Unraveling Sepsis Epidemiology in a Low- and Middle-Income Intensive Care Setting Reveals the Alarming Burden of Tropical Infections and Antimicrobial Resistance: A Prospective Observational Study (MARS-India).

BACKGROUND: Our study addresses the sepsis research gap in lower middle-income countries, notably India. Here, we investigate community-acquired sepsis comprehensively and explore the impact of tropical microbiology on aetiology and outcomes. METHODS: MARS-India was a prospective observational study from Dec-2018 to Sep-2022 in a tertiary-care hospital in South India. Adult patients within 24hrs of ICU admission meeting the Sepsis 3.0 definition were enrolled, with 6-months follow-up (http://clinicaltrials.gov number NCT03727243). RESULTS: Over 4000 patients were screened on ICU admission, with 1000 unique patients meeting the inclusion criteria. Median age was 55 years (IQR: 44-65) with a male preponderance (66%). Almost half the cohort resided in villages (46.5%) and 74.6% worked in the primary sector. Mortality in-hospital was 24.1%. Overall, ∼54% had confirmed microbiological diagnosis. Over 18% had a viral cause of sepsis. Surprisingly, we identified leptospirosis (10.6%), scrub typhus (4.1%), dengue (3.7%) and Kyasanur forest disease (1.6%) as notables causes of sepsis. All these infections showed seasonal variation around the monsoon. In community-acquired infections we observed substantial resistance to 3rd generation cephalosporins and carbapenems. CONCLUSIONS: In India, sepsis disproportionally affects a younger and lower socio-economic demographic, yielding high mortality. Tropical and viral sepsis carry a significant burden. Analyzing local data, we pinpoint priorities for public health and resources, offering valuable insights for global sepsis research.

Validation and user experience of a dry electrode based Health Patch for heart rate and respiration rate monitoring.

Successful implementation of remote monitoring of vital signs outside of the hospital setting hinges on addressing three crucial unmet needs: longer-term wear, skin comfort and signal quality. Earlier, we developed a Health Patch research platform that uses self-adhesive dry electrodes to measure vital digital biomarkers. Here, we report on the analytical validation for heart rate, heart rate variability and respiration rate. Study design included n = 25 adult participants with data acquisition during a 30-minute exercise protocol involving rest, squats, slow, and fast cycling. The Shimmer3 ECG Unit and Cosmed K5, were reference devices. Data analysis showed good agreement in heart rate and marginal agreement in respiratory rate, with lower agreement towards higher respiratory rates. The Lin's concordance coefficient was 0.98 for heart rate and 0.56 for respiratory rate. Heart rate variability (RMSSD) had a coefficient of 0.85. Participants generally expressed a positive experience with the technology, with some minor irritation from the medical adhesive. The results highlighted potential of this technology for short-to-medium term clinical use for cardiorespiratory health, due to its reliability, accuracy, and compact design. Such technology could become instrumental for remote monitoring providing healthcare professionals with continuous data, remote assessment and enhancing patient outcomes in cardiorespiratory health management.

A narrative on the neurobiological roots of attachment-system functioning.

Attachment theory is one of the most comprehensive frameworks in social and developmental psychology. It describes how selective, enduring emotional bonds between infants and their caregivers are formed and maintained throughout life. These attachment bonds exhibit distinct characteristics that are intimately tied to fundamental aspects of mammalian life, including pregnancy, birth, lactation, and infant brain development. However, there is a lack of a cohesive biological narrative that explains the psychological forces shaping attachment behavior and the emergence and consolidation of attachment patterns at a neurobiological level. Here, we propose a theoretical narrative focusing on organized attachment patterns that systematically link the two primary purposes of the attachment behavioral system: the provision of tangible protection or support and the corresponding subjective feeling of safety or security. We aim for this detailed delineation of neurobiological circuits to foster more comprehensive and interdisciplinary future research.

Wild-type MIC distributions and epidemiological cutoff values for 5-flucytosine and Candida species as determined by EUCAST broth microdilution.

