Durability and Underlying Physiological Factors: How Do They Change Throughout a Cycling Season in Semiprofessional Cyclists?

PURPOSE: To investigate how cycling time-trial (TT) performance changes over a cycling season, both in a "fresh" state and in a "fatigued" state (durability). Additionally, the aim was to explore whether these changes are related to changes in underlying physiological factors such as gross efficiency, energy expenditure (EE), and substrate oxidation (fat oxidation [FatOx] and carbohydrate oxidation [CarbOx]). METHODS: Sixteen male semiprofessional cyclists visited the laboratory on 3 occasions during a cycling season (PRE, START, and IN) and underwent a performance test in both fresh and fatigued states (after 38.1 [4.9] kJ/kg), containing a submaximal warm-up for the measurement of gross efficiency, EE, FatOx, and CarbOx and a maximal TT of 1 (TT1min) and 10 minutes (TT10min). Results were compared across states (fresh vs fatigued) and periods (PRE, START, and IN). RESULTS: The average power output (PO) in TT1min decreased (P < .05) from fresh to fatigued state across all observed periods, whereas there was no change in the PO in TT10min. Over the course of the season, the PO in TT1min in the fatigued state improved more compared with the PO in TT1min in the fresh state. Furthermore, while EE did not significantly change, there was an increase in FatOx and a decrease in CarbOx toward the fatigued state. These changes diminished during the cycling season (IN), indicating a greater contribution of CarbOx in the fatigued state. CONCLUSIONS: TT1min performance is more sensitive to fatigue compared with TT10min. Also, during a cycling season, durability improves more when compared with fresh maximal POs, which is also observed in the changes in substrate oxidation.

Are professional road cycling countries selecting their talents based on anthropometric characteristics which suit the countries' terrain?

BACKGROUND: This study investigates if countries are more focused on certain specializations (one day, climb, sprint, time trial [TT] and grand tour [GC]) in male professional road cycling and if this is possibly linked to the countries landscape (for example, does a mountainous country have more climbers?) and anthropometric characteristics (does the mountainous country also have lighter cyclists?) of their cyclists. METHODS: Body weight, height, procyclingstats (PCS) points per specialty were gathered from 1810 professional cyclists out of 15 countries, as well as the elevation span of those countries. To compare the anthropometric differences between different countries, height was normalized based on the average height of the countries' population, while BMI was used as a correction for body weight. RESULTS: The average anthropometrics (body weight and height) of professional cyclists in a country are related to the relative number of PCS points collected in GC, sprint and climb races. This means that when a country has shorter and lighter cyclists, they score relatively better in GC and climb races and vice versa for sprint races, which indicates that countries are focused on certain specialties. However, these relationships were not found for TT and one day PCS points. In addition, countries with larger cyclists have a less mountainous (elevation span) landscape compared to countries with lighter cyclists. CONCLUSIONS: The results suggest a selection bias towards smaller/lighter or taller/heavier cyclists in various countries, probably caused by the terrain of their home country, leading to missed opportunities for some cyclists to reach professional level.

Dual role of signaling pathways in myeloma requires cell type-specific targeting of ligand-receptor interactions.

ABSTRACT: Although most patients with multiple myeloma respond to treatment initially, therapy resistance develops almost invariably, and only a subset of patients show durable responses to immunomodulatory therapies. Although the immune microenvironment has been extensively studied in patients with myeloma, its composition is currently not used as prognostic markers in clinical routine. We hypothesized that the outcome of immune signaling pathway engagement can be highly variable, depending on which 2 cellular populations participate in this interaction. This would have important prognostic and therapeutic implications, suggesting that it is crucial for immune pathways to be targeted in a specific cellular context. To test this hypothesis, we investigated a cohort of 25 patients with newly diagnosed multiple myeloma. We examined the complex regulatory networks within the immune compartment and their impact on disease progression. Analysis of immune cell composition and expression profiles revealed significant differences in the B-cell compartment associated with treatment response. Transcriptional states in patients with short time to progression demonstrated an enrichment of pathways promoting B-cell differentiation and inflammatory responses, which may indicate immune dysfunction. Importantly, the analysis of molecular interactions within the immune microenvironment highlights the dual role of signaling pathways, which can either be associated with good or poor prognosis depending on the cell types involved. Our findings therefore argue that therapeutic strategies targeting ligand-receptor interactions should take into consideration the composition of the microenvironment and the specific cell types involved in molecular interactions.

