precise dose to the tumor. The concept is to increase the effectiveness of radiotherapy while sparing the surrounding heathy tissue. This can be achieved by the use of high-Z metal-based nanoparticles (NPs) as radio-enhancers and PET imaging for mapping NPs distribution to guide the irradiation. In the present study, radio-enhancing platinum NPs were radiolabeled and imaged to assess their pharmacokinetics over time. PET imaging of these NPs revealed high enhanced permeation and retention effect. The maximal tumor accumulation (4.8 ± 0.8 %ID/cc) was observed at 24 h post-injection along with persistent accumulation of the NPs, especially at the tumor ring, even after several days. These properties positively suggest the potential clinical use of these NPs.

Impact of Radiolabeling Strategies on the Pharmacokinetics and Distribution of an Anti-PD-L1 PET Ligand.

Molecular imaging with PET offers an alternative method to quantify programmed-death-ligand 1 (PD-L1) to accurately select patients for immunotherapies. More and more clinical and preclinical trials involve radiolabeling of antibody fragments for their desirably fast clearance and high tumor penetration. As the radiolabeling strategy can significantly impact pharmacokinetics and biodistribution, we explored in this work a site-specific radiofluorination strategy on an anti-PD-L1 fragment antigen-binding (Fab) and compared the pharmacokinetic and biodistribution properties with the same Fab labeled using stochastic radiolabeling chemistry. We applied an enzymatic bioconjugation mediated by a variant of the lipoic acid ligase (LplA) that promotes the formation of an amide bond between a short peptide cloned onto the C terminus of the Fab. A synthetic analogue of the enzyme natural substrate, lipoic acid, was radiolabeled with fluorine-18 for site-specific conjugation by LplA. We compared the biodistribution of the site-specifically labeled Fab with a stochastically labeled Fab on lysine side chains in tumor-bearing mice. The two methods of fluorination demonstrate a comparable whole-body biodistribution. The 89Zr-labeled Fab had different biodistribution compared to either 18F-labeled Fab. We attribute the difference to [89Zr] metabolism. Fab-LAP-[18F]FPyOctA therefore reflects better the true pharmacokinetic profile of the Fab.

Application and validation of a biotic ligand model for calculating acute toxicity of lead to Moina dubia in lakes of Hanoi, Vietnam.

It is increasingly being recognized that biotic ligand models (BLMs) can successfully predict the toxicity of divalent metals toward aquatic biota applied to temperate freshwater ecosystems. However, studies on the eutrophic lakes in tropical regions toward native tropical organisms, including Moina, are relatively limited. In this study, Moina dubia, the native organism of the Hanoi eutrophic urban lakes, were used in toxicological studies of lead (Pb); 24-h EC50 value of Pb was 523.19 µg/L under optimal living conditions for M. dubia in the laboratory. The constant binding of Pb2+ on M. dubia surface sites (log KPbBL = 2.38) was significantly low. Other stability constants were obtained under experiments as logKCaBL = 2.48, logKMgBL = 2.80, logKNaBL = 2.35, logKKBL = 2.49, and logKHBL = 3.026. A BLM was developed to calculate the acute toxicity (EC50-24 h) of lead on M. dubia based on the condition of the urban lakes of Hanoi. Validation with toxicity data in synthetic medium showed a coefficient determination of 79.16% and a mean absolute percentage error (MAPE) of 10.2%, while the validation with the toxicity data with natural water medium from 11 Hanoi lakes showed a coefficient determination of 73.7% and a MAPE of 13.66%. The BLM worked well with water at a pH of 7.0 to 8.0, but failed with water at a pH above 8.0. Eutrophic conditions proved to have a significant effect on the toxicity of lead on local zooplankton.

Survival after traumatic out-of-hospital cardiac arrest in Vietnam: a multicenter prospective cohort study.

BACKGROUND: Pre-hospital services are not well developed in Vietnam, especially the lack of a trauma system of care. Thus, the prognosis of traumatic out-of-hospital cardiac arrest (OHCA) might differ from that of other countries. Although the outcome in cardiac arrest following trauma is dismal, pre-hospital resuscitation efforts are not futile and seem worthwhile. Understanding the country-specific causes, risk, and prognosis of traumatic OHCA is important to reduce mortality in Vietnam. Therefore, this study aimed to investigate the survival rate from traumatic OHCA and to measure the critical components of the chain of survival following a traumatic OHCA in the country. METHODS: We performed a multicenter prospective observational study of patients (> 16 years) presenting with traumatic OHCA to three central hospitals throughout Vietnam from February 2014 to December 2018. We collected data on characteristics, management, and outcomes of patients, and compared these data between patients who died before hospital discharge and patients who survived to discharge from the hospital. RESULTS: Of 111 eligible patients with traumatic OHCA, 92 (82.9%) were male and the mean age was 39.27 years (standard deviation: 16.38). Only 5.4% (6/111) survived to discharge from the hospital. Most cardiac arrests (62.2%; 69/111) occurred on the street or highway, 31.2% (29/93) were witnessed by bystanders, and 33.7% (32/95) were given cardiopulmonary resuscitation (CPR) by a bystander. Only 29 of 111 patients (26.1%) were taken by the emergency medical services (EMS), 27 of 30 patients (90%) received pre-hospital advanced airway management, and 29 of 53 patients (54.7%) were given resuscitation attempts by EMS or private ambulance. No significant difference between patients who died before hospital discharge and patients who survived to discharge from the hospital was found for bystander CPR (33.7%, 30/89 and 33.3%, 2/6, P > 0.999; respectively) and resuscitation attempts (56.3%, 27/48, and 40.0%, 2/5, P = 0.649; respectively). CONCLUSION: In this study, patients with traumatic OHCA presented to the ED with a low rate of EMS utilization and low survival rates. The poor outcomes emphasize the need for increasing bystander first-aid, developing an organized trauma system of care, and developing a standard emergency first-aid program for both healthcare personnel and the community.