Objectives: EUCAST has established clinical breakpoints and epidemiological cutoff values (ECOFFs) for Candida spp. However, limited data are available for 5-flucytosine (5-FC). We assessed the in vitro susceptibility of 5-FC against a large collection of clinical Candida species using EUCAST methodology and determined the associated ECOFFs. Methods: A total of 5622 Candida isolates were collected from patients across the Netherlands between 2008 and 2024. 5-FC MICs were determined using the EUCAST microbroth dilution reference method. Furthermore, MICs were extracted from the EUCAST website. The MICs from this study and those extracted were used to determine ECOFFs and local ECOFFs (L-ECOFFs). Results: 5-FC exhibited potent in vitro activity against C. albicans, N. glabratus and C. parapsilosis, while decreased susceptibility was observed for C. tropicalis, Pichia species, K. marxianus, Y. lipolytica, and C. auris. The ECOFFs (mg/L) and the percentages of WT isolates for 5-FC were: C. albicans: 0.5 (97.2%), N. glabratus: 0.5 (96.6%), C. parapsilosis: 0.5 (99.5%) and P. kudriavzevii: 8 (99.4%). The L-ECOFF (mg/L) and the percentages of WT isolates for 5-FC were: C. dubliniensis: 0.25 (96.8%), C. tropicalis: 0.25 (67.2%), K. marxianus: 0.25 (48.0%), C. lusitaniae: 0.25 (86.5%), M. guillermondii: 0.125 (95.9%) and P. norvegiensis: 8 (94.2%). Conclusions: 5-FC remains a valuable drug to manage difficult-to-treat invasive Candida infections. In vitro susceptibility cannot be predicted based on species identification for most Candida species, but requires MIC-testing. ECOFFs will help to interpret the MICs to support treatment decisions.

Engineering the substrate specificity and regioselectivity of Burkholderia thailandensis lipoxygenase.

Lipoxygenases (LOXs) catalyze the regioselective dioxygenation of polyunsaturated fatty acids (PUFAs), generating fatty acid hydroperoxides (FAHPs) with diverse industrial applications. Bacterial LOXs have garnered significant attention in recent years due to their broad activity towards PUFAs, yet knowledge about the structural factors influencing their substrate preferences remains limited. Here, we characterized a bacterial LOX from Burkholderia thailandensis (Bt-LOX), and identified key residues affecting its substrate preference and regioselectivity through site-directed mutagenesis. Bt-LOX preferred ω-6 PUFAs and exhibited regioselectivity at the ω-5 position. Mutations targeting the substrate binding pocket and the oxygen access channel led to the production of three active variants with distinct catalytic properties. The A431G variant bifurcated dioxygenation between the ω-5 and ω-9 positions, while F446V showed reduced regioselectivity with longer PUFAs. Interestingly, L445A displayed altered substrate specificity, favoring ω-3 over ω-6 PUFAs. Furthermore, L445A shifted the regioselectivity of dioxygenation to the ω-2 position in ω-3 PUFAs, and, for some substrates, facilitated dioxygenation closer to the carboxylic acid terminus, suggesting an altered substrate orientation. Among these variants, L445A represents a significant milestone in LOX research, as these alterations in substrate specificity, dioxygenation regioselectivity, and substrate orientation were achieved by a single mutation only. These findings illuminate key residues governing substrate preference and regioselectivity in Bt-LOX, offering opportunities for synthesizing diverse FAHPs and highlighting the potential of bacterial LOXs as biocatalysts with widespread applications.

Inflammation and Tumor Progression: The Differential Impact of SAA in Breast Cancer Models.