Odor cueing of declarative memories during sleep enhances coordinated spindles and slow oscillations.

Long-term memories are formed by repeated reactivation of newly encoded information during sleep. This process can be enhanced by using memory-associated reminder cues like sounds and odors. While auditory cueing has been researched extensively, few electrophysiological studies have exploited the various benefits of olfactory cueing. We used high-density electroencephalography in an odor-cueing paradigm that was designed to isolate the neural responses specific to the cueing of declarative memories. We show widespread cueing-induced increases in the duration and rate of sleep spindles. Higher spindle rates were most prominent over centro-parietal areas and largely overlapping with a concurrent increase in the amplitude of slow oscillations (SOs). Interestingly, greater SO amplitudes were linked to a higher likelihood of coupling a spindle and coupled spindles expressed during cueing were more numerous in particular around SO up states. We thus identify temporally and spatially coordinated enhancements of sleep spindles and slow oscillations as a candidate mechanism behind cueing-induced memory processing. Our results further demonstrate the feasibility of studying neural activity patterns linked to such processing using olfactory cueing during sleep.

Deficient Immune Response following SARS-CoV-2 Vaccination in Patients with Hepatobiliary Carcinoma: A Forgotten, Vulnerable Group of Patients.

Introduction: Data on immune response rates following vaccination for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in patients with hepatobiliary carcinoma (HBC) are rare. However, impaired immunogenicity must be expected due to the combination of chronic liver diseases (CLDs) with malignancy and anticancer treatment. Methods: In this prospective, longitudinal study, 101 patients were included, of whom 59 were patients with HBC under anticancer treatment. A cohort of patients with a past medical history of gastrointestinal cancer, of whom 28.6% had HBC without detectable active tumor disease having been off therapy for at least 12 months, served as control. Levels of SARS-CoV-2 anti-spike IgG, surrogate neutralization antibodies (sNABs), and cellular immune responses were compared. In uni- and multivariable subgroup analyses, risk factors for impaired immunogenicity were regarded. Data on rates and clinical courses of SARS-CoV-2 infections were documented. Results: In patients with HBC under active treatment, levels of SARS-CoV-2 anti-spike IgG were significantly lower (2.55 log10 BAU/mL; 95% CI: 2.33-2.76; p < 0.01) than in patients in follow-up care (3.02 log10 BAU/mL; 95% CI: 2.80-3.25) 4 weeks after two vaccinations. Antibody levels decreased over time, and differences between the groups diminished. However, titers of SARS-CoV-2 sNAB were for a longer time significantly lower in patients with HBC under treatment (64.19%; 95% CI: 55.90-72.48; p < 0.01) than in patients in follow-up care (84.13%; 95% CI: 76.95-91.31). Underlying CLD and/or liver cirrhosis Child-Pugh A or B (less than 8 points) did not seem to further impair immunogenicity. Conversely, chemotherapy and additional immunosuppression were found to significantly reduce antibody levels. After a third booster vaccination for SARS-CoV-2, levels of total and neutralization antibodies were equalized between the groups. Moreover, cellular response rates were balanced. Clinically, infection rates with SARS-CoV-2 were low, and no severe courses were observed. Conclusion: Patients with active HBC showed significantly impaired immune response rates to basic vaccinations for SARS-CoV-2, especially under chemotherapy, independent of underlying cirrhotic or non-cirrhotic CLD. Although booster vaccinations balanced differences, waning immunity was observed over time and should be monitored for further recommendations. Our data help clinicians decide on individual additional booster vaccinations and/or passive immunization or antiviral treatment in patients with HBC getting infected with SARS-CoV-2.

Graft-versus-host disease following liver transplantation: A systematic review of literature.

