PfSPZ Vaccine induces focused humoral immune response in HIV positive and negative Tanzanian adults.

BACKGROUND: PfSPZ Vaccine, a promising pre-erythrocytic stage malaria vaccine candidate based on whole, radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), has proven safe and effective in mediating sterile protection from malaria in malaria-naïve and exposed healthy adults. Vaccine-induced protection presumably depends on cellular responses to early parasite liver stages, but humoral immunity contributes. METHODS: On custom-made Pf protein microarrays, we profiled IgG and IgM responses to PfSPZ Vaccine and subsequent homologous controlled human malaria infection (CHMI) in 21 Tanzanian adults with (n = 12) or without (n = 9) HIV infection. Expression of the main identified immunogens in the pre-erythrocytic parasite stage was verified by immunofluorescence detection using freshly purified PfSPZ and an in vitro model of primary human hepatocytes. FINDINGS: Independent of HIV infection status, immunisation induced focused IgG and IgM responses to circumsporozoite surface protein (PfCSP) and merozoite surface protein 5 (PfMSP5). We show that PfMSP5 is detectable on the surface and in the apical complex of PfSPZ. INTERPRETATION: Our data demonstrate that HIV infection does not affect the quantity of the total IgG and IgM antibody responses to PfCSP and PfMSP5 after immunization with PfSPZ Vaccine. PfMSP5 represents a highly immunogenic, so far underexplored, target for vaccine-induced antibodies in malaria pre-exposed volunteers. FUNDING: This work was supported by the Equatorial Guinea Malaria Vaccine Initiative (EGMVI), the Clinical Trial Platform of the German Center for Infection Research (TTU 03.702), the Swiss Government Excellence Scholarships for Foreign Scholars and Artists (grant 2016.0056) and the Interdisciplinary Center for Clinical Research doctoral program of the Tübingen University Hospital. The funders had no role in design, analysis, or reporting of this study.

Are new pediatric trauma centers located close to the high-risk populations? A geolocation study.

BACKGROUND: Higher rates of injury occur in children who live in low socioeconomic areas. Since 2010, the number of verified Level I and Level II pediatric trauma centers (PTCs) has doubled. The purpose of this study is to look at the location of new verified PTC in relation to children living in high-risk areas. METHODS: Historical and recent data about verified Level I and Level II PTCs were obtained from the American College of Surgeons (ACS), the American Trauma Society, and State Data where available. Census data were obtained from the US Census Bureau's American Community Survey for 2010 and 2020 for children younger than 18 years. The pediatric population was stratified by (1) poverty threshold and (2) living within 30 miles of PTC. The census data and trauma center locations were geocoded using the ArcGIS Pro program. Data analysis was performed at the census tract level. RESULTS: A total of 55 Level I or Level II ACS-verified PTCs were in the United States in 2010 and 116 in 2020. In 2010, there were 14.5 million children (19.6%) below the poverty threshold and 12.9 million (17.8%) in 2020. In 2010, 23 states did not have an ACS-verified PTC either in the state or in a neighboring state within 30 miles. By 2020, only nine states did not have an ACS-verified PTC or a center in a neighboring state within 30 miles. When state level data were included, this dropped to four. The 19 states who had new verified PTCs covered between 14% and 21% of children below the poverty level. The percentage of children below the poverty threshold and less than 30-mile access to a Level I or Level II PTC in 2010 was 74.56% compared with children above poverty and less than 30-mile access, which was 70.34% (p < 0.0001). In 2020, children below poverty without 30-mile access had been reduced to 52% and 45.54% for children above poverty level (p < 0.0001). Thus, there was a greater increase in 30-mile access for children above the poverty level than for those below the poverty level (24.8% vs. 22.6%, p < 0.001). CONCLUSION: On a national level, despite doubling the number of PTC, it has not improved 30-mile access for high-risk children. Alternatively, 19 states now have better access. LEVEL OF EVIDENCE: Retrospective Cohort Study, Level III.

Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study.

To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC-MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4-28 months and adults aged 19-65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable.

ROMI: a randomized two-stage basket trial design to optimize doses for multiple indications.

