Multimodal cell atlas of the ageing human skeletal muscle.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.

Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

A dialogue-like cell communication mechanism is conserved in filamentous ascomycete fungi and mediates interspecies interactions.

In many filamentous fungi, germinating spores cooperate by fusing into supracellular structures, which develop into the mycelial colony. In the model fungus Neurospora crassa, this social behavior is mediated by an intriguing mode of communication, in which two fusing cells take turns in signal sending and receiving. Here we show that this dialogue-like cell communication mechanism is highly conserved in distantly related fungal species and mediates interspecies interactions. In mixed populations, cells of N. crassa and the phytopathogenic gray mold Botrytis cinerea coordinate their behavior over a spatial distance and establish physical contact. Subsequent cell­cell fusion is, however, restricted to germlings of the same species, indicating that species specificity of germling fusion has evolved not on the level of the signal/receptor but at subsequent levels of the fusion process. In B. cinerea, fusion and infectious growth are mutually exclusive cellular programs. Remarkably, the presence of N. crassa can reprogram this behavior and induce fusion of the gray mold on plant surfaces, potentially weakening its pathogenic potential. In a third fungal species, the nematode-trapping fungus Arthrobotrys flagrans, the conserved signaling mechanism mediates vegetative fusion within mycelial colonies but has also been repurposed for the formation of nematode-catching traps. In summary, this study identified the cell dialogue mechanism as a conserved complex trait and revealed that even distantly related fungi possess a common molecular language, which promotes cellular contact formation across species borders.

Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain.

AIMS: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons. METHODS: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology. RESULTS: Our data support the existence of pathogenic α-syn in both the gut and the brain, thus reinforcing the potential role of the ENS as a contributing factor in PD aetiology. Additionally, we have analysed the effect of a DSS-based rat model of gut inflammation to demonstrate (i) the appearance of P-α-syn inclusions in both Auerbach's and Meissner's plexuses (gut), (ii) an increase in α-syn expression in the ventral mesencephalon (brain) and (iii) the degeneration of nigral dopaminergic neurons, which all are considered classical hallmarks in PD. CONCLUSION: These results strongly support the plausibility of Braak's hypothesis and emphasise the significance of peripheral inflammation and the gut-brain axis in initiating α-syn aggregation and transport to the substantia nigra, resulting in neurodegeneration.

Galectin-3 is upregulated in frontotemporal dementia patients with subtype specificity.

INTRODUCTION: Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential. METHODS: We examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored. RESULTS: Gal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3. DISCUSSION: Our findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers.

Artificial intelligence for dysplasia detection during surveillance colonoscopy in patients with ulcerative colitis: A cross-sectional, non-inferiority, diagnostic test comparison study.

BACKGROUND AND STUDY AIM: High-definition virtual chromoendoscopy, along with targeted biopsies, is recommended for dysplasia surveillance in ulcerative colitis patients at risk for colorectal cancer. Computer-aided detection (CADe) systems aim to improve colonic adenoma detection, however their efficacy in detecting polyps and adenomas in this context remains unclear. This study evaluates the CADe Discovery™ system's effectiveness in detecting colonic dysplasia in ulcerative colitis patients at risk for colorectal cancer. PATIENTS AND METHODS: A prospective cross-sectional, non-inferiority, diagnostic test comparison study was conducted on ulcerative colitis patients undergoing colorectal cancer surveillance colonoscopy between January 2021 and April 2021. Patients underwent virtual chromoendoscopy (VCE) with iSCAN 1 and 3 with optical enhancement. One endoscopist, blinded to CADe Discovery™ system results, examined colon sections, while a second endoscopist concurrently reviewed CADe images. Suspicious areas detected by both techniques underwent resection. Proportions of dysplastic lesions and patients with dysplasia detected by VCE or CADe were calculated. RESULTS: Fifty-two patients were included, and 48 lesions analyzed. VCE and CADe each detected 9 cases of dysplasia (21.4% and 20.0%, respectively; p=0.629) in 8 patients and 7 patients (15.4% vs. 13.5%, respectively; p=0.713). Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy for dysplasia detection using VCE or CADe were 90% and 90%, 13% and 5%, 21% and 2%, 83% and 67%, and 29.2% and 22.9%, respectively. CONCLUSIONS: The CADe Discovery™ system shows similar diagnostic performance to VCE with iSCAN in detecting colonic dysplasia in ulcerative colitis patients at risk for colorectal cancer.

Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City region.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.

Generation of optical frequency combs by Q-switching integrated multi-section semiconductor lasers.