BACKGROUND: Graft-versus-host disease following liver transplantation is a serious and usually fatal complication. Data identifying the risk factors and specifying the diagnosis and treatment options of the disease are scarce and contentious. Moreover, recommendations for therapeutic approaches are similarly sparse. METHODS: A systematic review of the literature from 1988 to 2020 on graft-versus-host disease following liver transplantation was performed using the PubMed and MEDLINE databases. Medical subject headings, such as graft-versus-host disease and GvHD were used in combination with solid organ transplant, transplantation, or liver transplant. Following duplicate removal, 9298 articles were screened for suitability. A total of 238 full-text articles were analyzed for eligibility, resulting in 130 eligible articles for meta-analysis. Two hundred twenty-five patients developing graft-versus-host disease following liver transplantation reported herein were mainly published in case reports and case series. RESULTS: Graft-versus-host disease occurred with an incidence of 1.2%. 85% developed following deceased donor liver transplant and 15% following living-related donor liver transplantation. The median follow-up period following liver transplantation was 84 days (interquartile range, 45-180). The median time from liver transplantation to graft-versus-host disease onset was 30 days (interquartile range, 21-42). The main clinical features included skin rash (59%), fever (43%), diarrhea (36%), and pancytopenia (30%). The overall mortality rate was 71%. Neither univariate (HR = 0.999; 95% CI, 0.493-2.023; p = 1.0) nor multivariate Cox regression analysis revealed a significant correlation between adaptation of immunosuppression and survival probability (HR = 1.475; 95% CI, 0.659-3.303; p = 0.3). CONCLUSIONS: This systematic review suggests that an increase in immunosuppressive regimen does not yield any survival benefit in patients suffering from graft-versus-host disease following liver transplantation.

Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering.

Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is promising, with early-phase clinical studies showing encouraging responses. However, the transcriptional signatures that control the fate of CAR-NK cells after infusion and factors that influence tumor control remain poorly understood. We performed single-cell RNA sequencing and mass cytometry to study the heterogeneity of CAR-NK cells and their in vivo evolution after adoptive transfer, from the phase of tumor control to relapse. Using a preclinical model of noncurative lymphoma and samples from a responder and a nonresponder patient treated with CAR19/IL-15 NK cells, we observed the emergence of NK cell clusters with distinct patterns of activation, function, and metabolic signature associated with different phases of in vivo evolution and tumor control. Interaction with the highly metabolically active tumor resulted in loss of metabolic fitness in NK cells that could be partly overcome by incorporation of IL-15 in the CAR construct.

Outcomes of Kidney Transplantation in Older Recipients.

BACKGROUND Access to kidney transplantation is limited for elderly patients with end-stage renal disease (ESRD), who often die while on the waiting list or receive kidneys from marginal deceased donors. In our transplantation center, most donated kidneys were from younger living relatives, in whom donations to elderly outcomes were not previously studied. In this study, we aimed to determine the short- and long-term outcomes of patients aged ³65 years to justify the use of kidneys from younger donors in older recipients. We also compared the outcomes between those who received kidneys from living donors (LDs) and deceased donors (DDs). MATERIAL AND METHODS We analyzed the patients' demographic data and the 1-, 5-, and 10-year patient and graft survival rates of patients aged ≥65 years who received kidney transplants between January 2005 and December 2020. RESULTS Among 158 patients, 136 received kidneys from LD and 22 from DD. The mean age was 69 years old. In this cohort, the most common cause of ESRD was diabetes. The graft survival rates were 99%, 96%, and 94% after 1, 5, and 10 years, respectively. Patient survival was 94%, 83%, and 61% after 1, 5, and 10 years, respectively. Delayed graft function rates, 1-year patient survival, and 5- and 10-year graft survival rates were lower in the DD group. Ischemic heart disease and transplantation from DD were independent risk factors for mortality. CONCLUSIONS Our study demonstrated reasonably good patient and graft survival rates in older patients. Outcomes were better in patients who received kidneys from LD.

Pediatric trauma and emergency surgery: an international cross-sectional survey among WSES members.

