High CD34-positive cell dose in matched unrelated donor allogeneic hematopoietic stem cell transplant is not associated with graft-versus-host disease or mortality.

BACKGROUND: CD34+ stem cells serve as the primary graft source for allogeneic transplants, with a minimum of 2-4 × 106 cells/kg needed for engraftment. There are conflicting data on outcomes at high stem cell doses, with studies limited by few patients receiving doses far above the minimum target. STUDY DESIGN AND METHODS: In this retrospective, single-center study of patients with hematologic malignancies who underwent matched unrelated donor transplants, we assessed outcomes for engraftment, survival, relapse, and graft-versus-host disease (GVHD) for the highest CD34+ dose quintile (>13 × 106 cells/kg, n = 36) compared to the remaining patients (n = 139). Similar analysis was performed correlating T cell dose and outcomes. RESULTS: There was no difference between the groups in neutrophil engraftment, with a trend toward faster platelet engraftment. There was no significant difference in mortality (adjusted risk ratio [aRR] = 1.02, 95% confidence interval [CI] = 0.85-1.22), relapse (aRR = 1.10, 95% CI = 0.85-1.42), or overall survival by Kaplan-Meier analysis (p = .44). High CD34+ dose was not associated with higher incidence of acute GVHD (aRR = 0.99 grades II-IV, aRR = 1.18 grades III-IV) or chronic GVHD (aRR = 0.87 overall, RR = 1.21 severe). There was limited correlation between CD34+ and T cell dose (R2 = .073), and there was no significant difference in survival, relapse, or GVHD in the highest T cell dose quintile (n = 33) compared to the remaining quintiles (n = 132). DISCUSSION: We found no difference in survival, relapse, or GVHD incidence or severity in patients receiving CD34+ doses above prior cutoffs reported in the literature. These data do not support the routine use of graft CD34+ dose reduction.

Veterinary students are willing to accept job flexibility by trading off some salary.

OBJECTIVE: To determine the value veterinary students place on nonpecuniary job benefits related to working arrangements. SAMPLE: 381 companion animal-focused veterinary students at 14 US veterinary colleges. METHODS: We employed a survey with a choice-based conjoint experiment. The experimental data were analyzed with a random parameter logit model, from which willingness to accept was calculated. RESULTS: The results indicated that students would prefer working 4 days a week and closer to 40 hours per week, with 13 days of paid time off. Flexible working arrangements were valued from approximately $1,500 to $3,400, depending on the attribute being analyzed. Paid time off was most highly valued. CLINICAL RELEVANCE: These results will help employers better identify the current preferences of soon-to-be associate veterinarians and can match job offer/working arrangements to enhance recruitment and retention within veterinary practices.

Differential G protein activation by the long and short isoforms of the dopamine D2 receptor.

BACKGROUND AND PURPOSE: The dopamine D2 receptor is expressed as a short (D2S) and a long (D2L) isoform with 29 additional amino acids in the third intracellular loop. The D2S isoform shows higher presynaptic expression than the D2L isoform, and decreased D2S expression has recently been linked to an increased risk for schizophrenia. Here, we present the first investigation, at receptor isoform level, of kinetic differences in the G protein activation profiles of the D2S, compared with the D2L isoform. EXPERIMENTAL APPROACH: We employed a NanoBRET-based approach to G protein dissociation to interrogate the time-resolved coupling profile of 3×HA-tagged D2L and D2S to Gαi/o/z proteins in vitro. KEY RESULTS: Using dopamine as a D2 receptor agonist, we observed a more pronounced activation of Gαo and Gαz than Gαi proteins by D2L compared with D2S. This differentiation was not observed for D2S, which activated Gαo and Gαz with lower efficacy than D2L. These signalling differences were preserved on second messenger level and were not due to differences in receptor expression. Expanding to a set of seven full and partial D2 receptor agonists showed these effects were not restricted to dopamine but rather a mutual, receptor-associated property. Contrasting this trend, we found that D2S activated G proteins faster than D2L upon full receptor activation. CONCLUSION AND IMPLICATIONS: The findings highlight that both D2L and D2S are mechanistically able to activate all non-visual Gαi/o proteins. Thereby, they add to previous reports about isoform-specificity to certain Gαi/o proteins observed in specific cell types.

