Study on the Association between Cesarean Section Birth and Asthma Risk in the Pediatric Population of the Health Area of Palencia between 1993 and 2020.

INTRODUCTION AND OBJECTIVES: Both asthma prevalence and the percentage of cesarean sections have increased in parallel in recent years. Research studies suggest an increased risk of developing atopic diseases and asthma after cesarean section birth compared to vaginal delivery. The main objective of this study is to analyze the risk of asthma admission after cesarean section birth compared to vaginal delivery in the pediatric population. POPULATION AND METHODS: Retrospective observational analytical case-control study from 1993 to 2020. The cases include all admitted patients to our health area hospital, for patients aged 7 to 16 diagnosed with asthma. For each case, a control without a diagnosis of asthma is selected with the same age, and that has also caused an episode of admission. RESULTS: A total of 290 admission episodes with a diagnosis of asthma were obtained, caused by 155 patients. Out of these, 145 cases with documented delivery types were selected. For cases, 155 controls were selected. The historical proportion of cesarean sections in the asthmatic group is 18.6%, compared to 14.2% in the non-asthmatic group. There is a statistically non-significant difference of 4.4% more cesarean sections in the asthmatic group compared to the control group. DISCUSSION: We have not demonstrated a statistically significant association between being born by cesarean section and an increased risk of asthma admission. Based on this finding, we cannot conclude that there is an association between being born by cesarean section and a higher risk of suffering from asthma, unlike what has been postulated in other research studies.

Holmium laser enucleation of the prostate (HoLEP) in short-circuit outpatient care: Is prostatic volume a limiting factor?

INTRODUCTION AND OBJECTIVES: Our goals were to study prostatic volume as a limiting factor after HoLEP surgery with short-circuit outpatient care (4 h) and to define other factors that affect the success of the proposed circuit. MATERIALS AND METHODS: An observational analysis and review was performed using a prospective database. Preoperative, intraoperative, and postoperative variables were included for patients who were scheduled for short-circuit outpatient care (SCOC) and who underwent HoLEP between 2020 and 2023. We defined SCOC as a postoperative hospital stay of 4 h. Subjects who required more than 4 h in hospital were categorized as conventional hospital admission (CHA). A descriptive populational study was conducted, expressing the mean using a 95% confidence interval and percentages for the continuous variables. In order to analyze them, we used the Student's t-test for the continuous variables and the chi-squared test for the categorical variables. RESULTS: Sixty-eight patients were included, 54 of which completed SCOC, which represented a success ratio of 79.5%. The mean age and prostatic volume of the whole cohort were 68.9 (±6.8) years and 79.5 (±29.1) mL, respectively. We found no significant differences in age, prostatic volume, antiplatelet drug use, indwelling bladder catheter, or applied energy among the subjects who completed SCOC and those who required CHA. No patient was presented with a complication of Grade 3 (or higher) in the modified Clavien-Dindo classification. At the six-month follow-up, no differences were observed in the uroflowmetry or International Prostate Symptoms Score variables. CONCLUSIONS: Prostatic volume does not seem to be a limiting factor after undergoing HoLEP with short-circuit outpatient care.

Thickness of the abdominal wall and pelvic floor dysfunctions in men who practice crossfit vs no crossfit: An observational study.

INTRODUCTION: The objective of this study is to compare the thickness of the transverse abdominis, internal oblique, external oblique, rectus abdominis, and rectus abdominis distance, the quality of life (SF-36), the presence of chronic pelvic pain (CPPQ-Mohedo), and sexual dysfunction (IIEF) in men who practice CrossFit® versus men who do not. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURES: Sixty-four healthy men with an average age of 37.19 were recruited at a private sports club and divided into two groups for this cross-sectional observational study. Additionally, participants completed the CPPQ-M, IIEF, and SF-36 questionnaires. RESULTS: Significant differences were found in the thickness of the internal oblique at rest (p = 0.018, d = 0.61), which was greater in the CrossFit® group. In the SF-36 quality of life questionnaire (p = 0.05, d = 0.50), the CrossFit® group also obtained a higher score. CONCLUSION: CrossFit® improves the quality of life and self-esteem of the participants, in addition to increasing the thickness of the internal oblique. Neither more chronic pelvic pain nor more erectile dysfunction was observed in the CrossFit® group.