Background: Previous research has shown that the Serum Amyloid A (SAA) protein family is intricately involved in inflammatory signaling and various disease pathologies. We have previously demonstrated that SAA is associated with increased colitis disease severity and the promotion of tumorigenesis. However, the specific role of SAA proteins in breast cancer pathology remains unclear. Therefore, we investigated the role of systemic SAA1 and SAA2 (SAA1/2) in a triple-negative breast cancer mouse model. Methods: Syngeneic breast tumors were established in wild-type mice, and mice lacking the SAA1/2 (SAADKO). Subsequently, tumor volume was monitored, species survival determined, the inflammatory profiles of mice assessed with a multiplex assay, and tumor molecular biology and histology characterized with Western blotting and H&E histological staining. Results: WT tumor-bearing mice had increased levels of plasma SAA compared to wild-type control mice, while SAADKO control and tumor-bearing mice presented with lower levels of SAA in their plasma. SAADKO tumor-bearing mice also displayed significantly lower concentrations of systemic inflammatory markers. Tumors from SAADKO mice overall had lower levels of SAA compared to tumors from wild-type mice, decreased apoptosis and inflammasome signaling, and little to no tumor necrosis. Conclusions: We demonstrated that systemic SAA1/2 stimulates the activation of the NLRP3 inflammasome in breast tumors, leading to the production of pro-inflammatory cytokines. This, in turn, promoted apoptosis and tumor necrosis but did not significantly impact tumor growth or histological grading.

Effect of single blastocyst-stage versus single cleavage-stage embryo transfer on cumulative live births in women with good prognosis undergoing in vitro fertilization: Multicenter Randomized Controlled Trial.

In this multicenter, non-inferiority, randomized trial, we randomly assigned 992 women undergoing in-vitro fertilization (IVF) with a good prognosis (aged 20-40, ≥3 transferrable cleavage-stage embryos) to strategies of blastocyst-stage (n = 497) or cleavage-stage (n = 495) single embryo transfer. Primary outcome was cumulative live-birth rate after up to three transfers. Secondary outcomes were cumulative live-births after all embryo transfers within 1 year of randomization, pregnancy outcomes, obstetric-perinatal complications, and livebirths outcomes. Live-birth rates were 74.8% in blastocyst-stage group versus 66.3% in cleavage-stage group (relative risk 1.13, 95%CI:1.04-1.22; Pnon-inferiority < 0.001, Psuperiority = 0.003) (1-year cumulative live birth rates of 75.7% versus 68.9%). Blastocyst transfer increased the risk of spontaneous preterm birth (4.6% vs 2.0%; P = 0.02) and neonatal hospitalization >3 days. Among good prognosis women, a strategy of single blastocyst transfer increases cumulative live-birth rates over single cleavage-stage transfer. Blastocyst transfer resulted in higher preterm birth rates. This information should be used to counsel patients on their choice between cleavage-stage and blastocyst-stage transfer (NCT03152643, https://clinicaltrials.gov/study/NCT03152643 ).

Polyphenol Oxidase Activity on Guaiacyl and Syringyl Lignin Units.

The natural heterogeneity of guaiacyl (G) and syringyl (S) compounds resulting from lignin processing hampers their direct use as plant-based chemicals and materials. Herein, we explore six short polyphenol oxidases (PPOs) from lignocellulose-degrading ascomycetes for their capacity to react with G-type and S-type phenolic compounds. All six PPOs catalyze the ortho-hydroxylation of G-type compounds (guaiacol, vanillic acid, and ferulic acid), forming the corresponding methoxy-ortho-diphenols. Remarkably, a subset of these PPOs is also active towards S-compounds (syringol, syringic acid, and sinapic acid) resulting in identical methoxy-ortho-diphenols. Assays with 18O2 demonstrate that these PPOs in particular catalyze ortho-hydroxylation and ortho-demethoxylation of S-compounds and generate methanol as a co-product. Notably, oxidative (ortho-)demethoxylation of S-compounds is a novel reaction for PPOs, which we propose occurs via a distinct reaction mechanism compared to aryl-O-demethylases. We further show that addition of a reducing agent can steer the PPO reaction to form methoxy-ortho-diphenols from both G- and S-type substrates rather than reactive quinones that lead to unfavorable polymerization. Application of PPOs opens for new routes to reduce the heterogeneity and methoxylation degree of mixtures of G and S lignin-derived compounds.

Cost Analysis of Robot-Assisted Versus On-Pump and Off-Pump Coronary Artery Bypass Grafting: A Single-Center Surgical and 30-Day Outcomes Comparison.