Optimizing doses for multiple indications is challenging. The pooled approach of finding a single optimal biological dose (OBD) for all indications ignores that dose-response or dose-toxicity curves may differ between indications, resulting in varying OBDs. Conversely, indication-specific dose optimization often requires a large sample size. To address this challenge, we propose a Randomized two-stage basket trial design that Optimizes doses in Multiple Indications (ROMI). In stage 1, for each indication, response and toxicity are evaluated for a high dose, which may be a previously obtained maximum tolerated dose, with a rule that stops accrual to indications where the high dose is unsafe or ineffective. Indications not terminated proceed to stage 2, where patients are randomized between the high dose and a specified lower dose. A latent-cluster Bayesian hierarchical model is employed to borrow information between indications, while considering the potential heterogeneity of OBD across indications. Indication-specific utilities are used to quantify response-toxicity trade-offs. At the end of stage 2, for each indication with at least one acceptable dose, the dose with highest posterior mean utility is selected as optimal. Two versions of ROMI are presented, one using only stage 2 data for dose optimization and the other optimizing doses using data from both stages. Simulations show that both versions have desirable operating characteristics compared to designs that either ignore indications or optimize dose independently for each indication.

Geographical Inequality in Access to Aortic Valve Intervention in England: A Report from the UK Transcatheter Aortic Valve Implantation Registry and National Adult Cardiac Surgery Audit.

Background: For patients with severe aortic stenosis, transcatheter aortic valve implantation (TAVI) is a less invasive but equally effective treatment option compared with surgical aortic valve replacement (SAVR). In 2019, we reported low rates of TAVI in the UK compared with other countries in western Europe and highlighted profound geographical variation in TAVI care. Here, we provide contemporary data on access to aortic valve replacement by either TAVI or SAVR across clinical commissioning groups in England. Methods: We obtained aggregated data from the UK TAVI registry and the National Adult Cardiac Surgery Audit between 2019 and 2023. Rates of TAVI and SAVR procedures per million population were reported by clinical commissioning groups. The relationship between TAVI and SAVR rates was determined using Pearson correlation coefficients. Results: In 2022/23, the rates of TAVI and SAVR in England were 136 per million population and 60 per million population, respectively. The observed increase in TAVI rates since 2019/20 corresponded with a decline in SAVR rates. There remains substantial variation in access to both procedures, with an over tenfold variation in TAVI rates, and an over fourfold variation in SAVR rates across clinical commissioning groups in England. No relationship was identified between the rates of TAVI and those for SAVR (correlation coefficient 0.06). Conclusion: Geographical heterogeneity in access to TAVI persists over time, with the low rates of TAVI in many areas not compensated for by higher rates of SAVR, indicating an overall inequality in the treatment of severe aortic stenosis.

Glycodiversification of gentamicins through in vivo glycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity.

Aminoglycosides (AGs) are a class of antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs, therefore referred to as genkamicins (GKs). The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.

Enhanced aqueous formation and neutralization of fine atmospheric particles driven by extreme cold.

The prevailing view for aqueous secondary aerosol formation is that it occurs in clouds and fogs, owing to the large liquid water content compared to minute levels in fine particles. Our research indicates that this view may need reevaluation due to enhancements in aqueous reactions in highly concentrated small particles. Here, we show that low temperature can play a role through a unique effect on particle pH that can substantially modulate secondary aerosol formation. Marked increases in hydroxymethanesulfonate observed under extreme cold in Fairbanks, Alaska, demonstrate the effect. These findings provide insight on aqueous chemistry in fine particles under cold conditions expanding possible regions of secondary aerosol formation that are pH dependent beyond conditions of high liquid water.

Crystal structures, bonding and electronic structures of α- and ß-Ir2B3-x compounds.