Patterns of Hemorrhagic Disease in White-Tailed Deer (Odocoileus Virginianus) in the Great Plains of the USA, 1982-2020.

Hemorrhagic disease (HD) of deer is caused by epizootic hemorrhagic disease virus (EHDV) or bluetongue virus (BTV) and is considered one of the most important viral diseases of white-tailed deer (Odocoileus virginianus). Despite evidence of changing patterns of HD in the northeastern and upper midwestern US, the historical and current patterns of HD in the Great Plains remain poorly described. We used results from an annual survey documenting HD mortality to characterize historic and current patterns of HD in the northern and central Great Plains (North Dakota, South Dakota, Nebraska, Kansas, and Oklahoma), US, between 1982 and 2020. Further, we assessed temporal change using linear regression to determine change in annual reporting intensity (percentage of counties in a state with reported HD) and change in reporting frequency (the number of years a county or state reported HD) during each decade between 1982 and 2020. Across the 38-yr study period, HD reports expanded northeast across latitude and longitude. Intensity of HD reports significantly increased during this period for three (North Dakota, South Dakota, Kansas) of five states examined. Frequency of reports also increased for all five states. Such changes in northern latitudes might lead to increased deer mortality in regions where HD epizootics have been historically less frequent. Understanding how patterns of HD are changing on the landscape is important when considering future deer management in the face of other mortality factors.

Partnership building for scale-up in the Veteran Sponsorship Initiative: Strategies for harnessing collaboration to accelerate impact in suicide prevention.

OBJECTIVE: To evaluate the implementation and trust-building strategies associated with successful partnership formation in scale-up of the Veteran Sponsorship Initiative (VSI), an evidence-based suicide prevention intervention enhancing connection to U.S. Department of Veterans Affairs (VA) and other resources during the military-to-civilian transition period. DATA SOURCES AND STUDY SETTING: Scaling VSI nationally required establishing partnerships across VA, the U.S. Department of Defense (DoD), and diverse public and private Veteran-serving organizations. We assessed partnerships formalized with a signed memorandum during pre- and early implementation periods (October 2020-October 2022). To capture implementation activities, we conducted 39 periodic reflections with implementation team members over the same period. STUDY DESIGN: We conducted a qualitative case study evaluating the number of formalized VSI partnerships alongside directed qualitative content analysis of periodic reflections data using Atlas.ti 22.0. DATA COLLECTION/EXTRACTION METHODS: We first independently coded reflections for implementation strategies, following the Expert Recommendations for Implementing Change (ERIC) taxonomy, and for trust-building strategies, following the Theoretical Model for Trusting Relationships and Implementation; a second round of inductive coding explored emergent themes associated with partnership formation. PRINCIPAL FINDINGS: During this period, VSI established 12 active partnerships with public and non-profit agencies. The VSI team reported using 35 ERIC implementation strategies, including building a coalition and developing educational and procedural documents, and trust-building strategies including demonstrating competence and credibility, frequent interactions, and responsiveness. Cultural competence in navigating DoD and VA and accepting and persisting through conflict also appeared to support scale-up. CONCLUSIONS: VSI's partnership-formation efforts leveraged a variety of implementation strategies, particularly around strengthening stakeholder interrelationships and refining procedures for coordination and communication. VSI implementation activities were further characterized by an intentional focus on trust-building over time. VSI's rapid scale-up highlights the value of partnership formation for achieving coordinated interventions to address complex problems.

Material Flow Analysis and Occupational Exposure Assessment in Additive Manufacturing End-of-Life Material Management.

Additive manufacturing (AM) offers a variety of material manufacturing techniques for a wide range of applications across many industries. Most efforts at process optimization and exposure assessment for AM are centered around the manufacturing process. However, identifying the material allocation and potentially harmful exposures in end-of-life (EoL) management is equally crucial to mitigating environmental releases and occupational health impacts within the AM supply chain. This research tracks the allocation and potential releases of AM EoL materials within the US through a material flow analysis. Of the generated AM EoL materials, 58% are incinerated, 33% are landfilled, and 9% are recycled by weight. The generated data set was then used to examine the theoretical occupational hazards during AM EoL material management practices through generic exposure scenario assessment, highlighting the importance of ventilation and personal protective equipment at all stages of AM material management. This research identifies pollution sources, offering policymakers and stakeholders insights to shape pollution prevention and worker safety strategies within the US AM EoL management pathways.