Generating universal anti-CD19 CAR T cells with a defined memory phenotype by CRISPR/Cas9 editing and safety evaluation of the transcriptome.

Introduction: Chimeric antigen receptor-expressing T cells (CAR T cells) have revolutionized cancer treatment, particularly in B cell malignancies. However, the use of autologous T cells for CAR T therapy presents several limitations, including high costs, variable efficacy, and adverse effects linked to cell phenotype. Methods: To overcome these challenges, we developed a strategy to generate universal and safe anti-CD19 CAR T cells with a defined memory phenotype. Our approach utilizes CRISPR/Cas9 technology to target and eliminate the B2M and TRAC genes, reducing graft-versus-host and host-versus-graft responses. Additionally, we selected less differentiated T cells to improve the stability and persistence of the universal CAR T cells. The safety of this method was assessed using our CRISPRroots transcriptome analysis pipeline, which ensures successful gene knockout and the absence of unintended off-target effects on gene expression or transcriptome sequence. Results: In vitro experiments demonstrated the successful generation of functional universal CAR T cells. These cells exhibited potent lytic activity against tumor cells and a reduced cytokine secretion profile. The CRISPRroots analysis confirmed effective gene knockout and no unintended off-target effects, validating it as a pioneering tool for on/off-target and transcriptome analysis in genome editing experiments. Discussion: Our findings establish a robust pipeline for manufacturing safe, universal CAR T cells with a favorable memory phenotype. This approach has the potential to address the current limitations of autologous CAR T cell therapy, offering a more stable and persistent treatment option with reduced adverse effects. The use of CRISPRroots enhances the reliability and safety of gene editing in the development of CAR T cell therapies. Conclusion: We have developed a potent and reliable method for producing universal CAR T cells with a defined memory phenotype, demonstrating both efficacy and safety in vitro. This innovative approach could significantly improve the therapeutic landscape for patients with B cell malignancies.

Open innovation and confidentiality agreements as key factors of innovative performance in the manufacturing and service industries.

The innovative performance of manufacturing and service companies can be impacted by the existing relationship between open innovation (OI) and the generation of confidentiality agreements (NDAs) as a tool for the protection of intellectual property. Based on the analysis of a cross-sectional sample of 6,798 industrial companies (2019-2020) and 9,304 companies in the service sector (2017-2019) that are part of the directory of the National Administrative Department of Statistics (DANE) in its Technological Innovation and Development Survey (EDIT and EDITS), it can be suggested that the interaction of these two variables (OI and NDAs) generate positive effects for the manufacturing industry but negative ones for the service sector. It could be deduced that the positive effect is due to the greater tradition of OI in the manufacturing industry and the negative effect to the caution that the service sector presents when collaborating with external actors.

Malaria in a vulnerable population living in quilombo remnant communities in the Brazilian Amazon: a cross-sectional study from 2005-2020.

Quilombo remnant communities are areas officially recognized by the Brazilian government as historical communities founded by formerly enslaved individuals. These communities are mostly located in the endemic areas of malaria in the Brazilian Amazon. We retrospectively described the prevalence of malaria among individuals living in 32 recognized quilombo remnant communities in the Baiao and Oriximina municipalities located in the Para State. The number of malaria cases and the Annual Parasitic Incidence (API) recorded by the Brazilian malaria surveillance system (SIVEP-Malaria) from January 2005 to December 2020 were analyzed. We found that all communities registered at least one case over the 16-year period, the most frequent parasitic species being Plasmodium vivax (76.1%). During this period, 0.44% (4,470/1,008,714) of the malaria cases registered in Para State were reported in these quilombo remnant communities, with frequencies of 10.9% (856/7,859) in Baiao municipality and 39.1% (3,614/9,238) in Oriximina municipality, showing that individuals living in these rural communities are exposed to malaria. These data indicate that effective surveillance requires improved measures to identify malaria transmission among vulnerable populations living in quilombo remnant communities in the Brazilian Amazon.