In this work we perform a theoretical and simulation analysis of the behavior of an integrated four section distributed Bragg reflector semiconductor laser under optical injection and Q-switching operation. An electro-absorption modulator is introduced into the laser cavity to control the total losses and perform Q-switching. The simulations are done using a rate equation model. Q-switching operation produces very short and high power pulses. This, together with the use of optical injection, allows obtaining flat and broad optical frequency combs with up to 2100 optical lines within 10 dB (642 lines within 3 dB) at a repetition frequency of 100 MHz. The high chirp of the pulses is responsible for the broad spectra of these combs in comparison with gain switched combs, and the device structure allows fabrication in commercial foundries using standard building blocks.

Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease.

Parkinson's Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which triggers neuronal degeneration in a mouse model of PD.

The effectiveness of matrix ablation with silver nitrate in the treatment of ingrown toenails. A single-center case-control study.

BACKGROUND: Partial onychectomy with chemical matrixectomy is considered the gold standard treatment for stage II-III ingrown toenails (IT). However, there are scarce reports describing the use of silver nitrate in IT management in adolescents. Our aim is to analyze the effectiveness of matrix ablation with silver nitrate and compare it with partial onychectomy by electrocautery. METHODS: A retrospective study of adolescent patients with stage II-III IT was performed. Those who underwent electrocautery matricectomy in a major outpatient surgical center (Group A) and those who were treated with silver nitrate at an outpatient clinic (Group B) were compared. Efficacy was determined by recurrence and postoperative infection rates. RESULTS: Two hundred and nine patients were included (86 group A; 123 group B), with a total of 382 partial onychectomies (151 group A; 231 group B). Group B patients exhibited a lower recurrence rate (4.7%) when compared to group A (11.2%, p = .02), and had a lower postoperative infection rate (4.0% group A vs. 1.7% group B; p = .18), although not statistically significant. CONCLUSION: Silver nitrate chemical matricectomy after partial onychectomy is an effective treatment for IT in adolescents, with few postoperative complications and low recurrence rate. Therefore, it should be considered as a possible alternative to electrocautery matricectomy.

Impacts of metal stress on extracellular microbial products, and potential for selective metal recovery.

Harnessing microbial capabilities for metal recovery from secondary waste sources is an eco-friendly and sustainable approach for the management of metal-containing wastes. Soluble microbial products (SMP) and extracellular polymeric substances (EPS) are the two main groups of extracellular compounds produced by microorganisms in response to metal stress that are of great importance for remediation and recovery of metals. These include various high-, and low, molecular weight components, which serve various functional and structural roles. These compounds often contain functional groups with metal binding potential that can attenuate metal stress by sequestering metal ions, making them less bioavailable. Microorganisms can regulate the content and composition of EPS and SMP in response to metal stress in order to increase the compounds specificity and capacity for metal binding. Thus, EPS and SMP represent ideal candidates for developing technologies for selective metal recovery from complex wastes. To discover highly metal-sorptive compounds with specific metal binding affinity for metal recovery applications, it is necessary to investigate the metal binding affinity of these compounds, especially under metal stressed conditions. In this review we critically reviewed microbial EPS and SMP production as a response to metal stress with a particular emphasis on the metal binding properties of these compounds and their role in altering metal bioavailability. Furthermore, for the first time, we compiled the available data on potential application of these compounds for selective metal recovery from waste streams.

Myotendinous Thermoregulation in National Level Sprinters after a Unilateral Fatigue Acute Bout-A Descriptive Study.

In the last decade there has been a growing interest in infrared thermography in the field of sports medicine in order to elucidate the mechanisms of thermoregulation. The aim of this study was to describe bilateral variations in skin temperature of the anterior thigh and patellar tendon in healthy athletes and to provide a model of baseline tendon and muscle thermoregulation in healthy sprinters following a unilateral isokinetic fatigue protocol. Fifteen healthy national-level sprinters (eleven men and four women), with at least 3 years of athletic training experience of 10-12 h/week and competing in national-level competitions, underwent unilateral isokinetic force testing and electrostimulation in which their body temperature was measured before, during, and after the protocol using an infrared thermographic camera. ANOVA detected a significant difference in the time × side interaction for patellar temperature changes (p ≤ 0.001) and a significant difference in the time/side interaction for quadriceps temperature changes (p ≤ 0.001). The thermal challenge produces homogeneous changes evident in quadriceps areas, but not homogeneous in tendon areas. These data show that metabolic and blood flow changes may depend on the physical and mechanical properties of each tissue. Future research could be conducted to evaluate the predictive value of neuromuscular fatigue in the patellar tendon and quadriceps after exercise in order to optimize post-exercise recovery strategies.