Interstitial Lung Disease and Progressive Pulmonary Fibrosis: a World Trade Center Cohort 20-Year Longitudinal Study.

PURPOSE: World Trade Center (WTC) exposure is associated with obstructive airway diseases and sarcoidosis. There is limited research regarding the incidence and progression of non-sarcoidosis interstitial lung diseases (ILD) after WTC-exposure. ILD encompasses parenchymal diseases which may lead to progressive pulmonary fibrosis (PPF). We used the Fire Department of the City of New York's (FDNY's) WTC Health Program cohort to estimate ILD incidence and progression. METHODS: This longitudinal study included 14,525 responders without ILD prior to 9/11/2001. ILD incidence and prevalence were estimated and standardized to the US 2014 population. Poisson regression modeled risk factors, including WTC-exposure and forced vital capacity (FVC), associated with ILD. Follow-up time ended at the earliest of incident diagnosis, end of study period/case ascertainment, transplant or death. RESULTS: ILD developed in 80/14,525 FDNY WTC responders. Age, smoking, and gastroesophageal reflux disease (GERD) prior to diagnosis were associated with incident ILD, though FVC was not. PPF developed in 40/80 ILD cases. Among the 80 cases, the average follow-up time after ILD diagnosis was 8.5 years with the majority of deaths occurring among those with PPF (PPF: n = 13; ILD without PPF: n = 6). CONCLUSIONS: The prevalence of post-9/11 ILD was more than two-fold greater than the general population. An exposure-response gradient could not be demonstrated. Half the ILD cases developed PPF, higher than previously reported. Age, smoking, and GERD were risk factors for ILD and PPF, while lung function was not. This may indicate that lung function measured after respirable exposures would not identify those at risk for ILD or PPF.

Cardiac lipotoxicity and fibrosis underlie impaired contractility in a mouse model of metabolic dysfunction-associated steatotic liver disease.

The leading cause of death among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte-specific peroxisome proliferator-activated receptor alpha knockout (Ppara HepKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. The goal of the present study was to determine mechanisms that underlie hepatic steatosis-induced cardiac dysfunction in Ppara HepKO mice. Experiments were performed in 30-week-old Ppara HepKO and littermate control mice fed regular chow. We observed decreased cardiomyocyte contractility (0.17 ± 0.02 vs. 0.24 ± 0.02 µm, p < 0.05), increased cardiac triglyceride content (0.96 ± 0.13 vs. 0.68 ± 0.06 mM, p < 0.05), collagen type 1 (4.65 ± 0.25 vs. 0.31 ± 0.01 AU, p < 0.001), and collagen type 3 deposition (1.32 ± 0.46 vs. 0.05 ± 0.03 AU, p < 0.05). These changes were associated with increased apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (30.9 ± 4.7 vs. 13.1 ± 0.8%, p < 0.006) and western blots showing increased cleaved caspase-3 (0.27 ± 0.006 vs. 0.08 ± 0.01 AU, p < 0.003) and pro-caspase-3 (5.4 ± 1.5 vs. 0.5 ± 0.3 AU, p < 0.02), B-cell lymphoma protein 2-associated X (0.68 ± 0.07 vs. 0.04 ± 0.04 AU, p < 0.001), and reduced B-cell lymphoma protein 2 (0.29 ± 0.01 vs. 1.47 ± 0.54 AU, p < 0.05). We further observed elevated circulating natriuretic peptides and exercise intolerance in Ppara HepKO mice when compared to controls. Our data demonstrated that lipotoxicity, and fibrosis underlie cardiac dysfunction in MASLD.

Predicting operative outcomes of total shoulder arthroplasty using the model for end-stage liver disease score.