Integration of ζ-deficient CARs into the CD3ζ gene conveys potent cytotoxicity in T and NK cells.

ABSTRACT: Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Random gene transfer modalities pose a risk of malignant transformation by insertional mutagenesis. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3ζ (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3ζ gene as the CAR's activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR expression and redirection of various immune cell types, including conventional T cells, TCRγ/δ T cells, regulatory T cells, and NK cells. In T cells, CD3ζ in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3ζ-CD19-CAR-T cells exhibited comparable leukemia control to TCRα chain constant (TRAC)-replaced and lentivirus-transduced CAR-T cells in vivo. Tuning of CD3ζ-CAR-expression levels significantly improved the in vivo efficacy. Notably, CD3ζ gene editing enabled redirection of NK cells without impairing their canonical functions. Thus, CD3ζ gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes.

Genomic and transcriptomic characterization of methylmercury detoxification in a deep ocean Alteromonas mediterranea ISS312.

Methylmercury (MeHg) is one of the most worrisome pollutants in marine systems. MeHg detoxification is mediated by merB and merA genes, responsible for the demethylation of MeHg and the reduction of inorganic mercury, respectively. Little is known about the biological capacity to detoxify this compound in marine environments, and even less the bacterial transcriptional changes during MeHg detoxification. This study provides the genomic and transcriptomic characterization of the deep ocean bacteria Alteromonas mediterranea ISS312 with capacity for MeHg degradation. Its genome sequence revealed four mer operons containing three merA gene and two merB gene copies, that could be horizontally transferred among distant related genomes by mobile genetic elements. The transcriptomic profiling in the presence of 5 µM MeHg showed that merA and merB genes are within the most expressed genes, although not all mer genes were equally transcribed. Besides, we aimed to identify functional orthologous genes that displayed expression profiles highly similar or identical to those genes within the mer operons, which could indicate they are under the same regulatory controls. We found contrasting expression profiles for each mer operon that were positively correlated with a wide array of functions mostly related to amino acid metabolism, but also to flagellar assembly or two component systems. Also, this study highlights that all merAB genes of the four operons were globally distributed across oceans layers with higher transcriptional activity in the mesopelagic deeper waters. Our study provides new insights about the transcriptional patterns related to the capacity of marine bacteria to detoxify MeHg, with important implications for the understanding of this process in marine ecosystems.

MgO/KH2PO4 and Curing Moisture Content in MKPC Matrices to Optimize the Immobilization of Pure Al and Al-Mg Alloys.

Magnesium Potassium Phosphate Cements (MKPCs) are considered a good alternative for the immobilization of aluminium radioactive waste. MKPC composition and moisture curing conditions are relevant issues to be evaluated. The corrosion of pure aluminium (A1050) and AlMg alloys (AA5754) with 3.5% of Mg is studied in MKPC systems prepared with different MgO/KH2PO4 (M/P) molar ratios (1, 2, and 3M) and moisture curing conditions (100% Relative Humidity (RH) and isolated in plastic containers (endogenous curing)). The Al corrosion potential (Ecorr) and corrosion kinetic (icorr and Vcorr) are evaluated over 90 days. Additionally, the pore ion evolution, the matrix electrical resistance, the pore structure, and compressive strength are analysed. The corrosion process of Al alloy is affected by the pH and ion content in the pore solution. The pore pH increases from near neutral for the 1M M/P ratio to 9 and 10 for the 2 and 3M M/P ratio, increasing in the same way the corrosion of pure Al (AA1050) and AlMg alloys (AA5754). The effect of Mg content in the alloy (AA5754) becomes more relevant with the increase in the M/P ratio. The presence of phosphate ions in the pore solution inhibits the corrosion process in both Al alloys. The MKPC physicochemical stability improved with the increase in the M/P ratio, higher mechanical strength, and more refined pore structure.

