An immunogenomic exome landscape of triple positive primary antiphospholipid patients.

Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti ß2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.

Automatic Detection of Nuclear Spins at Arbitrary Magnetic Fields via Signal-to-Image AI Model.

Quantum sensors leverage matter's quantum properties to enable measurements with unprecedented spatial and spectral resolution. Among these sensors, those utilizing nitrogen-vacancy (NV) centers in diamond offer the distinct advantage of operating at room temperature. Nevertheless, signals received from NV centers are often complex, making interpretation challenging. This is especially relevant in low magnetic field scenarios, where standard approximations for modeling the system fail. Additionally, NV signals feature a prominent noise component. In this Letter, we present a signal-to-image deep learning model capable of automatically inferring the number of nuclear spins surrounding a NV sensor and the hyperfine couplings between the sensor and the nuclear spins. Our model is trained to operate effectively across various magnetic field scenarios, requires no prior knowledge of the involved nuclei, and is designed to handle noisy signals, leading to fast characterization of nuclear environments in real experimental conditions. With detailed numerical simulations, we test the performance of our model in scenarios involving varying numbers of nuclei, achieving an average error of less than 2 kHz in the estimated hyperfine constants.

High-Resolution NMR Spectroscopy at Large Fields with Nitrogen Vacancy Centers.

Ensembles of nitrogen-vacancy (NV) centers are used as sensors to detect nuclear magnetic resonance signals from micron-sized samples at room temperature. In this scenario, the regime of large magnetic fields is especially interesting as it leads to a large nuclear thermal polarization-thus, to a strong sensor response even in low concentration samples-while chemical shifts and J couplings become more accessible. Nevertheless, this regime remains largely unexplored owing to the difficulties of coupling NV-based sensors with high-frequency nuclear signals. In this Letter, we circumvent this problem with a method that maps the relevant energy shifts in the amplitude of an induced nuclear spin signal that is subsequently transferred to the sensor. This stage is interspersed with free-precession periods of the sample nuclear spins where the sensor does not participate. Thus, our method leads to high spectral resolutions ultimately limited by the coherence of the nuclear spin signal.

Tailored ion beam for precise colour centre creation.

We present an invariant-based quantum control scheme leading to a highly monochromatic ion beam from a Paul trap. Our protocol is implementable by supplying the segmented electrodes in the trap with voltages of the order of volts. This mitigates the impact of fluctuations in previous designs and leads to a low-dispersion beam of ions. Moreover, our proposal does not rely on sympathetically cooling ions, which bypasses the need of loading different species in the trap-namely, the propelled ion and, e.g. a [Formula: see text] to exert sympathetic cooling-significantly incrementing the repetition rate of the launching procedure. Our scheme is based on an invariant operator linear in position and momentum, which enables us to control the average extraction energy and the outgoing momentum spread. In addition, we propose a sequential operation to tailor the transversal properties of the beam before the ejection to minimize the impact spot and to increase the lateral resolution of the implantation. This article is part of the theme issue 'Shortcuts to adiabaticity: theoretical, experimental and interdisciplinary perspectives'.

Measles Sclerosing Subacute PanEncephalitis (SSPE), an intriguing and ever-present disease: Data, assumptions and new perspectives.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare, non-treatable and fatal neurological complication of measles, still present due to the return of the epidemic linked to the loosening of vaccination policies. Its mechanism remains unexplained. OBJECTIVE: The main objective was to investigate explanatory variables relating to the risk of developing SSPE and its pathophysiology. METHODS: Literature analysis was focused on different varieties of SSPE: perinatal forms, short-incubation forms similar to acute measles inclusion body encephalitis (MIBE), rapidly evolving forms, forms occurring in the immunosuppressed, adult forms, and family forms. In addition, several studies on the parameters of innate immunity and interferon responses of patients were analyzed. RESULTS: Two main data were highlighted: a relationship between the so-called fulminant forms and the prescription of corticosteroids was established. In familial SSPE, two groups were individualized according to the duration of the latency period, prompting an analysis of patient exomes. CONCLUSION: Treatment with corticosteroids should be banned. Knowledge of the genes involved and epigenetics should be useful for understanding the pathophysiology of SSPE and other late-onset neurological infections with RNA viruses.

Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency.

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell-depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

Modulated Continuous Wave Control for Energy-Efficient Electron-Nuclear Spin Coupling.

We develop energy efficient, continuous microwave schemes to couple electron and nuclear spins, using phase or amplitude modulation to bridge their frequency difference. These controls have promising applications in biological systems, where microwave power should be limited, as well as in situations with high Larmor frequencies due to large magnetic fields and nuclear magnetic moments. These include nanoscale NMR where high magnetic fields achieves enhanced thermal nuclear polarization and larger chemical shifts. Our controls are also suitable for quantum information processors and nuclear polarization schemes.

