Modulation of neuronal activity in human centromedian nucleus during an auditory attention and working memory task.

Centromedian nucleus (CM) is one of several intralaminar nuclei of the thalamus and is thought to be involved in consciousness, arousal, and attention. CM has been suggested to play a key role in the control of attention, by regulating the flow of information to different brain regions such as the ascending reticular system, basal ganglia, and cortex. While the neurophysiology of attention in visual and auditory systems has been studied in animal models, combined single unit and LFP recordings in human have not, to our knowledge, been reported. Here, we recorded neuronal activity in the CM nucleus in 11 patients prior to insertion of deep brain stimulation electrodes for the treatment of epilepsy while subjects performed an auditory attention task. Patients were requested to attend and count the infrequent (p = 0.2) odd or "deviant" tones, ignore the frequent standard tones and report the total number of deviant tones at trial completion. Spikes were discriminated, and LFPs were band pass filtered (5-45 Hz). Average peri­stimulus time histograms and spectra were constructed by aligning on tone onsets and statistically compared. The firing rate of CM neurons showed selective, multi-phasic responses to deviant tones in 81% of the tested neurons. Local field potential analysis showed selective beta and low gamma (13-45 Hz) modulations in response to deviant tones, also in a multi-phasic pattern. The current study demonstrates that CM neurons are under top-down control and participate in the selective processing during auditory attention and working memory. These results, taken together, implicate the CM in selective auditory attention and working memory and support a role of beta and low gamma oscillatory activity in cognitive processes. It also has potential implications for DBS therapy for epilepsy and non-motor symptoms of PD, such as apathy and other disorders of attention.

Allogeneic haematopoietic cell transplantation for therapy-related myeloid neoplasms arising following treatment for lymphoma: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Therapy-related myeloid neoplasms (t-MN), either myelodysplastic neoplasms (t-MDS) or acute myeloid leukemias (t-AML), have a poor prognosis and allogeneic haematopoietic cell transplantation (allo-HCT) represents the only curative option. In this multicenter, registry-based study, we analyzed outcomes of 378 patients undergoing first allo-HCT between 2006-2017 for t-MN arising secondary to lymphoma treatment. Median age was 58 years at allo-HCT; 222 (59%) had a diagnosis of t-MDS and 156 (41%) of t-AML, respectively. At the time of allo-HCT, 46% of t-MN cases were reported as in complete remission (CR) and 15% of lymphomas were recorded as not in remission. A reduced intensity conditioning regimen was used in 70% of cases. For the entire cohort, 5-year OS, and t-MN PFS, relapse incidence and NRM were 32%, 28%, 35% and 37%, respectively. In multivariable analysis, undergoing allo-HCT with t-MN not in CR and older age were associated with significantly worse OS, PFS and NRM. At 5 years post allo-HCT, the relapse incidence of lymphoma was low at 3%, while the rate of secondary malignancies was 8%. This analysis shows the curative potential of allo-HCT for patients with t-MN arising secondary to lymphoma treatment in approximately a third of patients.

Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study.

BACKGROUND: We previously reported that the "Endothelial Activation and Stress Index" (EASIX; ((creatinine×lactate dehydrogenase)÷thrombocytes)) measured before start of conditioning predicts mortality after allogeneic hematopoietic stem cell transplantation (alloSCT) when used as continuous score. For broad clinical implementation, a prospectively validated EASIX-pre cut-off is needed that defines a high-risk cohort and is easy to use. METHOD: In the current study, we first performed a retrospective cohort analysis in n=2022 alloSCT recipients and identified an optimal cut-off for predicting non-relapse mortality (NRM) as EASIX-pre=3. For cut-off validation, we conducted a multicenter prospective study with inclusion of n=317 first alloSCTs from peripheral blood stem cell in adult patients with acute leukemia, lymphoma or myelodysplastic syndrome/myeloproliferative neoplasms in the European Society for Blood and Marrow Transplantation network. RESULTS: Twenty-three % (n=74) of alloSCT recipients had EASIX-pre ≥3 taken before conditioning. NRM at 2 years was 31.1% in the high EASIX group versus 11.5% in the low EASIX group (p<0.001). Patients with high EASIX-pre also had worse 2 years overall survival (51.6% vs 70.9%; p=0.002). We were able to validate the cut-off and found that EASIX ≥3 was associated with more than twofold increased risk for NRM in multivariate analysis (HR=2.18, 95% CI 1.2 to 3.94; p=0.01). No statistically significant difference could be observed for the incidence of relapse. CONCLUSIONS: The results of this study provide a prospectively validated standard laboratory biomarker index to estimate the transplant-related mortality risk after alloSCT. EASIX ≥3 taken before conditioning identifies a population of alloSCT recipients who have a more than twofold increased risk of treatment-related mortality.

Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT.

We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p < 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%, p < 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively, p = 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively, p = 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%, p < 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98, p = 0.9 and 23.4% versus 20.6%, HR = 0.92, p = 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95, p = 0.67; 61.4% versus 66.4%, HR = 0.91, p = 0.51 and 46.3% versus 48.2%, HR = 0.92, p = 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML.

Severe cytopenia after CD19 CAR T-cell therapy: a retrospective study from the EBMT Transplant Complications Working Party.

We investigated the incidence and outcome of anti-CD19 chimeric antigen receptor (CAR) T-cells-associated Common Terminology Criteria for Adverse Events (CTCAE) ≥grade 3 cytopenia. In the EBMT CAR-T registry, we identified 398 adult patients with large B-cell lymphoma who had been treated with CAR-T-cells with axicel (62%) or tisacel (38%) before August 2021 and had cytopenia status documented for the first 100 days. Most patients had received two or three previous lines of therapy, however, 22.3% had received four or more. Disease status was progressive in 80.4%, stable in 5.0% and partial/complete remission in 14.6%. 25.9% of the patients had received a transplantation before. Median age was 61.4 years (min-max; IQR=18.7-81; (52.9-69.5)).The cumulative incidence of ≥grade 3 cytopenia was 9.0% at 30 days (95% CI (6.5 to 12.1)) and 12.1% at 100 days after CAR T-cell infusion (95% CI (9.1 to 15.5)). The median time from CAR-T infusion to cytopenia onset was 16.5 days (min-max; IQR=1-90; (4-29.8)). Grade 3 and grade 4 CTCAE cytopenia occurred in 15.2% and 84.8%, respectively. In 47.6% there was no resolution.Severe cytopenia had no significant impact on overall survival (OS) (HR 1.13 (95% CI 0.74 to 1.73), p=0.57). However, patients with severe cytopenia had a poorer progression-free survival (PFS) (HR 1.54 (95% CI 1.07 to 2.22), p=0.02) and a higher relapse incidence (HR 1.52 (95% CI 1.04 to 2.23), p=0.03). In those patients who developed severe cytopenia during the first 100 days (n=47), OS, PFS, relapse incidence and non-relapse mortality at 12 months after diagnosis of severe cytopenia were 53.6% (95% CI (40.3 to 71.2)), 20% (95% CI (10.4 to 38.6)), 73.5% (95% CI (55.2 to 85.2)) and 6.5% (95% CI (1.7 to 16.2)), respectively.In multivariate analysis of severe cytopenia risk factors, only year of CAR-T infusion (HR=0.61, 95% CI (0.39 to 0.95), p=0.028) and total number of treatment lines before CAR-T infusion (one or two lines vs three or more, HR=0.41, 95% CI (0.21 to 0.83), p=0.013) had a significant positive association with the incidence of cytopenia. Other factors, such as previous transplantation, disease status at time of CAR-T, patient age and patient sex, had no significant association.Our data provide insight on frequency and clinical relevance of severe cytopenia after CAR T-cell therapy in the European real-world setting.

Role of allogeneic hematopoietic cell transplant for relapsed/refractory aggressive B-cell lymphomas in the CART era.

Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y Terapia Celular (GETH-TC) registry, we selected patients with the following characteristics: CART or alloHCT performed between 2016 and 2021; ≥18 years old; ABCL diagnosis; ≥2 lines of therapy; and either anti-CD19 CART or alloHCT as therapy at relapse. The analysis included a total of 316 (CART = 215, alloHCT = 101) patients. Median follow-up was 15 and 36 months for the CART and alloHCT cohorts, respectively. In the multivariate analysis, CART was confirmed to be similar to alloHCT for the primary study endpoint (progression-free survival) (hazard ratio [HR] 0.92, CI95%:0.56-1.51, p = 0.75). Furthermore, when the analysis was limited to only patients with chemo-sensitive diseases (complete and partial response) at infusion (CART = 26, alloHCT=93), no differences were reported (progression-free survival at month +18: 65% versus 55%, p = 0.59). However, CART had lower non-relapse mortality (HR 0.34, 95% CI: 0.13-0.85, p = 0.02). Given the lower toxicity and similar survival outcomes, these results suggest the use of CART before alloHCT.

Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P<0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.

Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT.

Whether to choose Haploidentical (Haplo) or one-antigen mismatched unrelated donor (1Ag-MMUD) hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) remains an unanswered question. We compared PTCy- Haplo-HCT to PTCy-1Ag-MMUD-HCT for acute myeloid leukemia (AML) in complete remission (three groups: 1Ag-MMUD using peripheral blood (1Ag-MMUD-PB; n = 155); Haplo using bone marrow (Haplo-BM; n = 647) or peripheral blood (Haplo-PB; n = 949)). Haplo-BM and Haplo-PB had a higher non-relapse mortality (NRM) compared to 1Ag-MMUD-PB (HR 2.28, 95% CI 1.23-4.24, p < 0.01; HR 2.65, 95% CI 1.46-4.81, p < 0.01, respectively). Haplo groups experienced a lower leukemia-free survival (LFS) compared to 1Ag-MMUD-PB (Haplo-BM: HR 1.51, 95% CI 1.06-2.14, p = 0.02; Haplo-PB: 1.47, 95% CI 1.05-2.05, p = 0.02); overall survival (OS) was also lower in Haplo-HCT (Haplo-BM: HR 1.50, 95% CI 1.02-2.21, p = 0.04; Haplo-PB: HR 1.51, 95% CI 1.05-2.19, p = 0.03). No differences were observed for graft-versus-host/relapse-free survival (GRFS) and relapse incidence (RI). Haplo-BM was associated with a lower risk of grade III-IV acute graft-versus-host disease (GVHD) (HR 0.44, 95% CI 0.24-0.81; p < 0.01), while no statistical differences were observed between groups for grade II-IV aGVHD and for cGVHD. Use of PTCy in 1Ag-MMUD-HCT is a valid alternative to consider when using alternative donors. Larger analysis of 1Ag-MMUD versus Haplo-HCT are warranted.

Popliteal artery pseudoaneurysm caused by non-penetrating trauma in a patient with hereditary multiple osteochondromatosis.

Hereditary multiple osteochondromatosis is a genetic condition characterized by the appearance of numerous osteochondromas, which can cause pseudoaneurysms in rare cases. The following article describes a 15-year-old patient with a history of current massages as part of his gym routine, who arrived at the emergency department with 4 days of pain, and ecchymosis in the right popliteal region. Therefore, duplex ultrasonography and arteriography were performed, confirming the diagnosis of popliteal pseudoaneurysm, which was subsequently treated by open surgery, providing a satisfactory outcome.

Prospective cohort study in the early stage of the COVID-19 pandemic, General Pueyrredón, Argentina (INECOVID): infection dynamics and risk factors. / Estudio de cohortes prospectivo en etapa temprana de la pandemia COVID-19, Partido de General Pueyrredón, Argentina (INECOVID): dinámica de infección y factores de riesgo.