Relationship between Nutrition and Development of the Jaws in Children: A Pilot Study.

Craniofacial growth and development have been shown to be influenced by various environmental factors that impact child development. This study aims to analyze the different patterns of feeding during early childhood, starting from birth, and assess the variability of nutrition during the first stage of childhood, along with the habits developed, to study their impact on jaw development. The study was conducted on a sample of twenty-five patients aged 3 to 5, following approval from the ethics committee of the Catholic University of Valencia. Informed consent was obtained from the fathers, mothers, and/or legal guardians, who were administered surveys on habits and diet. Cephalometric measurements within the parameters of ideal occlusion were subsequently taken. While previous studies examined this subject, the findings are challenging to evaluate. However, this study identified significant associations (p = 0.001) between clinical measurements and children's eating habits. The growth and development of the craniofacial cavity are influenced by multiple factors, including a child's diet and habits. Nonetheless, further research is required to determine whether diet can be considered a determining factor in proper jaw growth.

In Vitro Evaluation of Soft Contact Lens Wettability With a Nonmodified Commercial Videokeratoscope.

PURPOSE: To evaluate a new in vitro technique for measuring soft contact lens wettability using a nonmodified commercial videokeratoscope, the Medmont E300. To this end, the capability of different artificial tears containing hyaluronic acid (HA) to improve soft contact lens wettability in vitro was investigated. METHODS: An experimental in vitro study was conducted to assess the wetting properties of three artificial tears containing different concentrations of HA (0.1%, 0.2%, and 0.3%) on soft contact lenses. A saline solution was used as the control. For each solution, 15 hydrogel (Ocufilcon D) contact lenses and 15 silicone-hydrogel (Somofilcon A) contact lenses were evaluated. The in vitro wettability of the lenses was measured using the Medmont E300 with a self-developed technique, which involved measuring the tear film surface quality (TFSQ) mean, TFSQ area, TFSQ central, and TFSQ inferior. RESULTS: Compared with the saline solution, all the concentration of HA (0.1%, 0.2%, and 0.3%) improved the in vitro wettability of both soft contact lenses by decreasing their TFSQ mean and TFSQ area ( P <0.05). Regression models revealed an exponential relationship between contact lens wettability and the concentration of HA for both soft contact lenses ( R >0.5, P <0.05). Furthermore, the hydrogel contact lens presented a wetter surface than the silicone-hydrogel contact lens ( P <0.05). CONCLUSIONS: The measurement of in vitro wettability of soft contact lenses with a nonmodified Medmont E300 seems to be a useful technique to evaluate the wetting properties of contact lens products.

Unmasking the physiology of mercury detoxifying bacteria from polluted sediments.

Marine sediments polluted from anthropogenic activities can be major reservoirs of toxic mercury species. Some microorganisms in these environments have the capacity to detoxify these pollutants, by using the mer operon. In this study, we characterized microbial cultures isolated from polluted marine sediments growing under diverse environmental conditions of salinity, oxygen availability and mercury tolerance. Specific growth rates and percentage of mercury removal were measured in batch cultures for a selection of isolates. A culture affiliated with Pseudomonas putida (MERCC_1942), which contained a mer operon as well as other genes related to metal resistances, was selected as the best candidate for mercury elimination. In order to optimize mercury detoxification conditions for strain MERCC_1942 in continuous culture, three different dilution rates were tested in bioreactors until the cultures achieved steady state, and they were subsequently exposed to a mercury spike; after 24 h, strain MERCC_1942 removed up to 76% of the total mercury. Moreover, when adapted to high growth rates in bioreactors, this strain exhibited the highest specific mercury detoxification rates. Finally, an immobilization protocol using the sol-gel technology was optimized. These results highlight that some sediment bacteria show capacity to detoxify mercury and could be used for bioremediation applications.

