American Cutaneous Leishmaniasis: Imported cases in Berlin 2000-2023.

BACKGROUND: American Cutaneous Leishmaniasis (ACL) shows variable response to therapy, but data on species-specific treatment efficacy is scarce. We describe the clinical characteristics and outcome of patients with ACL imported to a tertiary centre in Germany and determine whether species-specific therapy according to the 2014 "LeishMan" group recommendations is associated with cure. METHODS: A retrospective chart review was conducted at the Charité Institute of International Health in Berlin. We analysed data on PCR-confirmed ACL cases collected between 2000 and 2023. Systemic therapy included liposomal amphotericin B, miltefosine, pentavalent antimony, ketoconazole or itraconazole. Localized therapy included perilesional pentavalent antimony or paromomycin ointment. Cure was defined as re-epithelialization of ulcers or disappearance of papular-nodular lesions after 3 months of treatment. Logistic regression models were used to quantify the effect of species-specific systemic therapy on the outcome. RESULTS: 75 cases were analysed. Most patients were male (62%), median age was 35 years, no patient had a history of immunosuppression. The most common reason for travel was tourism (60%), the most common destination was Costa Rica (28%), the median duration of illness was 8 weeks, and most patients presented with ulcers (87%). Lesions were complex in 43%. The most common Leishmania (L.) species was L. braziliensis (28%), followed by L. panamensis (21%). 51/73 (70%) patients were cured after initial therapy and 17/21 (81%) after secondary therapy. Cure after systemic therapy was more frequent when species-specific treatment recommendations were followed (33/45; 73%), compared to when not followed, (6/17; 35%, P = 0.008). This association was independent of age, sex, previous therapy, complex lesions, and Leishmania species (adjusted OR, 5.06; 95% CI, 1.22-24.16). CONCLUSIONS: ACL is a rare, imported disease in Germany. Complex lesions were common, challenging successful therapy. This study highlights the importance of identifying the parasite species and suggests that a species-specific approach to treatment leads to better outcomes.

Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.

Background: Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Methods: Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. Results: We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 µg/mL, p=0.004). Conclusions: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. Funding: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). Clinical trial number: NCT04359654.

The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation.

Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.

A multicenter study of asymmetric and symmetric dimethylarginine as predictors of mortality risk in hospitalized COVID-19 patients.

Mortality of patients hospitalized with COVID-19 has remained high during the consecutive SARS-CoV-2 pandemic waves. Early discrimination of patients at high mortality risk is crucial for optimal patient care. Symmetric (SDMA) and asymmetric dimethylarginine (ADMA) have been proposed as possible biomarkers to improve risk prediction of COVID-19 patients. We measured SDMA, ADMA, and other L-arginine-related metabolites in 180 patients admitted with COVID-19 in four German university hospitals as compared to 127 healthy controls. Patients were treated according to accepted clinical guidelines and followed-up until death or hospital discharge. Classical inflammatory markers (leukocytes, CRP, PCT), renal function (eGFR), and clinical scores (SOFA) were taken from hospital records. In a small subgroup of 23 COVID-19 patients, sequential blood samples were available and analyzed for biomarker trends over time until 14 days after admission. Patients had significantly elevated SDMA, ADMA, and L-ornithine and lower L-citrulline concentrations than controls. Within COVID-19 patients, SDMA and ADMA were significantly higher in non-survivors (n = 41, 22.8%) than in survivors. In ROC analysis, the optimal cut-off to discriminate non-survivors from survivors was 0.579 µmol/L for SDMA and 0.599 µmol/L for ADMA (both p < 0.001). High SDMA and ADMA were associated with odds ratios for death of 11.45 (3.37-38.87) and 5.95 (2.63-13.45), respectively. Analysis of SDMA and ADMA allowed discrimination of a high-risk (mortality, 43.7%), medium-risk (15.1%), and low-risk group (3.6%); risk prediction was significantly improved over classical laboratory markers. We conclude that analysis of ADMA and SDMA after hospital admission significantly improves risk prediction in COVID-19.

Gut microbiota dysbiosis is associated with altered tryptophan metabolism and dysregulated inflammatory response in COVID-19.