OBJECTIVE: Throughout Europe, the interest in implementing robot-assisted minimally invasive direct coronary artery bypass (RA-MIDCAB) has been growing. However, concerns about additional costs have emerged concurrently. In this analysis, we aim to provide a comparison of the cumulative perioperative costs of RA-MIDCAB, on-pump coronary artery bypass grafting (CABG), and off-pump CABG (OPCAB). METHODS: We conducted a propensity score-matched analysis comparing patients undergoing RA-MIDCAB with those undergoing CABG or OPCAB at our institution from January 2016 to December 2021. After matching, we analyzed the combined intraoperative surgical costs and 30-day postoperative costs. We first compared RA-MIDCAB costs to CABG and then to OPCAB separately. Violin plots illustrated the cost distribution among individual patients. Total cost uncertainty was estimated using 1,000 bootstrapping iterations. RESULTS: Seventy-nine RA-MIDCAB patients were matched to 158 CABG patients, and 80 RA-MIDCAB patients were matched to 149 OPCAB patients. Considering both surgical and clinical outcomes, RA-MIDCAB yielded an average cost of €17,121 per patient (€16,781 to €33,294), CABG was €16,571 per patient (€16,664 to €41,860), and OPCAB was €15,463 per patient (€10,895 to €57,867). After bootstrap iterations, RA-MIDCAB was found to be €472 (2.8%) and €1,599 (10.3%) more expensive per patient than CABG and OPCAB, respectively. CONCLUSIONS: In The Netherlands, the adoption of RA-MIDCAB did not show a significant economic impact on hospital resources. The additional robotic costs for the surgery were almost entirely offset by the cost savings during the postoperative hospital stay. However, these comparisons may differ when considering hybrid coronary revascularization with its additional percutaneous coronary intervention costs.

Substantiating the Short Burst Duration in Cortical Myoclonus.

BACKGROUND: Myoclonus is characterized by involuntary, shock-like movements, of which cortical (CM) and non-cortical myoclonus (NCM) are most common. Electrophysiology can help differentiate between these subtypes; however, the diagnostic value of several features is largely unknown. OBJECTIVE: This study aims to determine the diagnostic value of the burst duration in distinguishing CM and NCM. METHODS: We manually identified the burst duration of 8 patients with CM, confirmed by electromyography-electroencephalography registration or somatosensory-evoked potentials, and 19 patients with NCM, suspected due to a myoclonus-dystonia phenotype (MYC/DYT-SGCE positive and negative). RESULTS: The sensitivity and specificity were calculated to assess the diagnostic value. The burst duration of CM (31.1 ms) was significantly shorter than that of NCM (56.7 ms), with a sensitivity of 100% and a specificity of 89.5% at a threshold of 45.0 ms. A minimum of 10 randomly selected bursts were sufficient for reliable diagnostic accuracy. CONCLUSION: The burst duration seems a valuable supportive diagnostic criterion for distinguishing CM and NCM. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Functional dissection of mosquito humidity sensing reveals distinct Dry and Moist Cell contributions to blood feeding and oviposition.

Aedes aegypti mosquitoes are major vectors of dengue, chikungunya, and other arboviral diseases. Ae. aegypti's capacity to reproduce and to spread disease depends on the female mosquitoes' ability to obtain blood meals and find water-filled containers in which to lay eggs (oviposit). While humidity sensation (hygrosensation) has been implicated in these behaviors, the specific hygrosensory pathways involved have been unclear. Here, we establish the distinct molecular requirements and anatomical locations of Ae. aegypti Dry Cells and Moist Cells and examine their contributions to behavior. We show that Dry Cell and Moist Cell responses to humidity involve different ionotropic receptor (IR) family sensory receptors, with dry air-activated Dry Cells reliant upon the IR Ir40a, and humid air-activated Moist Cells upon Ir68a. Both classes of hygrosensors innervate multiple antennal sensilla, including sensilla ampullacea near the antennal base as well as two classes of coeloconic sensilla near the tip. Dry Cells and Moist Cells each support behaviors linked to mosquito reproduction but contribute differently: Ir40a-dependent Dry Cells act in parallel with Ir68a-dependent Moist Cells to promote blood feeding, while oviposition site seeking is driven specifically by Ir68a-dependent Moist Cells. Together these findings reveal the importance of distinct hygrosensory pathways in blood feeding and oviposition site seeking and suggest Ir40a-dependent Dry Cells and Ir68a-dependent Moist Cells as potential targets for vector control strategies.