Background: The aim of this study was to assess the efficacy of the Model for End-Stage Liver Disease (MELD) score in predicting postoperative complications following total shoulder arthroplasty (TSA). Methods: The American College of Surgeons National Surgical Quality Improvement database was queried for all patients who underwent TSA between 2015 and 2019. The study population was subsequently classified into two categories: those with a MELD score ≥ 10 and those with a MELD score < 10. A total of 5265 patients undergoing TSA between 2015 and 2019 were included in this study. Among these, 4690 (89.1%) patients had a MELD score ≥ 10, while 575 (10.9%) patients had a MELD score < 10. Postoperative complications within 30 days of the TSA were collected. Multivariate logistic regression analysis was conducted to explore the correlation between a MELD score ≥ 10 and postoperative complications. The anchor based optimal cutoff was calculated by receiver operating characteristic analysis to determine the MELD score cutoff that most accurately predicts a specific complication. Youden's index (J) determined the optimal cutoff point calculation for the maximum sensitivity and specificity; these were deemed to be "acceptable" if the area under curve (AUC) was greater than 0.7 and "excellent" if greater than 0.8. Results: Multivariate regression analysis found a MELD score ≥ 10 to be independently associated with higher rates of reoperation (OR, 2.08; P = .013), cardiac complications (OR, 3.37; P = .030), renal complications (OR, 7.72; P = .020), bleeding transfusions (OR, 3.23; P < .001), and nonhome discharge (OR, 1.75; P < .001). The receiver operating characteristic analysis showed that AUC for a MELD score cutoff of 7.61 as a predictor of renal complications was 0.87 (excellent) with sensitivity of 100.0% and specificity of 70.0%. AUC for a MELD score cutoff of 7.76 as a predictor of mortality was 0.76 (acceptable) with sensitivity of 81.8% and specificity of 71.0%. Conclusion: A MELD score ≥ 10 was correlated with high rates of reoperation, cardiac complications, renal complications, bleeding transfusions, and nonhome discharge following TSA. MELD score cutoffs of 7.61 and 7.76 were effective in predicting renal complications and mortality, respectively.

The role of hypertensive status in the preoperative patient selection of TSA.

Background: This study investigates the relationship between hypertension and postoperative complications following total shoulder arthroplasty (TSA). Methods: All patients who underwent TSA between 2015 and 2020 from the American College of Surgeons National Surgical Quality Improvement database were surveyed. The study population was divided into patients with no hypertension and patients with hypertension. Patient demographics, comorbidities, and 30-day postoperative complications were collected. Logistic regression analysis was used to investigate the relationship between hypertension and postoperative complications. Results: Compared to no hypertension, hypertension was significantly associated with an increased likelihood of experiencing sepsis (P = .021), pneumonia (P = .019), myocardial infarction (P = .038), blood transfusions (P = .006), readmission (P < .001), reoperation (P < .001), non-home discharge (P < .001), and any complication (P < .001). After accounting for significant patient variables, compared to no hypertension, hypertension was independently significantly associated with an increased likelihood of experiencing reoperation (odds ratio 1.48; 95% CI, 1.142-1.905; P = .003) and any complication (odds ratio 1.10; 95% CI, 1.008-1.205; P = .033). Conclusion: In this study, we identified hypertension as an independent significant predictor for both reoperation and any complication following TSA. This study provides evidence for incorporating a patient's hypertensive status into preoperative screening, aiming to improve surgical candidate selection and surgical outcomes following TSA.

Cumulative effect of chronic dehydration and age on postoperative complications after total shoulder arthroplasty.