Cannabis use disorder contributes to cognitive dysfunction in Veterans with traumatic brain injury.

Background: While emerging evidence supports a link between traumatic brain injury (TBI) and progressive cognitive dysfunction in Veterans, there is insufficient information on the impact of cannabis use disorder (CUD) on long-term cognitive disorders. This study aimed to examine the incidences of cognitive disorders in Veterans with TBI and CUD and to evaluate their relationship. Methods: This retrospective cohort study used the US Department of Veterans Affairs and Department of Defense administrative data from the Long-term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium Phenotype study. Diagnoses suggesting cognitive disorders after a TBI index date were identified using inpatient and outpatient data from 2003 to 2022. We compared the differential cognitive disorders incidence in Veterans who had the following: (1) no CUD or TBI (control group), (2) CUD only, (3) TBI only, and (4) comorbid CUD+TBI. Kaplan-Meier analyses were used to estimate the overall cognitive disorders incidence in the above study groups. The crude and adjusted Cox proportional hazards models were used to estimate crude and adjusted hazard ratios (HRs) for cognitive disorders. Results: A total of 1,560,556 Veterans [82.32% male, median (IQR) age at the time of TBI, 34.51 (11.29) years, and 61.35% white] were evaluated. The cognitive disorder incidence rates were estimated as 0.68 (95% CI, 0.62, 0.75) for CUD only and 1.03 (95% CI, 1.00, 1.06) for TBI only per 10,000 person-months of observations, with the highest estimated cognitive disorder incidence observed in participants with both TBI and CUD [1.83 (95% CI, 1.72, 1.95)]. Relative to the control group, the highest hazard of cognitive disorders was observed in Veterans with CUD+TBI [hazard ratio (HR), 3.26; 95% CI, 2.91, 3.65], followed by those with TBI only (2.32; 95 CI%, 2.13, 2.53) and with CUD (1.79; 95 CI%, 1.60, 2.00). Of note, in the CUD only subgroup, we also observed the highest risk of an early onset cognitive disorder other than Alzheimer's disease and Frontotemporal dementia. Discussion: The results of this analysis suggest that individuals with comorbid TBI and CUD may be at increased risk for early onset cognitive disorders, including dementia.

Racial/Ethnic and Geographic Disparities in Comorbid Traumatic Brain Injury-Renal Failure in US Veterans and Associated Veterans Affairs Resource Costs, 2000-2020.

Studies have identified disparities by race/ethnicity and geographic status among veterans with traumatic brain injury (TBI) and renal failure (RF). We examined the association of race/ethnicity and geographic status with RF onset in veterans with and without TBI, and the impact of disparities on Veterans Health Administration resource costs. METHODS: Demographics by TBI and RF status were assessed. We estimated Cox proportional hazards models for progression to RF and generalized estimating equations for inpatient, outpatient, and pharmacy cost annually and time since TBI + RF diagnosis, stratified by age. RESULTS: Among 596,189 veterans, veterans with TBI progressed faster to RF than those without TBI (HR 1.96). Non-Hispanic Black veterans (HR 1.41) and those in US territories (HR 1.71) progressed faster to RF relative to non-Hispanic Whites and those in urban mainland areas. Non-Hispanic Blacks (-$5,180), Hispanic/Latinos ($-4,984), and veterans in US territories (-$3,740) received fewer annual total VA resources. This was true for all Hispanic/Latinos, while only significant for non-Hispanic Black and US territory veterans < 65 years. For veterans with TBI + RF, higher total resource costs only occurred ≥ 10 years after TBI + RF diagnosis ($32,361), independent of age. Hispanic/Latino veterans ≥ 65 years received $8,248 less than non-Hispanic Whites and veterans living in US territories < 65 years received $37,514 less relative to urban veterans. CONCLUSION: Concerted efforts to address RF progression in veterans with TBI, especially in non-Hispanic Blacks and those in US territories, are needed. Importantly, culturally appropriate interventions to improve access to care for these groups should be a priority of the Department of Veterans Affairs priority for these groups.