OBJECTIVE: To establish the magnitude and risk factors for SARS-CoV-2 infection in the General Pueyrredón, Buenos Aires, Argentina: the INECOVID study. METHODS: Prospective cohort designed with participants from the District general population. The follow-up period was from June 22nd to December 18th, 2020, with a minimum appointment interval of 21 days. Data were obtained via questionnaires and serum or plasma samples. The primary event was considered as the time to seroconversion (IgG) as evidence of SARS-CoV-2 infection. The accumulated risk of infection was estimated using the Kaplan Meier method. Cox models were built with time-dependent variables. RESULTS: 345 participants were recruited (n=222 women, 64.3%; 123 men, 35.7%), with a median age of 45 years in women (Interquartile range: 19) and 49 in men (Interquartile range: 26). 12.8% of participants (n=44) had evidence of SARS-CoV-2 infection [incidence density of 9.1 cases (women: 11.1, men: 5.1) per 10,000 person-day]. 36.4% of the cases (n=16) were asymptomatic. The following factors were associated to the risk of infection: being in close contact of a confirmed COVID-19 case (HR=5.56; 95%CI 2.85-10.83), being a health worker (HR=2.93; 95%CI 1.55-5.52), living in crowded conditions (HR=2.23; 95%CI 1.13-4.49), and age (HR=0.98; 95%CI 0.95-1.00). CONCLUSION: The identified risk factors endorse the protection policies and protocols adopted by the Argentinian sanitary authorities for the general population and the care programs for health workers in the pre-vaccination phase.

OBJETIVO: Establecer la magnitud y los factores de riesgo de infección por SARS-CoV-2 en el Partido de General Pueyrredón, Buenos Aires, Argentina: estudio INECOVID. MÉTODOS: Diseño de cohortes prospectivo con participantes de población general del partido. El período de seguimiento fue del 22 de junio al 18 de diciembre de 2020, con un intervalo mínimo de citación de 21 días. Los datos se obtuvieron mediante cuestionarios y muestras de suero o plasma. El evento primario fue el tiempo hasta la seroconversión (IgG) como evidencia de infección por SARS-CoV-2. Se estimó el riesgo acumulado de infección por el método de Kaplan Meier. Se construyeron modelos de Cox con variables tiempo-dependientes. RESULTADOS: Fueron reclutados 345 participantes (n=222 mujeres, 64,3%; 123 hombres, 35,7%), con una edad mediana de 45 años en mujeres (Rango intercuartílico: 19) y 49 en hombres (Rango intercuartílico: 26). El 12,8% de los participantes (n=44) tuvieron evidencia de infección por SARS-CoV-2 [densidad de incidencia de 9,1 casos (mujeres: 11,1, hombres: 5,1) por 10.000 personas-días]. El 36,4% de los casos (n=16) fueron asintomáticos. Se mostraron asociados al riesgo de infección: ser contacto estrecho de un caso confirmado de COVID-19 (HR=5,56; IC95% 2,85­10,83), ser trabajador de salud (HR=2,93; IC95% 1,55-5,52), vivir en hacinamiento (HR=2,23; IC95% 1,13­4,49) y edad (HR=0,98; IC95% 0,95­1,00). CONCLUSIÓN: Los factores de riesgo de infección hallados avalan las políticas y protocolos de protección adoptados por las autoridades sanitarias de Argentina para la población general y los programas de atención a los trabajadores de la salud en la etapa pre-vacunación.

Prospective cohort study in the early stage of the COVID-19 pandemic, District of General Pueyrredón, Argentina (INECOVID): infection dynamics and risk factors / Estudio de cohortes prospectivo en etapa temprana de la pandemia COVID-19, Partido de General Pueyrredón, Argentina (INECOVID): dinámica de infección y factores de riesgo

Objective: to establish the magnitude and risk factors for SARS-CoV-2 infection in the District of General Pueyrredón, Buenos Aires, Argentina: the INECOVID study. Methodology: a prospective cohort was designed with participants from the District general population. The follow-up period was from June 22 to December 18, 2020, with a minimum appointment interval of 21 days. Data were obtained via questionnaires and serum or plasma samples. The primary event was considered as the time through seroconversion as evidence of SARS-CoV-2 infection. The accumulated risk of infection was estimated using the Kaplan Meier method. Cox models were built with time-dependent variables. Results: 345 participants were recruited (n = 222 women, 64.3%; 123 men, 35.7%), with a median age of 45 years in women (Interquartile range: 19) and 49 in men (Interquartile range: 26). 12.8% of participants (n = 44) had evidence of SARS-CoV-2 infection [incidence density of 9.1 cases (women: 11.1, men: 5.1) per 10,000 person-day]. 36.4% of the cases (n=16) were asymptomatic. The following factors were associated to the risk of infection: being a close contact of a confirmed COVID-19 case (HR=5,56; IC95% 2,85-10,83), being a health worker (HR=2,93; IC95% 1,55-5,52), living in crowded conditions (HR= 2,23; IC95% 1,13-4,49) and age (HR= 0,98; IC95% 0,95-1,00). Conclusion: the identified risk factors endorse the protection policies and protocols adopted by the Argentinian sanitary authorities for the general population and the care programs for health workers in the pre-vaccination phase.