Quantification of Antiphospholipid Antibodies: The Importance of Using an Appropriate Methodology for Each Clinical Profile.

The presence of antiphospholipid antibodies (aPLs) is associated with antiphospholipid syndrome (APS), characterized by thrombosis and obstetric morbidity. aPLs included in APS classification criteria are lupus anticoagulant, anti-cardiolipin and anti-beta-2-glycoprotein-I of IgG or IgM isotypes. Enzyme-linked immunosorbent assay is the most used diagnostic technique to determine aPLs. Recently, new automated technologies mainly based in antigen-coated beads have been developed. The aim is to compare a fluorescence enzyme immunoassay (M1) and an antigen-coated bead assay (M2) in obstetric and thrombotic APS patients. All samples from the first 1020 patients received in the Immune Service Laboratory (Hospital 12 de Octubre) during the recruitment period, without exclusions, were analysed for aPLs. The weighted kappa for both methods in all the patients was 0.39 (0.30-0.47). Agreement increased to 0.56 (0.38-0.73) in patients with autoimmune disease. Sensitivity and specificity obtained for M1 were 17.1% and 89.3%, respectively, and 12.7% and 91.4% for M2. The sensibility and specificity of IgG isotypes were higher than the IgM ones. Regarding obstetric patients, M1 obtained significant diagnostic performance and had more sensitivity 23.75 (14.95-34.58) compared to M2 12.50 (6.16-21.79). In conclusion, clinical suspicion-based method selection for aPLs should be considered. To identify obstetric APS patients, solid phase methods remain more preferable.

GWAS-Identified Variants for Obesity Do Not Influence the Risk of Developing Multiple Myeloma: A Population-Based Study and Meta-Analysis.

Multiple myeloma (MM) is an incurable disease characterized by the presence of malignant plasma cells in the bone marrow that secrete specific monoclonal immunoglobulins into the blood. Obesity has been associated with the risk of developing solid and hematological cancers, but its role as a risk factor for MM needs to be further explored. Here, we evaluated whether 32 genome-wide association study (GWAS)-identified variants for obesity were associated with the risk of MM in 4189 German subjects from the German Multiple Myeloma Group (GMMG) cohort (2121 MM cases and 2068 controls) and 1293 Spanish subjects (206 MM cases and 1087 controls). Results were then validated through meta-analysis with data from the UKBiobank (554 MM cases and 402,714 controls) and FinnGen cohorts (914 MM cases and 248,695 controls). Finally, we evaluated the correlation of these single nucleotide polymorphisms (SNPs) with cQTL data, serum inflammatory proteins, steroid hormones, and absolute numbers of blood-derived cell populations (n = 520). The meta-analysis of the four European cohorts showed no effect of obesity-related variants on the risk of developing MM. We only found a very modest association of the POC5rs2112347G and ADCY3rs11676272G alleles with MM risk that did not remain significant after correction for multiple testing (per-allele OR = 1.08, p = 0.0083 and per-allele OR = 1.06, p = 0.046). No correlation between these SNPs and functional data was found, which confirms that obesity-related variants do not influence MM risk.

Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression?

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS (p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT (p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patients.

Effect of metals on mesophilic anaerobic digestion of strawberry extrudate in batch mode.

According to recent studies, the anaerobic digestion of strawberry extrudate is a promising option with potential in the berry industry biorefinery. However, the lack and/or unbalance of concentrations of metals in some agro-industrial residues could hamper methane production during the anaerobic digestion of these kinds of wastes. In this study, a fractional factorial design was applied to screen the supplementation requirements regarding six metals (Co, Ni, Fe, Cu, Mn, and Zn) for methane production from strawberry extrudate (SE). The logistic model was used to fit the experimental data of methane production-time. It allowed identifying two different stages in the anaerobic process and obtaining the kinetic parameters for each step. Maximum methane production obtained in the first (Bmax) kinetic stage, the methane production in the second stage (P), and the maximum methane production rates (Rmax) concluded a statistically significant effect for Ni and Zn. The second set of experiments was carried out with Ni and Zn through a central composite design to study the concentration effect in the anaerobic digestion process of the strawberry extrudate. The parameters P and Rmax demonstrated a positive interaction between Ni and Zn. Although, Bmax did not prove a statistically significant effect between Ni and Zn.

Does External Load Reflect Acute Neuromuscular Fatigue and Rating of Perceived Exertion in Elite Young Soccer Players?

