Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan-Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448-4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619-8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093-0.732) and obesity (aOR 0.105, 95%CI 0.014-0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration. Interpretation: Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir. Funding: EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Phylogenomic analyses provide insights into primate evolution

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our study reveals that many key genomic innovations occurred in the Simiiformes ancestral node and may have had an impact on the adaptive radiation of the Simiiformes and human evolution

Posterior probability for the topology (A), second coalescent event (B) and first coalescent event (C) of a 100 kb msprime simulation.

“First” and “second” refer to the order in which coalescent events happen, backwards in time. The true empirical topology and coalescent times are plotted as green lines.</p

Supplementary notes, including Figs A to S, and Tables A and B.

S1 Text contains a detailed description of the theoretical framework and implementation of TRAILS, together with supplementary analyses. (PDF)</p

Increasing the complexity of TRAILS reduces the bias of the estimated parameters.

(A) Diagram (not to scale) of the demographic model with all the optimized parameters in blue for the non-ultrametric case. In an ultrametric model, t1 would correspond to the time from present to the shallowest speciation event, where t1 = tA = tB = tC − t2. (B) Relative error of parameter values estimated from 20 simulated msprime genomes for nAB = nABC = 1 (in pink) and nAB = nABC = 5 (in green). Each independent run corresponds to a dot, vertical lines are median values, and vertical lines correspond to interquartile ranges. Units are normalized as (estimated-true)/estimated to ease comparison across parameters.</p

TRAILS output for 50 Mb of chromosome 1 of the HCGO alignment.

(A) Estimates for the speciation times (green) and ancestral Ne (purple) of the speciation process, optimized using TRAILS and assuming a mutation rate of μ = 1.25 × 10−8 per site per generation. To convert time from generations to millions of years, a generation time of g = 25 years per generation was used. (B) Genome-wide variation of ILS, and first and second coalescent times. (C) Posterior decoding of the topology, and first and second coalescent events for a zoomed-in region in chromosome 1. As in Fig 3, both V0 and V1 correspond to the species topology (((H,C),G),O);, V2 corresponds to (((H,G),C),O);, and V3 to (((C,G),H),O);. The LDLRAD1 gene is plotted on top, where exons are represented as boxes, coding regions as filled boxes, and introns as horizontal lines.</p

The posterior probability can be used to detect deviations from the neutral expectation.

(A) Posterior probability of the second coalescent event for a simulated 200 kb region containing a positively selected variant at position 100 kb that arises in interval S0, represented by a triangle. The true simulated coalescent times are plotted as green horizontal lines. (B) Mean posterior probability for each second coalescent interval (purple), and the empirical true proportion of sites for each interval (green) for 20 simulated replicates with a selective sweep, using the same model as in (A). The theoretical neutral expectation is plotted as a black dashed line, and time intervals are adjusted so that all intervals have equal probability of observing a coalescent event. Continuous vertical lines represent mean values of the simulations. (C) Same as in (B), but for a neutrally evolving region, using the same model as in Fig 3.</p

TRAILS is a HMM that reconstructs the time-resolved multi-species ARG for three genomes.

TRAILS extends the isolation model (B) [19] to three species, by combining the time discretization of PSMC-like models (A) [8] with the topologically aware hidden states of CoalHMM (C) [20, 21]. The resulting hidden states of TRAILS (D) are three-leaved genealogies with two discretized coalescent events and one of four possible topologies. A full list of the 27 possible hidden states when nAB = nABC = 3 can be consulted in Fig K in S1 Text.</p

Utilidad diagnóstica de la ecografía tiroidea clínica a pie de cama en el paciente hospitalizado con sospecha de tirotoxicosis. Hospital General Universitario Gregorio Marañón

Objective: To analyze the diagnostic utility of thyroid ultrasound in hospitalized patients with suspected thyrotoxicosis. Materials and methods: An observational, cross-sectional and descriptive study was carried out in patients with suspected thyrotoxicosis whose consultation was sent to the Endocrinology and Nutrition Service of the aforementioned hospital during a period of 12 months (May 2018 to May 2019) evaluating a total of 14 patients. A member of the department's team of endocrinologists (who was unaware of the clinical data) performed the bedside ultrasound evaluation during hospitalization. Results: Of the 14 patients evaluated, 71.4% (n = 10) were women, overall age was 59.5 years (p25-p75: 50 - 70), with the most frequent admission service being cardiology with 50 % (n=7), presence of arrhythmia the most common reason for admission (39.9%; n=6) and the use of beta-blockers as the predominant drugs (50%; n=7). Only 28.6% n=4) of the evaluated patients had a history of hyperthyroidism. The level of concordance between the presumptive diagnosis prior to thyroid ultrasound and the final diagnosis during follow-up was k=0.424 (p&lt;0.001), while between the diagnosis after thyroid ultrasound and the final diagnosis during follow-up was k=0.832 (p&lt;0.001). Conclusion: Thyroid ultrasound is a useful tool in the management of patients with thyrotoxicosis in a hospitalization ward. Keywords: ultrasound, thyroid, thyrotoxicosis, diagnosis, thyroiditis.Objetivo: Valorar la utilidad diagnóstica de la ecografía tiroidea clínica en pacientes hospitalizados con sospecha de tirotoxicosis. Materiales y métodos: Se realizó un estudio observacional, transversal y descriptivo en pacientes con sospecha de tirotoxicosis cuya interconsulta fue enviada al Servicio de Endocrinología y Nutrición del mencionado hospital durante un periodo de 12 meses (mayo de 2018 a mayo de 2019) evaluándose un total de 14 pacientes. Un miembro del equipo de endocrinólogos del servicio (que desconocía los datos clínicos) efectuó la valoración ecográfica a pie de cama Resultados: De los 14 pacientes evaluados, el 71,4% (n=10) fueron mujeres, el promedio de edad fue 59,5 años (p25-p75: 50 – 70), siendo el servicio de ingreso más frecuente cardiología con 50% (n=7), la presencia de arritmia el motivo de ingreso más común (39,9%; n=6) y el uso de betabloqueantes como fármacos predominantes (50%; n=7). Solo 28,6% (n=4) de los pacientes evaluados presentaban antecedente de hipertiroidismo. El nivel de concordancia entre el diagnostico de presunción previo a la ecografía tiroidea y el diagnostico final durante el seguimiento fue k=0,424 (p&lt;0,001), mientras que la concordancia entre el diagnostico posterior a la ecografía tiroidea y el diagnostico final durante el seguimiento fue k=0,832 (p&lt;0,001). Conclusión: La ecografía tiroidea es una herramienta útil en el manejo de pacientes con tirotoxicosis en una planta de hospitalización Palabras clave: ecografía, tiroides, tirotoxicosis, diagnostico, tiroiditis