Trained immunity suppression determines kidney allograft survival.

The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.

Ethics of Wearable-Based Out-of-Hospital Cardiac Arrest Detection.

Out-of-hospital cardiac arrest is a major health problem, and immediate treatment is essential for improving the chances of survival. The development of technological solutions to detect out-of-hospital cardiac arrest and alert emergency responders is gaining momentum; multiple research consortia are currently developing wearable technology for this purpose. For the responsible design and implementation of this technology, it is necessary to attend to the ethical implications. This review identifies relevant ethical aspects of wearable-based out-of-hospital cardiac arrest detection according to four key principles of medical ethics. First, aspects related to beneficence concern the effectiveness of the technology. Second, nonmaleficence requires preventing psychological distress associated with wearing the device and raises questions about the desirability of screening. Third, grounded in autonomy are empowerment, the potential reidentification from continuously collected data, issues of data access, bystander privacy, and informed consent. Finally, justice concerns include the risks of algorithmic bias and unequal technology access. Based on this overview and relevant legislation, we formulate design recommendations. We suggest that key elements are device accuracy and reliability, dynamic consent, purpose limitation, and personalization. Further empirical research is needed into the perspectives of stakeholders, including people at risk of out-of-hospital cardiac arrest and their next-of-kin, to achieve a successful and ethically balanced integration of this technology in society.

Bacteriophage therapy reduces Staphylococcus aureus in a porcine and human ex vivo burn wound infection model.

Burn wounds are a major burden, with high mortality rates due to infections. Staphylococcus aureus is a major causative agent of burn wound infections, which can be difficult to treat because of antibiotic resistance and biofilm formation. An alternative to antibiotics is the use of bacteriophages, viruses that infect and kill bacteria. We investigated the efficacy of bacteriophage therapy for burn wound infections, in both a porcine and a newly developed human ex vivo skin model. In both models, the efficacy of a reference antibiotic treatment (fusidic acid) and bacteriophage treatment was determined for a single treatment, successive treatment, and prophylaxis. Both models showed a reduction in bacterial load after a single bacteriophage treatment. Increasing the frequency of bacteriophage treatments increased bacteriophage efficacy in the human ex vivo skin model, but not in the porcine model. In both models, prophylaxis with bacteriophages increased treatment efficacy. In all cases, bacteriophage treatment outperformed fusidic acid treatment. Both models allowed investigation of bacteriophage-bacteria dynamics in burn wounds. Overall, bacteriophage treatment outperformed antibiotic control underlining the potential of bacteriophage therapy for the treatment of burn wound infections, especially when used prophylactically.