BACKGROUND: In contrast to adults, the situation for pediatric trauma care from an international point of view and the global management of severely injured children remain rather unclear. The current study investigates structural management of pediatric trauma in centers of different trauma levels as well as experiences with pediatric trauma management around the world. METHODS: A web-survey had been distributed to the global mailing list of the World Society of Emergency Surgery from 10/2021-03/2022, investigating characteristics of respondents and affiliated hospitals, case-load of pediatric trauma patients, capacities and infrastructure for critical care in children, trauma team composition, clinical work-up and individual experiences with pediatric trauma management in response to patients´ age. The collaboration group was subdivided regarding sizes of affiliated hospitals to allow comparisons concerning hospital volumes. Comparable results were conducted to statistical analysis. RESULTS: A total of 133 participants from 34 countries, i.e. 5 continents responded to the survey. They were most commonly affiliated with larger hospitals (> 500 beds in 72.9%) and with level I or II trauma centers (82.0%), respectively. 74.4% of hospitals offer unrestricted pediatric medical care, but only 63.2% and 42.9% of the participants had sufficient experiences with trauma care in children ≤ 10 and ≤ 5 years of age (p = 0.0014). This situation is aggravated in participants from smaller hospitals (p < 0.01). With regard to hospital size (≤ 500 versus > 500 in-hospital beds), larger hospitals were more likely affiliated with advanced trauma centers, more elaborated pediatric intensive care infrastructure (p < 0.0001), treated children at all ages more frequently (p = 0.0938) and have higher case-loads of severely injured children < 12 years of age (p = 0.0009). Therefore, the majority of larger hospitals reserve either pediatric surgery departments or board-certified pediatric surgeons (p < 0.0001) and in-hospital trauma management is conducted more multi-disciplinarily. However, the majority of respondents does not feel prepared for treatment of severe pediatric trauma and call for special educational and practical training courses (overall: 80.2% and 64.3%, respectively). CONCLUSIONS: Multi-professional management of pediatric trauma and individual experiences with severely injured children depend on volumes, level of trauma centers and infrastructure of the hospital. However, respondents from hospitals at all levels of trauma care complain about an alarming lack of knowledge on pediatric trauma management.

Path instability of an air bubble rising in water.

It has been documented since the Renaissance that an air bubble rising in water will deviate from its straight, steady path to perform a periodic zigzag or spiral motion once the bubble is above a critical size. Yet, unsteady bubble rise has resisted quantitative description, and the physical mechanism remains in dispute. Using a numerical mapping technique, we for the first time find quantitative agreement with high-precision measurements of the instability. Our linear stability analysis shows that the straight path of an air bubble in water becomes unstable to a periodic perturbation (a Hopf bifurcation) above a critical spherical radius of R = 0.926 mm, within 2% of the experimental value. While it was previously believed that the bubble's wake becomes unstable, we now demonstrate a new mechanism, based on the interplay between flow and bubble deformation.

Characteristics of de novo cancer in liver transplant recipients.

Liver transplant recipients receive immunosuppressive treatment to avoid organ rejection, increasing the risk of developing de novo cancer after transplantation. We investigated the cumulative incidence of de novo cancer in a cohort of Danish liver transplant recipients. The study was a retrospective cohort study of adult liver transplant recipients transplanted at Rigshospitalet, Copenhagen, Denmark, between January 1, 2010, and December 31, 2019. De novo cancer was defined as cancer arising at least 30 days after liver transplantation, excluding relapses from prior cancers and donor-derived cancers. We determined the incidence of de novo cancer in the cohort using the Aalen-Johansen estimator, with death and retransplantation as competing risks. We included 389 liver transplant recipients and identified 47 recipients (12%) with de novo cancer after liver transplantation, including 25 recipients with non-melanoma skin cancers. The cumulative incidences at 5 years after liver transplantation for all cancers and non-skin cancers were 10.7% and 4.9%, respectively. De novo cancer after liver transplantation is relatively common, with the majority being non-melanoma skin cancer. Future studies of sufficient size are needed to identify risk factors for de novo cancer after liver transplantation.

The role of the relative age effect on talent identification in professional road cycling.