Objetivo: establecer la magnitud y los factores de riesgo de infección por SARS-CoV-2 en el Partido de General Pueyrredón, Buenos Aires, Argentina: estudio INECOVID. Métodos: diseño de cohortes prospectivo con participantes de población general del partido. El período de seguimiento fue del 22 de junio al 18 de diciembre de 2020, con un intervalo mínimo de citación de 21 días. Los datos se obtuvieron mediante cuestionarios y muestras de suero o plasma. El evento primario fue el tiempo hasta la seroconversión (IgG) como evidencia de infección por SARS-CoV-2. Se estimó el riesgo acumulado de infección por el método de Kaplan Meier. Se construyeron modelos de Cox con variables tiempo-dependientes. Resultados: fueron reclutados 345 participantes (n=222 mujeres, 64,3%; 123 varones, 35,7%), con una edad mediana de 45 años en mujeres (Rango intercuartílico: 19) y 49 en varones (Rango intercuartílico: 26).  El 12,8% de los participantes (n=44) tuvo evidencia de infección por SARS-CoV-2 [densidad de incidencia de 9,1 casos (mujeres: 11,1, varones: 5,1) por 10.000 días-persona]. El 36,4% de los casos (n=16) fue asintomático. Se mostraron asociados al riesgo de infección: ser contacto estrecho de un caso confirmado de COVID-19 (HR=5,56; IC95% 2,85-10,83), ser trabajador de salud (HR=2,93; IC95% 1,55-5,52), vivir en hacinamiento (HR= 2,23; IC95% 1,13-4,49) y edad (HR= 0,98; IC95% 0,95-1,00). Conclusión: los factores de riesgo de infección hallados avalan las políticas y protocolos de protección adoptadas por las autoridades sanitarias de Argentina para población general y los programas de cuidado de los trabajadores de salud en la etapa pre-vacunación.

Estudio de cohortes prospectivo en etapa temprana de la pandemia COVID-19, Partido de General Pueyrredón, Argentina (INECOVID): dinámica de infección y factores de riesgo / Prospective cohort study in the early stage of the COVID-19 pandemic, General Pueyrredón, Argentina (INECOVID): infection dynamics and risk factors

RESUMEN: Objetivo: Establecer la magnitud y los factores de riesgo de infección por SARS-CoV-2 en el Partido de General Pueyrredón, Buenos Aires, Argentina: estudio INECOVID. Métodos: Diseño de cohortes prospectivo con participantes de población general del partido. El período de seguimiento fue del 22 de junio al 18 de diciembre de 2020, con un intervalo mínimo de citación de 21 días. Los datos se obtuvieron mediante cuestionarios y muestras de suero o plasma. El evento primario fue el tiempo hasta la seroconversión (IgG) como evidencia de infección por SARS-CoV-2. Se estimó el riesgo acumulado de infección por el método de Kaplan Meier. Se construyeron modelos de Cox con variables tiempo-dependientes. Resultados: Fueron reclutados 345 participantes (n=222 mujeres, 64,3%; 123 hombres, 35,7%), con una edad mediana de 45 años en mujeres (Rango intercuartílico: 19) y 49 en hombres (Rango intercuartílico: 26). El 12,8% de los participantes (n=44) tuvieron evidencia de infección por SARS-CoV-2 [densidad de incidencia de 9,1 casos (mujeres: 11,1, hombres: 5,1) por 10.000 personas-días]. El 36,4% de los casos (n=16) fueron asintomáticos. Se mostraron asociados al riesgo de infección: ser contacto estrecho de un caso confirmado de COVID-19 (HR=5,56; IC95% 2,85-10,83), ser trabajador de salud (HR=2,93; IC95% 1,55-5,52), vivir en hacinamiento (HR=2,23; IC95% 1,13-4,49) y edad (HR=0,98; IC95% 0,95-1,00). Conclusión: Los factores de riesgo de infección hallados avalan las políticas y protocolos de protección adoptados por las autoridades sanitarias de Argentina para la población general y los programas de atención a los trabajadores de la salud en la etapa pre-vacunación.