The effect of prior hysterosalpingo-foam sonography or hysterosalpingography on tubal patency: a secondary analysis of a randomized controlled trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) prior to hysterosalpingography (HSG) or HSG prior to HyFoSy affect visible tubal patency when compared HSG or HyFoSy alone? SUMMARY ANSWER: Undergoing either HyFoSy or HSG prior to tubal patency testing by the alternative method does not demonstrate a significant difference in visible tubal patency when compared to HyFoSy or HSG alone. WHAT IS KNOWN ALREADY: HyFoSy and HSG are two commonly used visual tubal patency tests with a high and comparable diagnostic accuracy for evaluating tubal patency. These tests may also improve fertility, although the underlying mechanism is still not fully understood. One of the hypotheses points to a dislodgment of mucus plugs that may have disrupted the patency of the Fallopian tubes. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of the randomized controlled FOAM study, in which women underwent tubal patency testing by HyFoSy and HSG, randomized for order of the procedure. Participants either had HyFoSy first and then HSG, or vice versa. Here, we evaluate the relative effectiveness of tubal patency testing by HyFoSy or HSG prior to the alternative tubal patency testing method on visible tubal patency, compared to each method alone. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women aged between 18 and 41 years scheduled for tubal patency testing were eligible for participating in the FOAM study. Women with anovulatory cycles, endometriosis, or with a partner with male infertility were excluded. To evaluate the effect HyFoSy on tubal patency, we relied on HSG results by comparing the proportion of women with bilateral tubal patency visible on HSG in those who underwent and who did not undergo HyFoSy prior to their HSG (HyFoSy prior to HSG versus HSG alone). To evaluate the effect of HSG on tubal patency, we relied on HyFoSy results by comparing the proportion of women with bilateral tubal patency visible on HyFoSy in those who underwent and who did not undergo HSG prior to their HyFoSy (HSG prior to HyFoSy versus HyFoSy alone). MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, we randomized 1160 women (576 underwent HyFoSy first followed by HSG, and 584 underwent HSG first followed by HyFoSy). Among the women randomized to HyFoSy prior to HSG, bilateral tubal patency was visible on HSG in 467/537 (87%) women, compared with 472/544 (87%) women who underwent HSG alone (risk difference 0.2%; 95% CI: -3.8% to 4.2%). Among the women randomized to HSG prior to HyFoSy, bilateral tubal patency was visible on HyFoSy in 394/471 (84%) women, compared with 428/486 (88%) women who underwent HyFoSy alone (risk difference -4.4%; 95% CI: -8.8% to 0.0%). LIMITATIONS, REASONS FOR CAUTION: The results of this secondary analysis should be interpreted as exploratory and cannot be regarded as definitive evidence. Furthermore, it has to be noted that pregnancy outcomes were not considered in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: Tubal patency testing by either HyFoSy or HSG, prior to the alternative tubal patency testing method does not significantly affect visible tubal patency, when compared to alternative method alone. This suggests that both methods may have comparable abilities to dislodge mucus plugs in the Fallopian tubes. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, or interpretation of the data. H.R.V. reports consultancy fees from Ferring. M.v.W. received a travel grant from Oxford University Press in the role of Deputy Editor for Human Reproduction and participates in a Data Safety and Monitoring Board as an independent methodologist in obstetrics studies in which she has no other role. M.v.W. is coordinating editor of Cochrane Fertility and Gynaecology. B.W.J.M. received an investigator grant from NHMRC (GNT1176437) and research funding from Merck KGaA. B.W.J.M. reports consultancy for Organon and Merck KGaA, and travel support from Merck KGaA. B.W.J.M. reports holding stocks of ObsEva. V.M. received research grants from Guerbet, Merck and Ferring and travel and speaker fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

[Persistent dermatomycosis due toTrichophyton indotineae]. / Hardnekkige dermatomycose doorTrichophyton indotineae.

Trichophyton indotineae is a recently identified dermatophyte that frequently causes extensive and persistent dermatomycosis, particularly tinea corporis, tinea cruris, and tinea faciei. The infection is frequently encountered in countries of the Indian subcontinent and surrounding areas. In Europe, T. indotineae has mainly been detected in patients with an epidemiological link to the aforementioned regions. Unlike dermatomycoses caused by other dermatophyte species, infections caused by T. indotineae often exhibit treatment failure with commonly prescribed antifungal drugs. Reduced susceptibility to terbinafine is often observed in T. indotineae. In addition, reduced susceptibility to itraconazole has also been reported. Due to the extensive and persistent nature of the infection, as well as the reduced susceptibility to antifungal drugs, international experts recommend aggressive treatment of T. indotineae using a combination of oral and topical antifungals. Susceptibility testing may be warranted to guide treatment decisions. Early recognition of T. indotineae infections is crucial to prevent prolonged recurrences.

Medium and long-term patency results of distal anastomosis connectors: a meta-analysis.