The binary boron-rich compounds α-Ir2B3-x and ß-Ir2B3-x, formerly denoted as α- and ß-Ir4B5, were synthesized via both arc melting followed by annealing at 800 °C (900 °C) and high-temperature thermal treatment of mixtures of the elements. X-ray structure analysis of α-Ir2B3-x was performed on a single crystal (space group C2/m, a = 10.5515(11) Å, b = 2.8842(3) Å, c = 6.0965(7) Å, ß = 91.121(9)°). The orthorhombic structure of ß-Ir2B3-x was confirmed by X-ray powder diffraction (space group Pnma; a = 10.7519(3) Å, b = 2.83193(7) Å, c = 6.0293(1) Å). The α-Ir2B3-x structure exhibits ordered arrangements of iridium atoms. The structure is composed of corrugated layers of boron hexagons (interlinked via external B-B bonds) alternating with two corrugated layers of iridium along the c-direction; an additional boron atom (Oc. 0.46(7)) is located between iridium layers in Ir6 trigonal prisms. The boron partial structure in ß-Ir2B3-x is composed of ribbons made up of slightly corrugated quadrilateral units running along the b-direction in the channels formed by 8 iridium atoms each. DFT calculations revealed a number of bands crossing the Fermi level, predicting metallic behaviors of the two compounds. ß-Ir2B3-x is characterized by a pseudogap around the Fermi level and a smaller eDOS of 0.6405 states per eV per f.u. at the Fermi level, as compared to the α-Ir2B3-x value of 1.405 states per eV per f.u. The calculated electron localization functions revealed strong covalent bonds between boron atoms in the core part of the B6 hexagons, metallic B-B bonds within the quadrilateral boron partial structure and mixed covalent and metallic interactions between iridium and boron atoms. Structural relationships of α-Ir2B3-x and ß-Ir2B3-x with ReB2-type structures as well as the common structural features with layered binary borides with CrB-type related structures have been discussed.

The Pupillary Light-Off Reflex in Acute Disorders of Consciousness.

BACKGROUND: In intensive care patients with disorders of consciousness, the pupillary light reflex is a measure of pupillary parasympathetic function. By contrast, the pupillary light-off reflex leads to pupil dilation in response to an abrupt change from light to darkness ("light-off") and reflects combined parasympathetic and sympathetic pupillary function. To our knowledge, this reflex has not been systematically investigated in patients with disorders of consciousness. We hypothesized that the pupillary light-off reflex correlates with consciousness levels after acute brain injury. METHODS: From November 2022 to March 2023, we enrolled 100 study participants: 25 clinically unresponsive (coma or unresponsive wakefulness syndrome) and 25 clinically low-responsive (minimally conscious state or better) patients from the intensive care units of a tertiary referral center, and 50 age-matched and sex-matched healthy controls. Exclusion criteria were active or chronic eye disease. We used automated pupillometry to assess the pupillary light-off reflex and the pupillary light reflex of both eyes under scotopic conditions in all study participants. RESULTS: The pupillary light-off reflex was strongly correlated with consciousness levels (r = 0.62, p < 0.001), the increase in pupillary diameters being smallest in unresponsive patients (mean ± standard deviation 20% ± 21%), followed by low-responsive patients (mean ± standard deviation 47% ± 26%) and healthy controls (mean ± standard deviation 67% ± 17%; p < 0.001). Similar yet less pronounced patterns were observed for the pupillary light reflex. Twenty-one of 25 (84%) unresponsive patients had preserved pupillary light reflexes, but only seven (28%) had fully preserved pupillary light-off reflexes (p < 0.0001). Of these 7 patients, five (71%) regained awareness. CONCLUSIONS: The pupillary light-off reflex may be more sensitive to consciousness levels than the pupillary light reflex. The clinical implications of this finding seem worthy of further investigation, particularly regarding possible benefits for neuromonitoring and prognostication after brain injury.

Behaviour change intervention (education and text) to prevent dental caries in secondary school pupils: BRIGHT RCT, process and economic evaluation.