The clinical course of COVID-19 is variable and often unpredictable. To test the hypothesis that disease progression and inflammatory responses associate with alterations in the microbiome and metabolome, we analyzed metagenome, metabolome, cytokine, and transcriptome profiles of repeated samples from hospitalized COVID-19 patients and uninfected controls, and leveraged clinical information and post-hoc confounder analysis. Severe COVID-19 was associated with a depletion of beneficial intestinal microbes, whereas oropharyngeal microbiota disturbance was mainly linked to antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine and reduced levels of several other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Moreover, reduced concentrations of various tryptophan metabolites were associated with depletion of Faecalibacterium, and tryptophan decrease and kynurenine increase were linked to enhanced production of inflammatory cytokines. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.

[Significant increase in malaria deaths in Germany after the end of the COVID-19 pandemic]. / Deutlicher Anstieg der Malaria-Todesfälle in Deutschland nach dem Ende der COVID-19-Pandemie.

In the context of the end of restrictions due to the COVID-19 pandemic, the renewed increase in international travel was accompanied by a disproportionate rise in deaths due to importated malaria in Germany. The COVID-19 pandemic has led to a delay in establishing the diagnosis of imported malaria, which is associated with a deterioration in the prognosis. In order to significantly reduce the number or completely avoid malaria deaths in Germany in the future, there is an urgent need to raise awareness among those involved in the healthcare system.Measures to effectively communicate the risk and appropriate measures to prevent malaria to travellers are necessary to reverse the negative trend. Rapid diagnosis and adequate management are important to improve survival. For this reason early presentation in the healthcare system in case of fever after returning from the tropics is necessary.

Cortical gyrification in women and men and the (missing) link to prenatal androgens.

Previous studies have reported sex differences in cortical gyrification. Since most cortical folding is principally defined in utero, sex chromosomes as well as gonadal hormones are likely to influence sex-specific aspects of local gyrification. Classic congenital adrenal hyperplasia (CAH) causes high levels of androgens during gestation in females, whereas levels in males are largely within the typical male range. Therefore, CAH provides an opportunity to study the possible effects of prenatal androgens on cortical gyrification. Here, we examined the vertex-wise absolute mean curvature-a common estimate for cortical gyrification-in individuals with CAH (33 women and 20 men) and pair-wise matched controls (33 women and 20 men). There was no significant main effect of CAH and no significant CAH-by-sex interaction. However, there was a significant main effect of sex in five cortical regions, where gyrification was increased in women compared to men. These regions were located on the lateral surface of the brain, specifically left middle frontal (rostral and caudal), right inferior frontal, left inferior parietal, and right occipital. There was no cortical region where gyrification was increased in men compared to women. Our findings do not only confirm prior reports of increased cortical gyrification in female brains but also suggest that cortical gyrification is not significantly affected by prenatal androgen exposure. Instead, cortical gyrification might be determined by sex chromosomes either directly or indirectly-the latter potentially by affecting the underlying architecture of the cortex or the size of the intracranial cavity, which is smaller in women.

Corpus callosum morphology and relationships to illness phenotypes in individuals with anorexia nervosa.

Anorexia nervosa is an often-severe psychiatric illness characterized by significantly low body weight, fear of gaining weight, and distorted body image. Multiple neuroimaging studies have shown abnormalities in cortical morphology, mostly associated with the starvation state. Investigations of white matter, while more limited in number, have suggested global and regional volume reductions, as well as abnormal diffusivity in multiple regions including the corpus callosum. Yet, no study has specifically examined thickness of the corpus callosum, a large white matter tract instrumental in the inter-hemispheric integration of sensory, motor, and cognitive information. We analyzed MRI data from 48 adolescents and adults with anorexia nervosa and 50 healthy controls, all girls/women, to compare corpus callosum thickness and examined relationships with body mass index (BMI), illness duration, and eating disorder symptoms (controlling for BMI). There were no significant group differences in corpus callosum thickness. In the anorexia nervosa group, severity of body shape concerns was significantly, positively correlated with callosal thickness in the rostrum, genu, rostral body, isthmus, and splenium. In addition, there were significant positive correlations between eating disorder-related obsessions and compulsions and thickness of the anterior midbody, rostral body, and splenium. There were no significant associations between callosal thickness and BMI or illness duration. In sum, those with AN with worse concerns about bodily appearance and worse eating disorder-related obsessive thought patterns and compulsive behaviours have regionally thicker corpus callosum, independent of current weight status. These findings provide important neurobiological links to key, specific eating disorder behavioural phenotypes.

Soluble ACE2 correlates with severe COVID-19 and can impair antibody responses.

Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 µg/mL total sACE2 in moderate and severe patients. Fifty percent of COVID-19 sera inhibited ACE2 activity, in contrast to 1.3% of healthy donors and 4% of non-COVID-19 pneumonia patients. A mild inverse correlation of a-sACE2 with RBM-directed serum antibodies was observed. In silico, we show that sACE2 concentrations measured in COVID-19 sera can disrupt germinal center formation and inhibit timely production of high-affinity antibodies. We suggest that sACE2 is a biomarker for COVID-19 and that soluble receptors may contribute to immune suppression informing vaccine design.

Clinically used broad-spectrum antibiotics compromise inflammatory monocyte-dependent antibacterial defense in the lung.

Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial therapy is a major risk factor for HAP, the underlying mechanism remains incompletely understood. Here, we demonstrate that antibiotic therapy in hospitalized patients is associated with decreased diversity of the gut microbiome and depletion of short-chain fatty acid (SCFA) producers. Infection experiments with mice transplanted with patient fecal material reveal that these antibiotic-induced microbiota perturbations impair pulmonary defense against MDR Klebsiella pneumoniae. This is dependent on inflammatory monocytes (IMs), whose fatty acid receptor (FFAR)2/3-controlled and phagolysosome-dependent antibacterial activity is compromized in mice transplanted with antibiotic-associated patient microbiota. Collectively, we characterize how clinically relevant antibiotics affect antimicrobial defense in the context of human microbiota, and reveal a critical impairment of IM´s antimicrobial activity. Our study provides additional arguments for the rational use of antibiotics and offers mechanistic insights for the development of novel prophylactic strategies to protect high-risk patients from HAP.

Clinical spectrum and long-term outcomes of mpox: a cohort study spanning from acute infection to six-month follow-up.

BACKGROUND: Cases of mpox have been reported worldwide since May 2022. Limited knowledge exists regarding the long-term course of this disease. To assess sequelae in terms of scarring and quality of life (QoL) in mpox patients 4-6 months after initial infection. METHODS: Prospective observational study on clinical characteristics and symptoms of patients with polymerase chain reaction (PCR)-confirmed mpox, including both outpatients and inpatients. Follow-up visits were conducted at 4-6 months, assessing the Patient and Observer Scar Assessment Scale (POSAS), the Dermatology Life Quality Index (DLQI) and sexual impairment, using a numeric rating scale (NRS) from 0 to 10. RESULTS: Forty-three patients, age range 19-64 years, 41 men (all identifying as MSM) and 2 women, were included. Upon diagnosis, skin or mucosal lesions were present in 93.0% of cases, with 73.3% reporting pain (median intensity: 8, Q1-Q3: 6-10). Anal involvement resulted in a significantly higher frequency of pain than genital lesions (RR: 3.60, 95%-CI: 1.48-8.74). Inpatient treatment due to pain, superinfection, abscess or other indications was required in 20 patients (46.5%). After 4-6 months, most patients did not have significant limitations, scars or pain. However, compared to patients without such complications, patients with superinfection or abscess during the acute phase had significantly more extensive scar formation (median PSAS: 24.0 vs. 11.0, p = 0.039) and experienced a significantly greater impairment of their QoL (median DLQI: 2.0 vs. 0.0, p = 0.036) and sexuality (median NRS: 5.0 vs. 0.0, p = 0.017). CONCLUSION: We observed a wide range of clinical mpox manifestations, with some patients experiencing significant pain and requiring hospitalization. After 4-6 months, most patients recovered without significant sequelae, but those with abscesses or superinfections during the initial infection experienced a significant reduction in QoL and sexuality. Adequate treatment, including antiseptic and antibiotic therapy during the acute phase, may help prevent such complications, and hence, improve long-term outcomes.

Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19.

Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later stages, yet the mechanisms that contribute to this remain unclear. Here we profiled single-nucleus transcriptomes and proteomes of brainstem tissue from deceased individuals at various stages of COVID-19. We detected an inflammatory type I interferon response in acute COVID-19 cases, which resolves in the late disease phase. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation, one neuronal with a direct focus on cranial nerve nuclei and a separate diffuse pattern affecting the whole brainstem. The latter reflects a bystander effect of the respiratory infection that spreads throughout the vascular unit and alters the transcriptional state of mainly oligodendrocytes, microglia and astrocytes, while alterations of the brainstem nuclei could reflect the connection of the immune system and the central nervous system via, for example, the vagus nerve. Our results indicate that even without persistence of severe acute respiratory syndrome coronavirus 2 in the central nervous system, local immune reactions are prevailing, potentially causing functional disturbances that contribute to neurological complications of COVID-19.