ABSTRACT: Martínez-Serrano, A, Freitas, TT, Franquesa, X, Enrich, E, Mallol, M, and Alcaraz, PE. Does external load reflect acute neuromuscular fatigue and rating of perceived exertion in elite young soccer players? J Strength Cond Res 37(3): e1-e7, 2023-This study aimed to analyze the acute and residual effects of increased high-speed running (HSR) demands during an in-season training microcycle in young elite soccer players on localized neuromuscular fatigue (NMF) of the knee extensors (KE), posterior chain muscles, and rating of perceived exertion (RPE). Thirty-four elite young soccer players (age = 17.1 ± 0.8 years) were assessed in 2 consecutive days at different time points (baseline, POST-activation gym-based session, POST-small-sided game [SSG], POST-training 1 [TR1], POST-6H, POST-24H, POST-preventive gym-based session, and POST-training 2 [TR2]). Neuromuscular fatigue of the KE and posterior chain muscles was measured with a maximum voluntary isometric contraction (MVIC). External (total distance, number of accelerations or decelerations, and HSR distance) and internal (RPE) load was assessed during the SSG, TR1, and TR2 sessions. Players were divided through a median split, into "HIGH" or "LOW" group according to the training demands. The alpha level was set at p ≤ 0.05. A 2-way mixed effects model ANOVA showed a significant decreased in 90:20 MVIC after TR1 in the "HIGH" HSR group ( p = 0.037; effect size [ES] = 0.45). No significant differences in RPE were found after TR1 ( p = 0.637; ES = 0.58) and TR2 ( p = 0.109; ES = 0.62) when comparing the "HIGH" HSR group with the "LOW" HSR group. Assessing player's force production capabilities can be an effective strategy to detect NMF when HSR demands are acutely increased. Special caution should be taken when prescribing the training load of the training session based solely on RPE, as NMF might be present.

Fecal immunochemical test for hemoglobin versus fecal calprotectin to monitor endoscopic activity in inflammatory bowel disease.

AIM: endoscopy identifies inflammatory activity, however, it is an unpleasant test and is not always accessible. The aim of the study was to compare the usefulness of quantitative fecal immunochemical test (FIT) versus fecal calprotectin (FC) to determine endoscopic activity in patients with inflammatory bowel disease (IBD). METHODS: cross-sectional prospective observational study. The stool samples were collected within three days before starting the preparation for the colonoscopy. We used the Mayo index for ulcerative colitis (UC) and the simplified endoscopic index for Crohn's disease (CD). Mucosal healing (MH) was defined as the score 0 points in each of the endoscopic indices. RESULTS: eighty-four patients were included, 40 (47.6 %) with UC. In patients with IBD, FIT and FC showed a significant correlation with the presence of inflammatory activity/MH on endoscopy, with no statistically significant differences between the two receiver-operating characteristic (ROC) curves. Both tests improved their diagnostic performance when assessing patients with UC; the Spearman correlations between FIT and FC and endoscopic inflammatory activity were r = 0.6 (p = 0.0001) and r = 0.7 (p = 0.0001), respectively. In Crohn's disease, the diagnostic utility of both tests was lower. CONCLUSIONS: FIT is an alternative to monitor endoscopic activity among ulcerative colitis patients. In Crohn's disease, more studies are needed to determine the role of fecal biomarkers.

Immunogenicity of Anti-SARS-CoV-2 Vaccines in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and/or a defective antibody response to T-dependent and T-independent antigens. CVID response to immunization depends on the antigen type, the vaccine mechanism, and the specific patient immune defect. In CVID patients, humoral and cellular responses to the currently used COVID-19 vaccines remain unexplored. Eighteen CVID subjects receiving 2-dose anti-SARS-CoV-2 vaccines were prospectively studied. S1-antibodies and S1-specific IFN-γ T cell response were determined by ELISA and FluoroSpot, respectively. The immune response was measured before the administration and after each dose of the vaccine, and it was compared to the response of 50 healthy controls (HC). The development of humoral and cellular responses was slower in CVID patients compared with HC. After completing vaccination, 83% of CVID patients had S1-specific antibodies and 83% had S1-specific T cells compared with 100% and 98% of HC (p = 0.014 and p = 0.062, respectively), but neutralizing antibodies were detected only in 50% of the patients. The strength of both humoral and cellular responses was significantly lower in CVID compared with HC, after the first and second doses of the vaccine. Absent or discordant humoral and cellular responses were associated with previous history of autoimmunity and/or lymphoproliferation. Among the three patients lacking humoral response, two had received recent therapy with anti-B cell antibodies. Further studies are needed to understand if the response to COVID-19 vaccination in CVID patients is protective enough. The 2-dose vaccine schedule and possibly a third dose might be especially necessary to achieve full immune response in these patients.