Background: The presence of dental caries impacts on children's daily lives, particularly among those living in deprived areas. There are successful interventions across the United Kingdom for young children based on toothbrushing with fluoride toothpaste. However, evidence is lacking for oral health improvement programmes in secondary-school pupils to reduce dental caries and its sequelae. Objectives: To determine the clinical and cost effectiveness of a behaviour change intervention promoting toothbrushing for preventing dental caries in secondary-school pupils. Design: A multicentre, school-based, assessor-blinded, two-arm cluster randomised controlled trial with an internal pilot and embedded health economic and process evaluations. Setting: Secondary schools in Scotland, England and Wales with above-average proportion of pupils eligible for free school meals. Randomisation occurred within schools (year-group level), using block randomisation stratified by school. Participants: Pupils aged 11-13 years at recruitment, who have their own mobile telephone. Interventions: Two-component intervention based on behaviour change theory: (1) 50-minute lesson delivered by teachers, and (2) twice-daily text messages to pupils' mobile phones about toothbrushing, compared with routine education. Main outcome measures: Primary outcome: presence of at least one treated or untreated carious lesion using DICDAS4-6MFT (Decayed, Missing and Filled Teeth) in any permanent tooth, measured at pupil level at 2.5 years. Secondary outcomes included: number of DICDAS4-6MFT; presence and number of DICDAS1-6MFT; plaque; bleeding; twice-daily toothbrushing; health-related quality of life (Child Health Utility 9D); and oral health-related quality of life (Caries Impacts and Experiences Questionnaire for Children). Results: Four thousand six hundred and eighty pupils (intervention, n = 2262; control, n = 2418) from 42 schools were randomised. The primary analysis on 2383 pupils (50.9%; intervention 1153, 51.0%; control 1230, 50.9%) with valid data at baseline and 2.5 years found 44.6% in the intervention group and 43.0% in control had obvious decay experience in at least one permanent tooth. There was no evidence of a difference (odds ratio 1.04, 95% confidence interval 0.85 to 1.26, p = 0.72) and no statistically significant differences in secondary outcomes except for twice-daily toothbrushing at 6 months (odds ratio 1.30, 95% confidence interval 1.03 to 1.63, p = 0.03) and gingival bleeding score (borderline) at 2.5 years (geometric mean difference 0.92, 95% confidence interval 0.85 to 1.00, p = 0.05). The intervention had higher incremental mean costs (£1.02, 95% confidence interval -1.29 to 3.23) and lower incremental mean quality-adjusted life-years (-0.003, 95% confidence interval -0.009 to 0.002). The probability of the intervention being cost-effective was 7% at 2.5 years. However, in two subgroups, pilot trial schools and schools with higher proportions of pupils eligible for free school meals, there was an 84% and 60% chance of cost effectiveness, respectively, although their incremental costs and quality-adjusted life-years remained small and not statistically significant. The process evaluation revealed that the intervention was generally acceptable, although the implementation of text messages proved challenging. The COVID-19 pandemic hampered data collection. High rates of missing economic data mean findings should be interpreted with caution. Conclusions: Engagement with the intervention and evidence of 6-month change in toothbrushing behaviour was positive but did not translate into a reduction of caries. Future work should include work with secondary-school pupils to develop an understanding of the determinants of oral health behaviours, including toothbrushing and sugar consumption, particularly according to free school meal eligibility. Trial registration: This trial is registered as ISRCTN12139369. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/166/08) and is published in full in Health Technology Assessment; Vol. 28, No. 52. See the NIHR Funding and Awards website for further award information.

Tooth decay has an impact on children and young people's daily lives, particularly those living in deprived areas. For young children, programmes to improve toothbrushing with fluoride toothpaste help prevent tooth decay. The Brushing RemInder 4 Good oral HealTh trial (BRIGHT) investigated whether a secondary-school-based toothbrushing programme would work. We developed a new programme which included a lesson and twice-daily text messages sent to pupils' phones. In total, 4680 pupils, aged 11­13 years, from 42 secondary schools in the United Kingdom took part in the trial. At each school, one year group was randomly selected to receive the programme, while the other year group did not receive it. All pupils were followed up for 2.5 years to see whether there were any differences in levels of tooth decay, frequency of toothbrushing, plaque or quality of life. We also considered the programme's value for money and the views of pupils and school staff. We followed up 2383 pupils and found no difference in tooth decay, plaque or quality of life. We found those who had the programme were more likely to brush their teeth twice daily after 6 months than those who did not. The programme was not good value for money overall. However, the programme appeared to be of more benefit at preventing tooth decay in pupils eligible for free school meals compared to those not eligible. In the schools with more pupils eligible for free school meals, the chance of the programme representing good value for money increased. The programme was generally liked by the pupils and school staff. Some pupils found the text messages useful, although others said they were annoying. The programme helped pupils brush their teeth more frequently in the short term, but this did not lead to less tooth decay. Further research is needed to understand how to prevent tooth decay in secondary-school pupils.