This study aims to investigate the presence of the relative age effect (RAE) in (semi-)professional cycling, especially within selecting cyclists for Continental (CT) development teams. Data were collected from www.procyclingstats.com (PCS). Cyclists out of the top-25 countries of the PCS ranking that were part of a CT team between 2005 and 2016 and born between January 1986 and December 1997 were included (n = 2854). Distributions of cyclists in different birth quarters (Q1, Q2, Q3 and Q4) as well as for different starting years at CT level (U23year1, U23year2, U23year3 and U23year4) and reaching professional level or not were investigated using the Chi-square goodness-of-fit test. A RAE was found for cyclists that did not reach professional level, which can be explained by cyclists starting at CT level U23year1 and U23year2 (19 and 20 years old). Meaning that for cyclists at 19 and 20 years old, there is a selection bias towards relatively older (Q1) cyclists at the expense of relatively younger (Q4) cyclists. Within the cyclists that reached professional level, no RAE was found, indicating that the RAE diminishes at professional level. This study provides insight into possible selection errors while selecting cyclists for CT development teams.

Stem rust on barberry species in Europe: Host specificities and genetic diversity.

The increased emergence of cereal stem rust in southern and western Europe, caused by the pathogen Puccinia graminis, and the prevalence of alternate (sexual) host, Berberis species, have regained attention as the sexual host may serve as source of novel pathogen variability that may pose a threat to cereal supply. The main objective of the present study was to investigate the functional role of Berberis species in the current epidemiological situation of cereal stem rust in Europe. Surveys in 11 European countries were carried out from 2018 to 2020, where aecial infections from five barberry species were collected. Phylogenetic analysis of 121 single aecial clusters of diverse origin using the elongation factor 1-α gene indicated the presence of different special forms (aka formae speciales) of P. graminis adapted to different cereal and grass species. Inoculation studies using aecial clusters from Spain, United Kingdom, and Switzerland resulted in 533 stem rust isolates sampled from wheat, barley, rye, and oat, which confirmed the presence of multiple special forms of P. graminis. Microsatellite marker analysis of a subset of 192 sexually-derived isolates recovered on wheat, barley and rye from the three populations confirmed the generation of novel genetic diversity revealed by the detection of 135 multilocus genotypes. Discriminant analysis of principal components resulted in four genetic clusters, which grouped at both local and country level. Here, we demonstrated that a variety of Berberis species may serve as functional alternate hosts for cereal stem rust fungi and highlights the increased risks that the sexual cycle may pose to cereal production in Europe, which calls for new initiatives within rust surveillance, epidemiological research and resistance breeding.

Structural Characterization of Functionally Important Chloride Binding Sites in the Marine Vibrio Alkaline Phosphatase.

Enzyme stability and function can be affected by various environmental factors, such as temperature, pH, and ionic strength. Enzymes that are located outside the relatively unchanging environment of the cytosol, such as those residing in the periplasmic space of bacteria or extracellularly secreted, are challenged by more fluctuations in the aqueous medium. Bacterial alkaline phosphatases (APs) are generally affected by ionic strength of the medium, but this varies substantially between species. An AP from the marine bacterium Vibrio splendidus (VAP) shows complex pH-dependent activation and stabilization in the 0-1.0 M range of halogen salts and has been hypothesized to specifically bind chloride anions. Here, using X-ray crystallography and anomalous scattering, we have located two chloride binding sites in the structure of VAP, one in the active site and another one at a peripheral site. Further characterization of the binding sites using site-directed mutagenesis and small-angle X-ray scattering showed that upon binding of chloride to the peripheral site, structural dynamics decreased locally, resulting in thermal stabilization of the VAP active conformation. Binding of the chloride ion in the active site did not displace the bound inorganic phosphate product, but it may promote product release by facilitating rotational stabilization of the substrate-binding Arg129. Overall, these results reveal the complex nature and dynamics of chloride binding to enzymes through long-range modulation of electronic potential in the vicinity of the active site, resulting in increased catalytic efficiency and stability.

Enhanced recovery after surgery is feasible and safe in liver transplantation: a cohort study.