Soft Quantum Control for Highly Selective Interactions among Joint Quantum Systems.

We propose a quantum control scheme aimed at interacting systems that gives rise to highly selective coupling among their near-to-resonance constituents. Our protocol implements temporal control of the interaction strength, switching it on and off again adiabatically. This soft temporal modulation significantly suppresses off-resonant contributions in the interactions. Among the applications of our method we show that it allows us to perform an efficient rotating-wave approximation in a wide parameter regime, the elimination of side peaks in quantum sensing experiments, and selective high-fidelity entanglement gates on nuclear spins with close frequencies. We apply our theory to nitrogen-vacancy centers in diamond and demonstrate the possibility for the detection of weak electron-nuclear coupling under the presence of strong perturbations.

Vulvar Basal Cell Carcinoma: Four Case Reports With Immunohistochemical Study.

Basal cell carcinomas (BCC) are the most frequent tumours in humans and normally appear in photoexposed areas of the skin. It is widely accepted that BCCs originate at follicular stem cells and consequently are very rare in nonhairy areas. Here, we report 4 cases of vulvar BCC, 3 of which were located in a vulvar semimucous area, a nonphotoexposed area, and a nonhairy area. We have determined the CK7 and CK19 profile of all cases; both are markers of simple epithelium with glandular differentiation. Interestingly, all cases were positively stained for CK7 and CK19. Considering that the vulvar region is rich in sebaceous and apocrine units, we hypothesise a glandular origin of BCCs situated in the vulvar region.

Early life traits of farm and wild Atlantic salmon Salmo salar and first generation hybrids in the south coast of Newfoundland.

This study examined fertilization rates, survival and early life-trait differences of pure farm, wild and first generation (F1) hybrid origin embryos after crossing farm and wild Atlantic salmon Salmo salar. Results show that despite a trend towards higher in vitro fertilization success for wild females, differences in fertilization success in river water are not significantly different among crosses. In a hatchery environment, wild females' progeny (pure wild and hybrids with wild maternal parent) hatched 7-11 days earlier than pure farm crosses and hybrids with farm maternal parents. In addition, pure wild progeny had higher total lengths (LT ) at hatch than pure farm crosses and hybrids. Directions in trait differences need to be tested in a river environment, but results clearly show the maternal influence on early stages beyond egg-size differences. Differences in LT were no longer significant at 70 days post hatch (shortly after the onset of exogenous feeding) showing the need to investigate later developmental stages to better assess somatic growth disparities due to genetic differences. Higher mortality rates of the most likely hybrids (farm female × wild male hybrids) at egg and fry stages and their delayed hatch suggest that these F1 hybrids might be less likely to survive the early larval stages than wild stocks.

A genome-wide association study of pulmonary tuberculosis in Morocco.

Although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (PTB) susceptibility, the identification of specific genes and alleles influencing PTB risk has proven to be difficult. Previous genome-wide association (GWA) studies have identified only three novel loci with modest effect sizes in sub-Saharan African and Russian populations. We performed a GWA study of 550,352 autosomal SNPs in a family-based discovery Moroccan sample (on the full population and on the subset with PTB diagnosis at <25 years), which identified 143 SNPs with p < 1 × 10(-4). The replication study in an independent case/control sample identified four SNPs displaying a p < 0.01 implicating the same risk allele. In the combined sample including 556 PTB subjects and 650 controls these four SNPs showed suggestive association (2 × 10(-6) < p < 4 × 10(-5)): rs358793 and rs17590261 were intergenic, while rs6786408 and rs916943 were located in introns of FOXP1 and AGMO, respectively. Both genes are involved in the function of macrophages, which are the site of latency and reactivation of Mycobacterium tuberculosis. The most significant finding (p = 2 × 10(-6)) was obtained for the AGMO SNP in an early (<25 years) age-at-onset subset, confirming the importance of considering age-at-onset to decipher the genetic basis of PTB. Although only suggestive, these findings highlight several avenues for future research in the human genetics of PTB.

Noise-Resilient Quantum Computing with a Nitrogen-Vacancy Center and Nuclear Spins.

Selective control of qubits in a quantum register for the purposes of quantum information processing represents a critical challenge for dense spin ensembles in solid-state systems. Here we present a protocol that achieves a complete set of selective electron-nuclear gates and single nuclear rotations in such an ensemble in diamond facilitated by a nearby nitrogen-vacancy (NV) center. The protocol suppresses internuclear interactions as well as unwanted coupling between the NV center and other spins of the ensemble to achieve quantum gate fidelities well exceeding 99%. Notably, our method can be applied to weakly coupled, distant spins representing a scalable procedure that exploits the exceptional properties of nuclear spins in diamond as robust quantum memories.