Multifunctional protein 4.1R regulates the asymmetric segregation of Numb during terminal erythroid maturation.

The asymmetric cell division of stem or progenitor cells generates daughter cells with distinct fates that balance proliferation and differentiation. Asymmetric segregation of Notch signaling regulatory protein Numb plays a crucial role in cell diversification. However, the molecular mechanism remains unclear. Here, we examined the unequal distribution of Numb in the daughter cells of murine erythroleukemia cells (MELCs) that undergo DMSO-induced erythroid differentiation. In contrast to the cytoplasmic localization of Numb during uninduced cell division, Numb is concentrated at the cell boundary in interphase, near the one-spindle pole in metaphase, and is unequally distributed to one daughter cell in anaphase in induced cells. The inheritance of Numb guides this daughter cell toward erythroid differentiation while the other cell remains a progenitor cell. Mitotic spindle orientation, critical for distribution of cell fate determinants, requires complex communication between the spindle microtubules and the cell cortex mediated by the NuMA-LGN-dynein/dynactin complex. Depletion of each individual member of the complex randomizes the position of Numb relative to the mitotic spindle. Gene replacement confirms that multifunctional erythrocyte protein 4.1R (4.1R) functions as a member of the NuMA-LGN-dynein/dynactin complex and is necessary for regulating spindle orientation, in which interaction between 4.1R and NuMA plays an important role. These results suggest that mispositioning of Numb is the result of spindle misorientation. Finally, disruption of the 4.1R-NuMA-LGN complex increases Notch signaling and decreases the erythroblast population. Together, our results identify a critical role for 4.1R in regulating the asymmetric segregation of Numb to mediate erythropoiesis.

Quantitative Tissue Pharmacokinetics and EPR Effect of AGuIX Nanoparticles: A Multimodal Imaging Study in an Orthotopic Glioblastoma Rat Model and Healthy Macaque.

AGuIX are emerging radiosensitizing nanoparticles (NPs) for precision radiotherapy (RT) under clinical evaluation (Phase 2). Despite being accompanied by MRI thanks to the presence of gadolinium (Gd) at its surface, more sensitive and quantifiable imaging technique should further leverage the full potential of this technology. In this study, it is shown that 89 Zr can be labeled on such NPs directly for positron emission tomography (PET) imaging with a simple and scalable method. The stability of such complexes is remarkable in vitro and in vivo. Using a glioblastoma orthotopic rat model, it is shown that injected 89 Zr-AGuIX is detectable inside the tumor for at least 1 week. Interestingly, the particles seem to efficiently infiltrate the tumor even in necrotic areas, which places great hope for the treatment of radioresistant tumor. Lastly, the first PET/MR whole-body imaging is performed in non-human primate (NHP), which further demonstrates the translational potential of these bimodal NP.

In the interest of public safety: rapid response to the COVID-19 epidemic in Vietnam.

We describe the status of the COVID-19 epidemic in Vietnam, major response successes, factors that prompted implementation of certain public health actions, and the impact of these actions. In addition, information for three case studies is reported, with crucial learnings to inform future response. Findings from this study suggest that as early as 20 January 2020, Vietnam held a national risk assessment, established a national COVID-19 Response Plan and Technical Treatment and Care Guidelines, and prepared public health laboratories to accurately diagnose cases and hospitals to effectively treat patients. The first COVID-19 case was detected on 23 January. As of 30 September, there had been three waves of the COVID-19 epidemic totalling 1095 cases, and resulting in 35 deaths all among people with underlying health conditions. Evidence of potential transmission of SARS-CoV-2 from a commercial passenger flight inbound to Vietnam was reported. This study also highlights the importance of early technical preparedness, strong political commitment, multisectoral and multilevel efforts, increased resourcing and coordination towards an effective COVID-19 response. Controlling outbreaks in settings, such as crowded public places (bars and hospitals), within certain villages and over cities, required early detection, aggressive trace-test-quarantine efforts, a geographically extensive lockdown area and an adoption of several non-pharmaceutical interventions. Many low-income and middle-income countries have experienced their second or third wave of the COVID-19 epidemic, and they can learn from Vietnam's response across the three epidemic waves. Swift governmental action, strict border control measures, effective communication of health promotion measures, widespread community engagement, expanded testing capacity and effective social measures to slow the spread of SARS-CoV-2, are highly important in these locations.