BACKGROUND: The principles of enhanced recovery after surgery (ERAS) are being applied to still more advanced procedures. Liver transplantation offers a unique opportunity for a multimodal approach including donor care as well. Our objective was to determine if ERAS was applicable and safe in orthotopic liver transplantation (OLT). METHODS: A national single centre retrospective study showing the implementation of ERAS from 2013 to 2019 with the proceeding 2 years serving as baseline. The primary endpoints were mortality, length of stay (LOS) in the ward and intensive care unit stay. Secondary endpoints were complications estimated by Dindo-Clavien classification, comprehensive complication index (CCI®) and re-admissions. RESULTS: A total of 334 patients were included. LOS was significantly reduced from a median of 22.5 days at introduction to 14 days at 2019. Cold ischaemia time was reduced from a mean of 10.7 to 6.0 h and the use of blood products (erythrocytes, plasma and thrombocytes) from a median of 28 to 6 units. Complications were reduced in severity. Mortality and readmission rates were not affected. CONCLUSION: ERAS principles are safe and recommended in patients undergoing OLT resulting in reduced severity of complications and LOS without affecting re-admissions or mortality.

Protocol for spike-triggered closed-loop auditory stimulation during sleep in patients with epilepsy.

Several epilepsies are characterized by interictal spikes in the electroencephalogram occurring preferentially during sleep. We present a closed-loop auditory stimulation protocol with potential for treating sleep epilepsies. We describe the pre-sleep preparations, sleep recordings, the auditory stimulation, in which tones are triggered upon spike detection, and post-sleep procedures. This protocol has been shown to decrease likelihood and amplitude of subsequent spikes in patients with BECTS (Benign epilepsy with centrotemporal spikes) and can be applied to study non-pharmacological treatments of sleep epilepsies. For complete details on the use and execution of this protocol, please refer to Klinzing et al. (2021).

Floral morphology and phenology of Sassafras tzumu (Lauraceae).

BACKGROUND: Sassafras has been considered to belong to trib. Laureae of Lauraceae and has been assumed to have unisexual flowers. However, recent molecular phylogenetic studies have consistently suggested that Sassafras does not belong to the trib. Laureae but to Cinnamomeae and that it is nested within Cinnamomum. A recent morphological study revealed that one of the Asian species, S. randaiense, possesses bisexual flowers that are plesiomorphic in the family Lauraceae. As reports on the flower structure of the second Asian species, S. tzumu, have been contradictory, we wanted to ascertain if it has bisexual flowers or not. If the flowers were bisexual, could earlier reports that they were unisexual have been based on dichogamous flowering? RESULTS: In this study, we investigated two populations of S. tzumu. We found that this species has determinate botryoid racemes, and possesses bisexual flowers. Among the three extant species, S. tzumu is more similar to its sister species S. randaiense but markedly different from the American S. albidum: the two Asian species possess bisexual flowers while the American species has unisexual flowers. The bisexual flower of S. tzumu is protogynous, and shows two phenological phases typical of Lauraceae: 1) in a flower, the pistil functions first, the stigma is fresh and white, stamens of the outer two whorls are spreading, anthers do not open, and the staminodes secrete nectar at this stage; 2) in the second phase, the stigma becomes brown, staminodes are withered, stamens of the third whorl stand up and surround the pistil, glands of the third whorl of stamens secrete nectar, and the anthers open and release pollen. CONCLUSIONS: The similarity of racemose inflorescences between Sassafras and some members of Laureae were caused by parallel evolution; the racemose inflorescence of ancestral Sassafras originated from the thyrsoid-cymose inflorescence in Cinnamomum. The Asian species S. tzumu and S. randaiense possess bisexual flowers with two phenological phases, the American S. albidum evolved unisexual flowers independently from other clades with unisexual flowers in the Lauraceae, i.e., the Laureae, Alseodaphnopsis in the Perseeae and the unisexual clade in the Ocotea complex of the Cinnamomeae.

Ex situ arterial reconstruction prior normothermic machine perfusion of liver grafts.