Background: The difficulty of suturing perfect anastomoses in limited-access conditions prevents the transition of traditional coronary artery bypass grafting (CABG) to sternal-sparing approaches, even in the robotic era. Automated coronary anastomotic connector technologies may address these difficulties, but to date, none have achieved broad adoption. Besides versatility, ease-of-use and cost-effectiveness, the key performance parameter of such technology is anastomotic patency. In this meta-analysis, we aim to evaluate published connector devices by examining their patency outcomes in distal anastomoses. Methods: The literature was systematically searched for studies comparing the angiographic patency of connector constructed coronary anastomoses to handsewn (HS) connections in adult patients undergoing CABG. The primary outcome was anastomosis patency across early (<30 days), mid-term (30 days to 1 year) and long-term (>1 year) follow-up. Random-effects meta-analyses were employed to analyze and compare patency using pooled risk ratios (RR) with 95% confidence intervals (CI). Results: The search yielded 14 studies concerning eight connector devices. In 4,311 patients, a total of 4,328 anastomoses were constructed, 674 with connector devices and 3,654 with a HS technique. The pooled device patency over all timeframes was non-inferior to the HS technique (RR 0.90, 95% CI: 0.56-1.44). Technologies having a relatively large blood-exposed non-intimal surface area (BENIS, >15 mm2) performed acceptably when applied to large target vessels [>2.0-2.5 mm inner diameter (ID)]. A tiny anastomotic orifice area (AOA, < ca. 4 mm2) appeared to adversely affect results. Technologies realizing a generous AOA in combination with a limited BENIS showed superior results and applicability by performing well across the entire range of target coronary artery diameters (>1.0-1.5 mm ID). Conclusions: The overall results suggest that connectors yield at least non-inferior anastomosis patency outcomes compared to HS techniques in all observed timeframes. Optimizing device characteristics like BENIS and AOA appear fundamental for broad applicability.

Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling.

Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.

The W792R HCM missense mutation in the C6 domain of cardiac myosin binding protein-C increases contractility in neonatal mouse myocardium.

Missense mutations in cardiac myosin binding protein C (cMyBP-C) are known to cause hypertrophic cardiomyopathy (HCM). The W792R mutation in the C6 domain of cMyBP-C causes severe, early onset HCM in humans, yet its impact on the function of cMyBP-C and the mechanism through which it causes disease remain unknown. To fully characterize the effect of the W792R mutation on cardiac morphology and function in vivo, we generated a murine knock-in model. We crossed heterozygous W792RWR mice to produce homozygous mutant W792RRR, heterozygous W792RWR, and control W792RWW mice. W792RRR mice present with cardiac hypertrophy, myofibrillar disarray and fibrosis by postnatal day 10 (PND10), and do not survive past PND21. Full-length cMyBP-C is present at similar levels in W792RWW, W792RWR and W792RRR mice and is properly incorporated into the sarcomere. Heterozygous W792RWR mice displayed normal heart morphology and contractility. Permeabilized myocardium from PND10 W792RRR mice showed increased Ca2+ sensitivity, accelerated cross-bridge cycling kinetics, decreased cooperativity in the activation of force, and increased expression of hypertrophy-related genes. In silico modeling suggests that the W792R mutation destabilizes the fold of the C6 domain and increases torsion in the C5-C7 region, possibly impacting regulatory interactions of cMyBP-C with myosin and actin. Based on the data presented here, we propose a model in which mutant W792R cMyBP-C preferentially forms Ca2+ sensitizing interactions with actin, rather than inhibitory interactions with myosin. The W792R-cMyBP-C mouse model provides mechanistic insights into the pathology of this mutation and may provide a mechanism by which other central domain missense mutations in cMyBP-C may alter contractility, leading to HCM.

Polymersomes with splenic avidity target red pulp myeloid cells for cancer immunotherapy.

Regulating innate immunity is an emerging approach to improve cancer immunotherapy. Such regulation requires engaging myeloid cells by delivering immunomodulatory compounds to hematopoietic organs, including the spleen. Here we present a polymersome-based nanocarrier with splenic avidity and propensity for red pulp myeloid cell uptake. We characterized the in vivo behaviour of four chemically identical yet topologically different polymersomes by in vivo positron emission tomography imaging and innovative flow and mass cytometry techniques. Upon intravenous administration, relatively large and spherical polymersomes accumulated rapidly in the spleen and efficiently targeted myeloid cells in the splenic red pulp. When loaded with ß-glucan, intravenously administered polymersomes significantly reduced tumour growth in a mouse melanoma model. We initiated our nanotherapeutic's clinical translation with a biodistribution study in non-human primates, which revealed that the platform's splenic avidity is preserved across species.