Background: Dehydration is a modifiable risk factor that should be optimized prior to all surgical procedures. The aim of this study was to determine the effects of dehydration on postoperative complications following total shoulder arthroplasty (TSA). Methods: The American College of Surgeons National Surgical Quality Improvement database was queried for all patients who underwent TSA between 2015 and 2019 and a total of 16,993 patients were included in this study. The study population was subsequently classified into 3 categories: 8498 (50.0%) nondehydrated patients with blood urea nitrogen/creatinine (BUN/Cr) < 20, 4908 (28.9%) moderately dehydrated patients with 20 ≤ BUN/Cr ≤ 25, and 3587 (21.1%) severely dehydrated patients with 25 < BUN/Cr. A subgroup analysis involving only elderly patients aged > 65 years and normalized gender-adjusted Cr values was also performed. Postoperative complications within 30 days of the TSA were collected. Multivariate logistic regression analysis was conducted to explore the correlation between dehydration and postoperative complications. Results: Adjusted multivariate logistic regression analysis showed that the severely dehydrated cohort had a greater risk of postoperative transfusion, mortality, nonhome discharge, and increased length of stay (all P < .05). The moderately dehydrated cohort had a greater risk of wound dehiscence (P = .044). Among the elderly, severely dehydrated patients had a greater risk of cardiac complications, postoperative transfusion, mortality, nonhome discharge, and increased length of stay (all P < .05). Finally, the elderly moderately dehydrated cohort had a greater risk of postoperative transfusion and nonhome discharge (all P < .05). Conclusion: BUN/Cr ratio is an important preoperative diagnostic tool to identify at-risk dehydrated patients. Providers should optimize dehydration to prevent complications, decrease costs, and improve discharge planning.

The incidence of neurological complications in mechanically ventilated COVID-19 ICU patients: An observational single-center cohort study in three COVID-19 periods.

BACKGROUND: Neurological complications in COVID-19 patients admitted to an intensive care unit (ICU) have been previously reported. As the pandemic progressed, therapeutic strategies were tailored to new insights. This study describes the incidence, outcome, and types of reported neurological complications in invasively mechanically ventilated (IMV) COVID-19 patients in relation to three periods during the pandemic. METHODS: IMV COVID-19 ICU patients from the Dutch Maastricht Intensive Care COVID (MaastrICCht) cohort were included in a single-center study (March 2020 - October 2021). Demographic, clinical, and follow-up data were collected. Electronic medical records were screened for neurological complications during hospitalization. Three distinct periods (P1, P2, P3) were defined, corresponding to periods with high hospitalization rates. ICU survivors with and without reported neurological complications were compared in an exploratory analysis. RESULTS: IMV COVID-19 ICU patients (n=324; median age 64 [IQR 57-72] years; 238 males (73.5%)) were stratified into P1 (n=94), P2 (n=138), and P3 (n=92). ICU mortality did not significantly change over time (P1=38.3%; P2=41.3%; P3=37.0%; p=.787). The incidence of reported neurological complications during ICU admission gradually decreased over the periods (P1=29.8%; P2=24.6%; P3=18.5%; p=.028). Encephalopathy/delirium (48/324 (14.8%)) and ICU-acquired weakness (32/324 (9.9%)) were most frequently reported and associated with ICU treatment intensity. ICU survivors with neurological complications (n=53) were older (p=.025), predominantly male (p=.037), and had a longer duration of IMV (p<.001) and ICU stay (p<.001), compared to survivors without neurological complications (n=132). A multivariable analysis revealed that only age was independently associated with the occurrence of neurological complications (ORadj=1.0541; 95% CI=1.0171-1.0925; p=.004). Health-related quality-of-life at follow-up was not significantly different between survivors with and without neurological complications (n = 82, p=.054). CONCLUSIONS: A high but decreasing incidence of neurological complications was reported during three consecutive COVID-19 periods in IMV COVID-19 patients. Neurological complications were related to the intensity of ICU support and treatment, and associated with prolonged ICU stay, but did not lead to significantly worse reported health-related quality-of-life at follow-up.

Highly variable timing renders immunotherapy efficacy and toxicity impractical biomarkers of one another in clinical practice.

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Intracerebral Hemorrhage in a Patient With Newly Diagnosed Immune Thrombocytopenic Purpura Precipitated by a Viral Illness.

Intracerebral hemorrhage (ICH) is a rare and severe complication of immune thrombocytopenic purpura (ITP) that can be spontaneous. Viral illnesses, other infections, autoimmune disorders, and medications can cause ITP. ITP causes a significant decrease in platelet levels, increasing bleeding risk. ITP can be treated by steroids, intravenous immunoglobulin, plasmapheresis, platelet transfusion, biological agents, and splenectomy. ICH treatment involves the treatment of underlying ITP, as well as any neuro-interventional procedures needed. In this case report, we look at the presenting symptoms and treatment course of an interesting case of ICH in a patient who developed ITP after a viral upper respiratory infection.