PURPOSE: Atypical variants of the hepatic artery are common and pose a technical challenge for normothermic machine perfusion (NMP). The transplant surgeon has three options when confronted with hepatic arterial variation in a liver graft to be subjected to NMP: to perform arterial reconstruction (i) prior, (ii) during, or (iii) following NMP. METHODS: Herein, we report our experience and technical considerations with pre-NMP reconstruction. Out of 52 livers, 9 had an atypical hepatic artery (HA): 3 replaced right HA, 3 replaced left HA, 1 accessory left HA, 1 accessory left and right HA, and 1 replaced left and right HA. RESULTS: Reconstruction was conducted during back-table preparation. A single vascular conduit was created in all grafts to allow single arterial cannulation for NMP, necessitating only one arterial anastomosis within the recipient. All grafts were subjected to NMP and subsequently successfully transplanted. CONCLUSION: Our approach is being advocated for as it preserves the ability to alter the reconstruction in case of problems resulting from the reconstruction itself, thereby allowing functional evaluation of the reconstruction prior transplantation, permitting simultaneous reperfusion in the recipient, and providing the shortest possible duration for vascular reconstruction once the graft is rewarming non-perfused within the recipient. In addition, in light of the frequency of technically demanding reconstructions with very small vessels, we consider our technique beneficial as the procedure can be performed under ideal conditions at the back-table.

Diagnostic prediction models for CT-confirmed and bacterial rhinosinusitis in primary care: individual participant data meta-analysis.

BACKGROUND: Antibiotics are overused in patients with acute rhinosinusitis (ARS) as it is difficult to identify those who benefit from antibiotic treatment. AIM: To develop prediction models for computed tomography (CT)-confirmed ARS and culture-confirmed acute bacterial rhinosinusitis (ABRS) in adults presenting to primary care with symptoms suggestive of ARS. DESIGN AND SETTING: This was a systematic review and individual participant data meta-analysis. METHOD: CT-confirmed ARS was defined as the presence of fluid level or total opacification in any maxillary sinuses, whereas culture-confirmed ABRS was defined by culture of fluid from antral puncture. Prediction models were derived using logistic regression modelling. RESULTS: Among 426 patients from three studies, 140 patients (32.9%) had CT-confirmed ARS. A model consisting of seven variables: previous diagnosis of ARS, preceding upper respiratory tract infection, anosmia, double sickening, purulent nasal discharge on examination, need for antibiotics as judged by a physician, and C-reactive protein (CRP) showed an optimism-corrected c-statistic of 0.73 (95% confidence interval [CI] = 0.69 to 0.78) and a calibration slope of 0.99 (95% CI = 0.72 to 1.19). Among 225 patients from two studies, 68 patients (30.2%) had culture-confirmed ABRS. A model consisting of three variables: pain in teeth, purulent nasal discharge, and CRP showed an optimism-corrected c-statistic of 0.70 (95% CI = 0.63 to 0.77) and a calibration slope of 1.00 (95% CI = 0.66 to 1.52). Clinical utility analysis showed that both models could be useful to rule out the target condition. CONCLUSION: Simple prediction models for CT-confirmed ARS and culture-confirmed ABRS can be useful to safely reduce antibiotic use in adults with ARS in high-prescribing countries.

Regulatory Programs of B-cell Activation and Germinal Center Reaction Allow B-ALL Escape from CD19 CAR T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy has led to tremendous successes in the treatment of B-cell malignancies. However, a large fraction of treated patients relapse, often with disease expressing reduced levels of the target antigen. Here, we report that exposing CD19+ B-cell acute lymphoblastic leukemia (B-ALL) cells to CD19 CAR T cells reduced CD19 expression within hours. Initially, CD19 CAR T cells caused clustering of CD19 at the T cell-leukemia cell interface followed by CD19 internalization and decreased CD19 surface expression on the B-ALL cells. CD19 expression was then repressed by transcriptional rewiring. Using single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing, we demonstrated that a subset of refractory CD19low cells sustained decreased CD19 expression through transcriptional programs of physiologic B-cell activation and germinal center reaction. Inhibiting B-cell activation programs with the Bruton's tyrosine kinase inhibitor ibrutinib increased the cytotoxicity of CD19 CAR T cells without affecting CAR T-cell viability. These results demonstrate transcriptional plasticity as an underlying mechanism of escape from CAR T cells and highlight the importance of combining CAR T-cell therapy with targeted therapies that aim to overcome this plasticity. See related Spotlight by Zhao and Melenhorst, p. 1040.