A snake toxin as a theranostic agent for the type 2 vasopressin receptor.

Rationale: MQ1, a snake toxin which targets with high nanomolar affinity and absolute selectivity for the type 2 vasopressin receptor (V2R), is a drug candidate for renal diseases and a molecular probe for imaging cells or organs expressing V2R. Methods: MQ1's pharmacological properties were characterized and applied to a rat model of hyponatremia. Its PK/PD parameters were determined as well as its therapeutic index. Fluorescently and radioactively labeled MQ1 were chemically synthesized and associated with moderate loss of affinity. MQ1's dynamic biodistribution was monitored by positron emission tomography. Confocal imaging was used to observe the labeling of three cancer cell lines. Results: The inverse agonist property of MQ1 very efficiently prevented dDAVP-induced hyponatremia in rats with low nanomolar/kg doses and with a very large therapeutic index. PK (plasma MQ1 concentrations) and PD (diuresis) exhibited a parallel biphasic decrease. The dynamic biodistribution showed that MQ1 targets the kidneys and then exhibits a blood and kidney biphasic decrease. Whatever the approach used, we found a T1/2α between 0.9 and 3.8 h and a T1/2ß between 25 and 46 h and demonstrated that the kidneys were able to retain MQ1. Finally, the presence of functional V2R expressed at the membrane of cancer cells was, for the first time, demonstrated with a specific fluorescent ligand. Conclusion: As the most selective V2 binder, MQ1 is a new promising drug for aquaresis-related diseases and a molecular probe to visualize in vitro and in vivo V2R expressed physiologically or under pathological conditions.

Using GIS and stakeholder involvement to innovate marine mammal bycatch risk assessment in data-limited fisheries.

Fisheries bycatch has been identified as the greatest threat to marine mammals worldwide. Characterizing the impacts of bycatch on marine mammals is challenging because it is difficult to both observe and quantify, particularly in small-scale fisheries where data on fishing effort and marine mammal abundance and distribution are often limited. The lack of risk frameworks that can integrate and visualize existing data have hindered the ability to describe and quantify bycatch risk. Here, we describe the design of a new geographic information systems tool built specifically for the analysis of bycatch in small-scale fisheries, called Bycatch Risk Assessment (ByRA). Using marine mammals in Malaysia and Vietnam as a test case, we applied ByRA to assess the risks posed to Irrawaddy dolphins (Orcaella brevirostris) and dugongs (Dugong dugon) by five small-scale fishing gear types (hook and line, nets, longlines, pots and traps, and trawls). ByRA leverages existing data on animal distributions, fisheries effort, and estimates of interaction rates by combining expert knowledge and spatial analyses of existing data to visualize and characterize bycatch risk. By identifying areas of bycatch concern while accounting for uncertainty using graphics, maps and summary tables, we demonstrate the importance of integrating available geospatial data in an accessible format that taps into local knowledge and can be corroborated by and communicated to stakeholders of data-limited fisheries. Our methodological approach aims to meet a critical need of fisheries managers: to identify emergent interaction patterns between fishing gears and marine mammals and support the development of management actions that can lead to sustainable fisheries and mitigate bycatch risk for species of conservation concern.

Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using 89Zr-cetuximab.

Epidermal growth factor receptor (EGFR), involved in cell proliferation and migration, is overexpressed in ~50% of glioblastomas. Anti-EGFR based strategies using monoclonal antibodies (mAb) such as cetuximab (CTX) have been proposed for central nervous system (CNS) cancer therapy. However, the blood-brain barrier (BBB) drastically restricts their brain penetration which limits their efficacy for the treatment of glioblastomas. Herein, a longitudinal PET imaging study was performed to assess the relevance and the impact of focused ultrasound (FUS)-mediated BBB permeabilization on the brain exposure to the anti-EGFR mAb CTX over time. For this purpose, FUS permeabilization process with microbubbles was applied on intact BBB mouse brain before the injection of 89Zr-labeled CTX for longitudinal imaging monitoring. FUS induced a dramatic increase in mAb penetration to the brain, 2 times higher compared to the intact BBB. The transfer of 89Zr-CTX from blood to the brain was rendered significant by FUS (kuptake = 1.3 ± 0.23 min-1 with FUS versus kuptake = 0 ± 0.006 min-1 without FUS). FUS allowed significant and prolonged exposure to mAb in the brain parenchyma. This study confirms the potential of FUS as a target delivery method for mAb in CNS.