Oscillatory vs. non-oscillatory subthalamic beta activity in Parkinson's disease.

Parkinson's disease is characterized by exaggerated beta activity (13-35 Hz) in cortico-basal ganglia motor loops. Beta activity includes both periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and excitation/inhibition balance (i.e. non-oscillatory activity). However, the relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non-oscillatory beta activity remain unclear. We recorded, modelled and analysed subthalamic local field potentials in parkinsonian patients at rest while off or on medication. Autoregressive modelling with additive 1/f noise clarified the relationships between measures of beta activity in the time domain (i.e. amplitude and duration of beta bursts) or in the frequency domain (i.e. power and sharpness of the spectral peak) and oscillatory vs. non-oscillatory activity: burst duration and spectral sharpness are specifically sensitive to oscillatory activity, whereas burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non-oscillatory activity. Our experimental data confirmed the model predictions and assumptions. We subsequently analysed the effect of levodopa, obtaining strong-to-extreme Bayesian evidence that oscillatory beta activity is reduced in patients on vs. off medication, with moderate evidence for absence of modulation of the non-oscillatory component. Finally, specifically the oscillatory component of beta activity correlated with the rate of motor progression of the disease. Methodologically, these results provide an integrative understanding of beta-based biomarkers relevant for adaptive deep brain stimulation. Biologically, they suggest that primarily the oscillatory component of subthalamic beta activity is dopamine dependent and may play a role not only in the pathophysiology but also in the progression of Parkinson's disease. KEY POINTS: Beta activity in Parkinson's disease includes both true periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and synaptic balance (i.e. non-oscillatory activity). The relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non-oscillatory beta activity remain unclear. Burst duration and spectral sharpness are specifically sensitive to oscillatory activity, while burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non-oscillatory activity. Only the oscillatory component of subthalamic beta activity is dopamine-dependent. Stronger beta oscillatory activity correlates with faster motor progression of the disease.

Malaria in a vulnerable population living in quilombo remnant communities in the Brazilian Amazon: a cross-sectional study from 2005-2020

ABSTRACT Quilombo remnant communities are areas officially recognized by the Brazilian government as historical communities founded by formerly enslaved individuals. These communities are mostly located in the endemic areas of malaria in the Brazilian Amazon. We retrospectively described the prevalence of malaria among individuals living in 32 recognized quilombo remnant communities in the Baiao and Oriximina municipalities located in the Para State. The number of malaria cases and the Annual Parasitic Incidence (API) recorded by the Brazilian malaria surveillance system (SIVEP-Malaria) from January 2005 to December 2020 were analyzed. We found that all communities registered at least one case over the 16-year period, the most frequent parasitic species being Plasmodium vivax (76.1%). During this period, 0.44% (4,470/1,008,714) of the malaria cases registered in Para State were reported in these quilombo remnant communities, with frequencies of 10.9% (856/7,859) in Baiao municipality and 39.1% (3,614/9,238) in Oriximina municipality, showing that individuals living in these rural communities are exposed to malaria. These data indicate that effective surveillance requires improved measures to identify malaria transmission among vulnerable populations living in quilombo remnant communities in the Brazilian Amazon.

Integration of ζ-deficient CARs into the CD3-zeta gene conveys potent cytotoxicity in T and NK cells.