Measuring Entanglement in a Photonic Embedding Quantum Simulator.

Measuring entanglement is a demanding task that usually requires full tomography of a quantum system, involving a number of observables that grows exponentially with the number of parties. Recently, it was suggested that adding a single ancillary qubit would allow for the efficient measurement of concurrence, and indeed any entanglement monotone associated with antilinear operations. Here, we report on the experimental implementation of such a device-an embedding quantum simulator-in photonics, encoding the entangling dynamics of a bipartite system into a tripartite one. We show that bipartite concurrence can be efficiently extracted from the measurement of merely two observables, instead of 15, without full tomographic information.

Practical application of brief cognitive tests.

INTRODUCTION: Brief cognitive tests (BCT) may help detect cognitive impairment (CI) in the clinical setting. Several BCT have been developed and/or validated in our country, but we lack specific recommendations for use. DEVELOPMENT: Review of studies on the diagnostic accuracy of BCT for CI, using studies conducted in Spain with BCT which take less than 20 min. We provide recommendations of use based on expert consensus and established on the basis of BCT characteristics and study results. CONCLUSION: The Fototest, the Memory Impairment Screen (MIS) and the Mini-Mental State Examination (MMSE) are the preferred options in primary care; other BCT (Clock Drawing Test [CDT], test of verbal fluency [TVF]) may also be administered in cases of negative results with persistent suspected CI or concern (stepwise approach). In the specialised care setting, a systematic assessment of the different cognitive domains should be conducted using the Montreal Cognitive Assessment, the MMSE, the Rowland Universal Dementia Assessment, the Addenbrooke's Cognitive Examination, or by means of a stepwise or combined approach involving more simple tests (CDT, TVF, Fototest, MIS, Memory Alteration Test, Eurotest). Associating an informant questionnaire (IQ) with the BCT is superior to the BCT alone for the detection of CI. The choice of instruments will depend on the patient's characteristics, the clinician's experience, and available time. The BCT and IQ must reinforce - but never substitute - clinical judgment, patient-doctor communication, and inter-professional dialogue.

Core Content for Undergraduate Medical Education in Spain: Recommendations of the Instructors' Group of the Spanish Academy of Dermatology and Venereology (AEDV).

BACKGROUND: Skin problems are among the most frequent reasons for seeking medical attention in primary care. In recent years, as a result of the process of adapting medical curricula to the requirements of the European Higher Education Area, the amount of time students spend learning the concepts of dermatology has been reduced in many universities. MATERIAL AND METHODS: In order to reach a consensus on core content for undergraduate education in dermatology, we sent a survey to the 57 members of the instructors' group of the Spanish Academy of Dermatology and Venereology (AEDV), asking their opinions on what objectives should be set for a dermatology course in Spain. A total of 131 previously selected objectives were listed. We then applied the Delphi method to achieve consensus on which ones the respondents considered important or very important (score≥4 on a Likert scale). RESULTS: Nineteen responses (33%) were received. On the second round of the Delphi process, 68 objectives achieved average scores of at least 4. The respondents emphasized that graduates should understand the structure and functions of the skin and know about bacterial, viral, and fungal skin infections, the most common sexually transmitted diseases (STDs), and the 4 main inflammatory dermatoses. Students should also learn about common complaints, such as itching and bald patches; the management of dermatologic emergencies; purpura and erythema nodosum as signs of internal disease; and the prevention of STDs and skin cancer. During clinical clerkships students should acquire the communication skills they will need to interview patients, write up a patient's medical history, and refer the patient to a specialist. CONCLUSIONS: The AEDV's group of instructors have defined their recommendations on the core content that medical faculties should adopt for the undergraduate subject of dermatology in Spain.

Fermion-fermion scattering in quantum field theory with superconducting circuits.

We propose an analog-digital quantum simulation of fermion-fermion scattering mediated by a continuum of bosonic modes within a circuit quantum electrodynamics scenario. This quantum technology naturally provides strong coupling of superconducting qubits with a continuum of electromagnetic modes in an open transmission line. In this way, we propose qubits to efficiently simulate fermionic modes via digital techniques, while we consider the continuum complexity of an open transmission line to simulate the continuum complexity of bosonic modes in quantum field theories. Therefore, we believe that the complexity-simulating-complexity concept should become a leading paradigm in any effort towards scalable quantum simulations.