Endoscopic Features of Post-COVID-19 Cholangiopathy and Its Management Using ERCP.

INTRODUCTION: Despite growing awareness of post-coronavirus disease 2019 (COVID-19) cholangiopathy as one of the most serious long-term gastrointestinal consequences of COVID-19, the endoscopic features of this disease are still poorly characterized. This study aimed to more precisely define its endoscopic features and to outline the role of endoscopic retrograde cholangiopancreatography (ERCP) in the management of this entity. METHODS: In this observational study, 46 patients with confirmed post-COVID-19 cholangiopathy were included. RESULTS: Based on the endoscopic features observed in 141 ERCP procedures, post-COVID-19 cholangiopathy can be classified as a variant of secondary sclerosing cholangitis in critically ill patients. It appeared early in the course of intensive care treatment of patients with COVID-19 (cholestasis onset 4.5 days after intubation, median). This form of cholangiopathy was more destructive than stricturing in nature and caused irreversible damage to the bile ducts. A centripetal pattern of intrahepatic bile duct destruction, the phenomenon of vanishing bile ducts, the absence of extrahepatic involvement, and the presence of intraductal biliary casts (85% of patients) were typical cholangiographic features of post-COVID-19 cholangiopathy. This cholangiopathy was often complicated by small peribiliary liver abscesses with isolation of Enterococcus faecium and Candida spp. in bile culture. The prognosis was dismal, with a 1-year liver transplantation-free survival rate of 44%. In particular, patients with peribiliary liver abscesses or destruction of the central bile ducts tended to have a poor prognosis (n.s.). As shown by multivariate analysis, bilirubin levels (on intensive care unit day 25-36) negatively correlated with liver transplantation-free survival (hazard ratio 1.08, P < 0.001). Interventional endoscopy with cast removal had a positive effect on cholestasis parameters (gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubin); approximately 60% of all individual values decreased. DISCUSSION: Gastrointestinal endoscopy makes an important contribution to the management of post-COVID-19 cholangiopathy. ERCP is not only of great diagnostic and prognostic value but also has therapeutic value and therefore remains indispensable.

Oxonium ion scanning mass spectrometry for large-scale plasma glycoproteomics.

Protein glycosylation, a complex and heterogeneous post-translational modification that is frequently dysregulated in disease, has been difficult to analyse at scale. Here we report a data-independent acquisition technique for the large-scale mass-spectrometric quantification of glycopeptides in plasma samples. The technique, which we named 'OxoScan-MS', identifies oxonium ions as glycopeptide fragments and exploits a sliding-quadrupole dimension to generate comprehensive and untargeted oxonium ion maps of precursor masses assigned to fragment ions from non-enriched plasma samples. By applying OxoScan-MS to quantify 1,002 glycopeptide features in the plasma glycoproteomes from patients with COVID-19 and healthy controls, we found that severe COVID-19 induces differential glycosylation in IgA, haptoglobin, transferrin and other disease-relevant plasma glycoproteins. OxoScan-MS may allow for the quantitative mapping of glycoproteomes at the scale of hundreds to thousands of samples.

Reduced Age-Related Gray Matter Loss in the Orbitofrontal Cortex in Long-Term Meditators.

The orbitofrontal cortex (OFC) is a functionally heterogeneous brain region contributing to mental processes relating to meditation practices. The OFC has been reported to decline in volume with increasing age and differs in volume between meditation practitioners and non-practitioners. We hypothesized that the age-related decline of the OFC is diminished in meditation practitioners. We tested this hypothesis in a sample of 50 long-term meditators and 50 matched controls by correlating chronological age with regional gray matter volumes of the left and right OFC, as well as in seven left and right cytoarchitectonically defined subregions of the OFC (Fo1-Fo7). In both meditators and controls, we observed a negative relationship between age and OFC (sub)volumes, indicating that older participants have smaller OFC volumes. However, in meditators, the age-related decline was less steep compared to controls. These age-related differences reached significance for left and right Fo2, Fo3, Fo4, and Fo7, as well as left Fo5 and right Fo6. Since different subregions of the OFC are associated with distinct brain functions, further investigations are required to explore the functional implications of these findings in the context of meditation and the aging brain.