History of infertility and risk of endometrial cancer in the Women's Health Initiative.

BACKGROUND: Several studies have suggested an association between infertility and risk of endometrial cancer. However, most studies have evaluated this relationship in premenopausal people, yet the mean age of endometrial cancer is 60 years old, after the average age of menopause. METHODS: Our study included Women's Health Initiative participants who self-reported whether they had a history of infertility. Cox proportional hazards models were used to examine the association between infertility and incident endometrial cancer. Given that all infertility diagnoses occurred prior to study enrollment, we conducted secondary analyses using logistic regression examining prevalent endometrial cancer cases diagnosed before study baseline. RESULTS: Approximately 18% of participants reported a history of infertility. No statistically significant association was observed between infertility and risk of incident endometrial cancer overall (incident cases=1622; hazard ratio [HR]=1.12; 95% confidence interval [CI]=0.99-1.26). While point estimates suggested an increase in risk of endometrial cancer among women with BMI ≥25 (HR=1.15; 95% CI=0.99-1.33), none of the associations were statistically significant. There was an association between history of infertility and prevalent endometrial cancer cases (odds ratio [OR]=1.19; 95% CI=1.06-1.34), with the strongest association for infertility diagnosis due to endometriosis (OR=2.42; 95% CI=1.83-3.19). CONCLUSIONS: In a population of postmenopausal participants, we observed a modest, but not statistically significant, association between overall infertility and incident endometrial cancer, with the suggestion of a higher risk among those with a BMI ≥25. IMPACT: Our findings highlight, as observed in previous studies, that risk factors for endometrial cancer may vary by body mass index.

A modern approach to multiple pulmonary resections in children with recurrent metastatic pulmonary disease.

Implications of repeated resections of pulmonary metastasis (PM) are not well documented in the modern era. Fifteen children underwent two (n = 8), three (n = 3), or four or more (n = 3) resections (total = 38 procedures), most commonly for osteosarcoma (71%). Operative approach included muscle-sparing thoracotomy (71%), non-muscle-sparing thoracotomy (18%), and video-assisted thoracoscopy (11%). Median resected nodules per procedure was four (range = 1-95). Prolonged air leaks were the most common postoperative complication (29%). Median hospital stay was 4 days, and no children were discharged with or have required oxygen. Event-free survival is 67% at median follow-up time of 54 months, with an overall survival rate of 64%. Repeat resection of PM appears to be well tolerated, without prolonged hospital stays or compromised pulmonary function.

The effects of human-caused mortality on mammalian cooperative breeders: a synthesis.

Human-caused mortality can be pervasive and even highly selective for individuals in groups of cooperative breeders. Many studies of cooperative breeders, however, do not address human-caused mortality. Similarly, studies focused on the effects of human-caused mortality on wildlife populations often do not consider the ecology of cooperative breeders. We searched the literature and identified 58 studies where human-caused mortality affected a group characteristic, vital rate, or population state of a cooperative breeder. Of studies reporting population growth or decline, 80% reported a link between human-caused mortality and population declines in cooperative breeders. Such studies often did not identify the mechanism behind population declines, but 28% identified concurrent declines in adult survival and another 21% reported concurrent declines in recruitment or reproduction. There was little overlap between the cooperative breeding and human-caused mortality literatures, limiting our ability to accrue knowledge. Future work would be beneficial if it (i) identified the vital rate(s) causing population declines, (ii) leveraged management actions such as lethal removal to ask questions about the ecology of group-living in cooperative breeders, and (iii) used insights from cooperative breeding theory to inform management actions and conservation of group-living species.

Local administration of regulatory T cells promotes tissue healing.

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.

Synthesizing the temporal self: robotic models of episodic and autobiographical memory.

Episodic memories are experienced as belonging to a self that persists in time. We review evidence concerning the nature of human episodic memory and of the sense of self and how these emerge during development, proposing that the younger child experiences a persistent self that supports a subjective experience of remembering. We then explore recent research in cognitive architectures for robotics that has investigated the possibility of forms of synthetic episodic and autobiographical memory. We show that recent advances in generative modeling can support an understanding of the emergence of self and of episodic memory, and that cognitive architectures which include a language capacity are showing progress towards the construction of a narrative self with autobiographical memory capabilities for robots. We conclude by considering the prospects for a more complete model of mental time travel in robotics and the implications of this modeling work for understanding human episodic memory and the self in time. This article is part of the theme issue 'Elements of episodic memory: lessons from 40 years of research'.