Chimeric antigen receptor (CAR)-reprogrammed immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in non-physiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3 ζ (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3 ζ gene as the CAR's activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR-expression and reprogramming of various immune cell types, including conventional T cells, TCRγ/δ T cells, regulatory T cells, and NK cells. In T cells, CD3 ζ in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3 ζ-CD19-CAR-T cells exhibited comparable leukemia control to T cell receptor alpha constant ( TRAC )-replaced and lentivirus-transduced CAR-T cells in vivo . Tuning of CD3 ζ-CAR-expression levels significantly improved the in vivo efficacy. Compared to TRAC -edited CAR-T cells, integration of a Her2-CAR into CD3 ζ conveyed similar in vitro tumor lysis but reduced susceptibility to activation-induced cell death and differentiation, presumably due to lower CAR-expression levels. Notably, CD3 ζ gene editing enabled reprogramming of NK cells without impairing their canonical functions. Thus, CD3 ζ gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes. Key points: Integration of ζ-deficient CARs into CD3 ζ gene allows generation of functional TCR-ablated CAR-T cells for allogeneic off-the-shelf use CD3 ζ-editing platform allows CAR reprogramming of NK cells without affecting their canonical functions.

Co-occurring implementation strategies: The effects of academic detailing for opioid use disorder campaign on the advancing pharmacological treatments for opioid use disorder (ADaPT-OUD) study.

Background: Barriers at the system, clinician, and patient level limit access to medications for opioid use disorder (MOUD). The Advancing Pharmacological Treatments for Opioid Use Disorder (ADaPT-OUD) study implemented an external facilitation strategy within the Veterans Health Administration (VHA) aimed at facility-level barriers to improve uptake of MOUD. During ADaPT-OUD, an independent Academic Detailing Services Opioid Agonist Treatment of OUD Campaign was co-occurring and aimed to increase evidence-based practice for OUD at the clinician level. While both these initiatives aim to increase MOUD reach, they address different barriers and did not intentionally collaborate. Thus, understanding the interaction between these two independent implementation initiatives and their effect on MOUD reach will further inform and mold future implementation efforts of MOUD. Methods: This was a secondary analysis of the ADaPT-OUD study that included 35 VHA facilities in the lowest quartile of MOUD reach; eight received the ADaPT-OUD external facilitation and 27 matched sites received implementation as usual. The number of academic detailing (AD) visits during ADaPT-OUD was used as a proxy for the intensity of Academic Detailing for OUD Campaign activity. The interaction between external facilitation status and AD intensity was evaluated by comparing the change in facility-level MOUD reach. Results: There was a general increase in the number of AD visits, in both external facilitation and implementation as usual sites, over the course of ADaPT-OUD's implementation period. A non-statistically significant, positively sloped, linear relationship was observed between average number of AD visits per quarter and change in MOUD reach in facilities also receiving ADaPT-OUD external facilitation that was not observed in the implementation as usual sites. Conclusion: Co-occurring initiatives focusing on different barriers to MOUD access have the potential to further increase MOUD in low-performing facilities, but further research into timing, quality, and collaboration between initiatives are warranted.

Medication treatment of opioid use disorder (MOUD) is a key element in addressing the opioid epidemic. The development, approval, and effectiveness of buprenorphine and naltrexone have expanded access to MOUD from specialty opioid treatment programs to office-based treatment. However, uptake of these evidence-based treatments across the Veterans Health Administration (VHA) is variable. To address this gap in care within the VHA, The Advancing Pharmacological Treatment for Opioid Use Disorder (ADaPT-OUD) study implemented an external facilitation strategy aimed at facility-level barriers at low-adopting VHA facilities while the VHA Pharmacy Benefits Management Academic Detailing Services Opioid Agonist Treatment of OUD Campaign implemented academic detailing with the goal to address clinician-level barriers. This article evaluates the effect these two co-occurring and independent initiatives had on each other and MOUD reach. The results suggest a trend toward a positive synergistic relationship between the two initiatives, that warrants further study and evaluation to inform further implementation efforts.

Costs of implementing a multi-site facilitation intervention to increase access to medication treatment for opioid use disorder.