Comparative Genitourinary Safety of In-class Sodium-Glucose Cotransporter-2 Inhibitors among Patients with Heart Failure with Preserved Ejection Fraction: A Cohort Study.

PURPOSE: The American Heart Association recommended sodium-glucose cotransporter-2 inhibitors (SGLT2i) for the management of heart failure with preserved ejection fraction (HFpEF). However, little is known about their real-world in-class comparative safety in patients with HFpEF. We aimed to assess the comparative safety of SGLT2i in the risk of urinary tract infection (UTI) or genital infection separately or as a composite outcome among patients with HFpEF. METHODS: This cohort study using MarketScan® Commercial and Medicare supplemental databases (2012-2020) included patients aged ≥ 18 years with a diagnosis of HFpEF who initiated SGLT2i therapy. Three pairwise comparison groups were established: cohort 1, dapagliflozin versus canagliflozin; cohort 2, empagliflozin versus canagliflozin; and cohort 3, dapagliflozin versus empagliflozin. After stabilized inverse probability treatment weighting, Cox proportional hazards regression was used to compare the risk of UTI or genital infection separately or as a composite outcome in each cohort. RESULTS: The risk of the composite outcome did not significantly differ between canagliflozin and dapagliflozin (adjusted hazard ratio [aHR] 0.64; 95% confidence interval [CI] 0.36-1.14) or between empagliflozin and canagliflozin (aHR 1.25; 95% CI 0.77-2.05). Similarly, there was no evidence of difference between dapagliflozin and empagliflozin in this risk (aHR 0.76; 95% CI 0.48-1.21). The results of analyses separately assessing UTI or genital infection were similar. CONCLUSIONS: There was no significant difference in the risk of UTI or genital infection among patients with HFpEF who initiated canagliflozin, dapagliflozin, or empagliflozin.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are used for the management of heart failure with preserved ejection fraction (HFpEF). It is important to assess their comparative risk of urinary tract infection (UTI) or genital infection among patients with HFpEF. We compared patients with HFpEF using SGLT2i in three pairwise groups: cohort 1, dapagliflozin versus canagliflozin; cohort 2, empagliflozin versus canagliflozin; and cohort 3, dapagliflozin versus empagliflozin. We found that there was no significant difference in the risk of genitourinary infections including UTI or genital infections among dapagliflozin, empagliflozin, and canagliflozin.

Vaccination for healthy aging.

As the world's population grows older, vaccination is becoming a key strategy for promoting healthy aging. Despite scientific progress in adult vaccine development, obstacles such as immunosenescence and vaccine hesitancy remain. To unlock the potential of adult vaccines fully, we must enhance immunization programs, dispel misinformation, and invest in research that deepens our understanding of aging and immunity.

Edible mycelium as proliferation and differentiation support for anchorage-dependent animal cells in cultivated meat production.

Cultivated meat production requires bioprocess optimization to achieve cell densities that are multiple orders of magnitude higher compared to conventional cell culture techniques. These processes must maximize resource efficiency and cost-effectiveness by attaining high cell growth productivity per unit of medium. Microcarriers, or carriers, are compatible with large-scale bioreactor use, and offer a large surface-area-to-volume ratio for the adhesion and proliferation of anchorage-dependent animal cells. An ongoing challenge persists in the efficient retrieval of cells from the carriers, with conflicting reports on the effectiveness of trypsinization and the need for additional optimization measures such as carrier sieving. To surmount this issue, edible carriers have been proposed, offering the advantage of integration into the final food product while providing opportunities for texture, flavor, and nutritional incorporation. Recently, a proof of concept (POC) utilizing inactivated mycelium biomass derived from edible filamentous fungus demonstrated its potential as a support structure for myoblasts. However, this POC relied on a model mammalian cell line combination with a single mycelium species, limiting realistic applicability to cultivated meat production. This study aims to advance the POC. We found that the species of fungi composing the carriers impacts C2C12 myoblast cell attachment-with carriers derived from Aspergillus oryzae promoting the best proliferation. C2C12 myoblasts effectively differentiated on mycelium carriers when induced in myogenic differentiation media. Mycelium carriers also supported proliferation and differentiation of bovine satellite cells. These findings demonstrate the potential of edible mycelium carrier technology to be readily adapted in product development within the cultivated meat industry.