Total Shoulder Arthroplasty in Patients With Hemophilia A: Greater Odds of Postoperative Bleeding and Thromboembolic Events but No Difference in 5-year Implant Survival.

BACKGROUND: Patients with hemophilia A can develop joint hemarthroses, degenerative changes, and eventually undergo total shoulder arthroplasty (TSA). Few data exist concerning complications and prosthesis survival after TSA in this population. QUESTIONS/PURPOSES: (1) Is hemophilia A associated with more bleeding and thromboembolic adverse events after TSA relative to matched controls? (2) Is 5-year TSA prosthesis survival reduced in patients with hemophilia A compared with matched controls? METHODS: The 2010 to 2022 PearlDiver M161 database was used to identify patients who underwent primary anatomic or reverse TSA. Given that the X-linked recessive condition hemophilia A presents nearly exclusively in males, male patients with hemophilia A who underwent TSA were matched 1:10 with male patients without hemophilia who underwent TSA based on age and Elixhauser comorbidity index (ECI). This yielded 73 patients with hemophilia A who underwent TSA who were matched 1:10 with 729 patients without hemophilia. Ninety-day adverse events were compared with multivariable analysis. Revision within 5 years was assessed using Kaplan-Meier analysis. RESULTS: Compared with the control cohort, patients with hemophilia had greater odds of bleeding issues (hematoma, OR 6.8 [95% CI 3.0 to 15.3]; p < 0.001; anemia, OR 2.5 [95% CI 1.5 to 4.2]; p < 0.001, transfusion, OR 5.0 [95% CI 2.4 to 10.3]; p < 0.001), venous thromboembolic events (VTE) (OR 1.9 [95% CI 1.1 to 3.1]; p = 0.01), and prosthetic loosening (OR 3.5 [95% CI 1.4 to 8.0]; p = 0.004). Based on available data, 5-year implant survival was not different in patients with hemophilia (97.3% [95% CI 93.6% to 100.0%]) relative to matched controls (95.2% [95% CI 93.4% to 97.2%]; p = 0.60). CONCLUSION: The elevated risks of both 90-day bleeding complications (hematoma, anemia, and transfusion) and VTE (DVT and PE) in patients with hemophilia emphasize the special challenges of carefully balancing factor replacement and VTE prophylaxis pre-, intra-, and postoperatively on an individual patient basis with careful hematologist coordination. Further study on Factor VIII levels and targets as well as tranexamic acid and VTE prophylaxis in this population is necessary to provide further guidance. Furthermore, 5-year implant survival was not different between patients with hemophilia and matched controls (patients without hemophilia) based on available data, suggesting that TSA survivorship remains durable and may be offered to patients in this population as indicated. LEVEL OF EVIDENCE: Level III, therapeutic study.

Correction: Immunogenic Salivary Proteins of Triatoma infestans: Development of a Recombinant Antigen for the Detection of Low-Level Infestation of Triatomines.

[This corrects the article DOI: 10.1371/journal.pntd.0000532.].

Feasibility and barriers to rapid establishment of patient-derived primary osteosarcoma cell lines in clinical management.

Osteosarcoma is a highly aggressive primary bone tumor that has seen little improvement in survival rates in the past three decades. Preclinical studies are conducted on a small pool of commercial cell lines which may not fully reflect the genetic heterogeneity of this complex cancer, potentially hindering translatability of in vitro results. Developing a single-site laboratory protocol to rapidly establish patient-derived primary cancer cell lines (PCCL) within a clinically actionable time frame of a few weeks will have significant scientific and clinical ramifications. These PCCL can widen the pool of available cell lines for study while patient-specific data could derive therapeutic correlation. This endeavor is exceedingly challenging considering the proposed time constraints. By proposing key definitions and a clear theoretical framework, this evaluation of osteosarcoma cell line establishment methodology over the past three decades assesses feasibility by identifying barriers and suggesting solutions, thereby facilitating systematic experimentation and optimization.