BACKGROUND: The United States has been grappling with the opioid epidemic, which has resulted in over 75,000 opioid-related deaths between April 2020 and 2021. Evidence-based pharmaceutical interventions (buprenorphine, methadone, and naltrexone) are available to reduce opioid-related overdoses and deaths. However, adoption of these medications for opioid use disorder has been stifled due to individual- and system-level barriers. External facilitation is an evidence-based implementation intervention that has been used to increase access to medication for opioid use disorder (MOUD), but the implementation costs of external facilitation have not been assessed. We sought to measure the facility-level direct costs of implementing an external facilitation intervention for MOUD to provide decision makers with estimates of the resources needed to implement this evidence-based program. METHODS: We performed a cost analysis of the pre-implementation and implementation phases, including an itemization of external facilitation team and local site labor costs. We used labor estimates from the Bureau of Labor and Statistics, and sensitivity analyses were performed using labor estimates from the Veterans Health Administration (VHA) Financial Management System general ledger data. RESULTS: The average total costs for implementing an external facilitation intervention for MOUD per site was $18,847 (SD 6717) and ranged between $11,320 and $31,592. This translates to approximately $48 per patient with OUD. Sites with more encounters and participants with higher salaries in attendance had higher costs. This was driven mostly by the labor involved in planning and implementation activities. The average total cost of the pre-implementation and implementation activities were $1031 and $17,816 per site, respectively. In the sensitivity analysis, costs for VHA were higher than BLS estimates likely due to higher wages. CONCLUSIONS: Implementing external facilitation to increase MOUD prescribing may be affordable depending on the payer's budget constraints. Our study reported that there were variations in the time invested at each phase of implementation and the number and type of participants involved with implementing an external facilitation intervention. Participant composition played an important role in total implementation costs, and decision makers will need to identify the most efficient and optimal number of stakeholders to involve in their implementation plans.

Healthcare costs and use before and after opioid overdose in Veterans Health Administration patients with opioid use disorder.

AIMS: To compare healthcare costs and use between United States (US) Veterans Health Administration (VHA) patients with opioid use disorder (OUD) who experienced an opioid overdose (OD cohort) and patients with OUD who did not experience an opioid overdose (non-OD cohort). DESIGN: This is a retrospective cohort study of administrative and clinical data. SETTING: The largest integrated national health-care system is the US Veterans Health Administration's healthcare systems. PARTICIPANTS: We included VHA patients diagnosed with OUD from October 1, 2017 through September 30, 2018. We identified the index date of overdose for patients who had an overdose. Our control group, which included patients with OUD who did not have an overdose, was randomly assigned an index date. A total of 66 513 patients with OUD were included for analysis (OD cohort: n = 1413; non-OD cohort: n = 65 100). MEASUREMENTS: Monthly adjusted healthcare-related costs and use in the year before and after the index date. We used generalized estimating equation models to compare patients with an opioid overdose and controls in a difference-in-differences framework. FINDINGS: Compared with the non-OD cohort, an opioid overdose was associated with an increase of $16 890 [95% confidence interval (CI) = $15 611-18 169; P < 0.001] in healthcare costs for an estimated $23.9 million in direct costs to VHA (95% CI = $22.1 million, $25.7 million) within the 30 days following overdose after adjusting for baseline characteristics. Inpatient costs ($13 515; 95% CI = $12 378-14 652; P < 0.001) reflected most of this increase. Inpatient days (+6.15 days; 95% CI, = 5.33-6.97; P < 0.001), inpatient admissions (+1.01 admissions; 95% CI = 0.93-1.10; P < 0.001) and outpatient visits (+1.59 visits; 95% CI = 1.34-1.84; P < 0.001) also increased in the month after opioid overdose. Within the overdose cohort, healthcare costs and use remained higher in the year after overdose compared with pre-overdose trends. CONCLUSIONS: The US Veterans Health Administration patients with opioid use disorder (OUD) who have experienced an opioid overdose have increased healthcare costs and use that remain significantly higher in the month and continuing through the year after overdose than OUD patients who have not experienced an overdose.