COVID-19 vaccine hesitancy prevalence in Mexico: A systematic review and metanalysis.

Background: Vaccine hesitancy (VH) is a recognized threat to public health that undermines efforts to mitigate disease burden. This study aims to gather available evidence regarding COVID-19 VH in Mexico, estimate the prevalence of VH, and its determinants to inform policymaking in this country. Methods: Following PRISMA guidelines, a systematic review of the MEDLINE literature, articles that estimated the prevalence of COVID-19 VH in Mexico were included in the analysis to obtain a pooled estimate. We used a binomial-normal model for meta-analysis of proportions (i.e., generalized linear mixed model) to perform the metanalysis. We then performed a narrative review of COVID-19 VH in Mexican subpopulations. Results: Seven studies met inclusion criteria. We estimated a pooled prevalence of COVID-19 VH of 16 % (95 % CI: 11-23 %) in Mexico. We found an association between VH and demographic characteristics, intrinsic vaccine factors, and beliefs. Subgroup analyses from specific studies suggested that patients with clinical conditions such as breast cancer or rheumatologic diseases had a higher prevalence of VH. Conclusions: VH is a highly complex and dynamic phenomenon in Mexico. Characterizing and understanding COVID-19 vaccine hesitancy in the Mexican population helps target future policy interventions to mitigate the spread and impact of infectious diseases. The implications of VH differ among groups that may be at higher risk of severe disease, underscoring the importance of prompt research among these groups as well as targeted interventions to address VH.

Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Cohort profile: the Environmental Reproductive and Glucose Outcomes (ERGO) Study (Boston, Massachusetts, USA) - a prospective pregnancy cohort study of the impacts of environmental exposures on parental cardiometabolic health.

PURPOSE: Pregnancy and the postpartum period are increasingly recognised as sensitive windows for cardiometabolic disease risk. Growing evidence suggests environmental exposures, including endocrine-disrupting chemicals (EDCs), are associated with an increased risk of pregnancy complications that are associated with long-term cardiometabolic risk. However, the impact of perinatal EDC exposure on subsequent cardiometabolic risk post-pregnancy is less understood. The Environmental Reproductive and Glucose Outcomes (ERGO) Study was established to investigate the associations of environmental exposures during the perinatal period with post-pregnancy parental cardiometabolic health. PARTICIPANTS: Pregnant individuals aged ≥18 years without pre-existing diabetes were recruited at <15 weeks of gestation from Boston, Massachusetts area hospitals. Participants completed ≤4 prenatal study visits (median: 12, 19, 26, 36 weeks of gestation) and 1 postpartum visit (median: 9 weeks), during which we collected biospecimens, health histories, demographic and behavioural data, and vitals and anthropometric measurements. Participants completed a postpartum fasting 2-hour 75 g oral glucose tolerance test. Clinical data were abstracted from electronic medical records. Ongoing (as of 2024) extended post-pregnancy follow-up visits occur annually following similar data collection protocols. FINDINGS TO DATE: We enrolled 653 unique pregnancies and retained 633 through delivery. Participants had a mean age of 33 years, 10% (n=61) developed gestational diabetes and 8% (n=50) developed pre-eclampsia. Participant pregnancy and postpartum urinary phthalate metabolite concentrations and postpartum glycaemic biomarkers were quantified. To date, studies within ERGO found higher exposure to phthalates and phthalate mixtures, and separately, higher exposure to radioactive ambient particulate matter, were associated with adverse gestational glycaemic outcomes. Additionally, certain personal care products used in pregnancy, notably hair oils, were associated with higher urinary phthalate metabolite concentrations, earlier gestational age at delivery and lower birth weight. FUTURE PLANS: Future work will leverage the longitudinal data collected on pregnancy and cardiometabolic outcomes, environmental exposures, questionnaires, banked biospecimens and paediatric data within the ERGO Study.