[Functional-neurosurgical treatment options for functional pelvic floor disorders : Value of sacral neuromodulation]. / Funktionell-neurochirurgische Therapieoptionen bei Funktionsstörungen des Beckenbodens : Stellenwert der sakralen Neuromodulation.

BACKGROUND: Sacral neuromodulation is an established minimally invasive therapy indicated for the treatment of functional pelvic floor disorders. While it received its original US Food and Drug Administration (FDA) approval for the treatment of overactive bladder symptoms, it is now regarded as a therapeutic option to treat both urinary/fecal incontinence and retention. In addition, it has proven to be a valuable tool in the treatment of chronic pelvic pain, and preliminary results indicate a potential to elicit improvements in sexual functioning. OBJECTIVE: This article serves to provide a summary of the therapy and its applications. METHOD: Selective literature review. RESULTS: Sacral neuromodulation implants allow for the controlled shifting of the autonomic control of bladder and rectum towards an inhibition or facilitation of voiding, dependent on the patient's needs and under the patient's control. At the same time and depending on the applied stimulation, the implants can interfere with the nerve's conduction of pain signals. This makes them a therapeutic option for pelvic pain that fails to respond to conventional treatment. Finally, there have been first reports suggesting improvements in sexual dysfunction under sacral neuromodulation, thus, potentially opening up a new line of therapy for those disorders. DISCUSSION: Sacral neuromodulation is a flexible and efficient form of therapy for functional disorders of the pelvic floor. Specifically, the same intervention can treat seemingly contradictory disorders such as urinary/fecal incontinence and retention as well as chronic pain.

Serum neurofilament light chain in COVID-19 and the influence of renal function.

COVID-19 is associated with various neurological symptoms. Serum neurofilament light chain (sNfL) is a robust marker for neuroaxonal injury. Recent studies have shown that elevated levels of sNfL are associated with unfavorable outcome in COVID-19 patients. However, neuroaxonal injury is rare in COVID-19, and renal dysfunction and hypoxia, both of which are known in severe COVID-19, can also increase sNfL levels. Thus, the meaning and mechanisms of sNfL elevation in COVID-19 patients remain unclear. We evaluated sNfL levels in 48 patients with COVID-19 (mean age = 63 years) and correlated them to clinical outcome, the form of oxygen therapy, and creatinine. Levels of sNfL were age adjusted and compared with normal values and z-scores. COVID-19 patients treated with nasal cannula had normal sNfL levels (mean sNfL = 19.6 pg/ml) as well as patients with high-flow treatment (mean sNfL = 40.8 pg/ml). Serum NfL levels were statistically significantly higher in COVID-19 patients treated with mechanical ventilation on intensive care unit (ICU) (mean sNfL = 195.7 pg/ml, p < 0.01). There was a strong correlation between sNfL elevation and unfavorable outcome in COVID-19 patients (p < 0.01). However, serum creatinine levels correlated directly and similarly with sNfL elevation and with unfavorable outcome in COVID-19 patients (p < 0.01). Additionally, multivariate analysis for serum creatinine and sNfL showed that both variables are jointly associated with clinical outcomes. Our results identify renal dysfunction as an important possible confounder for sNfL elevation in COVID-19. Thus, serum creatinine and renal dysfunction should be strongly considered in studies evaluating sNfL as a biomarker in COVID-19.

Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.

A design strategy to generate a SARS-CoV-2 RBD vaccine that abrogates ACE2 binding and improves neutralizing antibody responses.

The structure-based design of antigens holds promise for developing vaccines with higher efficacy and improved safety profiles. We postulate that abrogation of host receptor interaction bears potential for the improvement of vaccines by preventing antigen-induced modification of receptor function as well as the displacement or masking of the immunogen. Antigen modifications may yet destroy epitopes crucial for antibody neutralization. Here, we present a methodology that integrates deep mutational scans to identify and score SARS-CoV-2 receptor binding domain variants that maintain immunogenicity, but lack interaction with the widely expressed host receptor. Single point mutations were scored in silico, validated in vitro, and applied in vivo. Our top-scoring variant receptor binding domain-G502E prevented spike-induced cell-to-cell fusion, receptor internalization, and improved neutralizing antibody responses by 3.3-fold in rabbit immunizations. We name our strategy BIBAX for body-inert, B-cell-activating vaccines, which in the future may be applied beyond SARS-CoV-2 for the improvement of vaccines by design.