ABSTRACT Objective: To establish the magnitude and risk factors for SARS-CoV-2 infection in the General Pueyrredón, Buenos Aires, Argentina: the INECOVID study. Methods: Prospective cohort designed with participants from the District general population. The follow-up period was from June 22nd to December 18th, 2020, with a minimum appointment interval of 21 days. Data were obtained via questionnaires and serum or plasma samples. The primary event was considered as the time to seroconversion (IgG) as evidence of SARS-CoV-2 infection. The accumulated risk of infection was estimated using the Kaplan Meier method. Cox models were built with time-dependent variables. Results: 345 participants were recruited (n=222 women, 64.3%; 123 men, 35.7%), with a median age of 45 years in women (Interquartile range: 19) and 49 in men (Interquartile range: 26). 12.8% of participants (n=44) had evidence of SARS-CoV-2 infection [incidence density of 9.1 cases (women: 11.1, men: 5.1) per 10,000 person-day]. 36.4% of the cases (n=16) were asymptomatic. The following factors were associated to the risk of infection: being in close contact of a confirmed COVID-19 case (HR=5.56; 95%CI 2.85-10.83), being a health worker (HR=2.93; 95%CI 1.55-5.52), living in crowded conditions (HR=2.23; 95%CI 1.13-4.49), and age (HR=0.98; 95%CI 0.95-1.00). Conclusion: The identified risk factors endorse the protection policies and protocols adopted by the Argentinian sanitary authorities for the general population and the care programs for health workers in the pre-vaccination phase.

EMA Review of Daratumumab (Darzalex) for the Treatment of Adult Patients Newly Diagnosed with Multiple Myeloma.

The use of daratumumab in combination with established regimens for the treatment of newly diagnosed multiple myeloma has recently been authorized by the European Medicines Agency based on results from three separate phase III randomized, active controlled, open-label studies that have confirmed enhanced efficacy and tolerability in both transplant-ineligible (MMY3008 and MMY3007) and transplant-eligible (MMY3006) patients, without compromising transplant ability. Trial MMY3008 showed an improvement in progression-free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone; the median PFS had not been reached in the daratumumab arm and was 31.9 months in the control arm (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.43-0.73; p < .0001). Trial MMY3007 showed an improvement in PFS when daratumumab was added to bortezomib, melphalan, and prednisone compared with bortezomib, melphalan, and prednisone; PFS had not been reached in the daratumumab arm and was 18.1 months in the control arm (HR, 0.5; 95% CI, 0.38-0.65; p < .0001). In trial MMY3006, daratumumab added to bortezomib, thalidomide, and dexamethasone was compared with bortezomib, thalidomide, and dexamethasone as induction and consolidation treatment prior to autologous stem cell transplant. The stringent complete response rate at day 100 after transplant in the daratumumab group was 29% compared with 20% in the control group (odds ratio, 1.60; 1.21-2.12 95% CI; p = .0010). Overall adverse events were manageable, with an increased rate of neutropenia and infections in the daratumumab arms. Regulatory assessment of efficacy and safety results from trials MMY3006, MMY3007, and MMY3008 confirmed a positive benefit-risk ratio leading to an approval of the extensions of indication. IMPLICATIONS FOR PRACTICE: A set of extensions of indication was recently approved for daratumumab (Darzalex) in the setting of newly diagnosed multiple myeloma in combination with established regimens. Results of the MMY3006, MMY3007, and MMY3008 trials have shown enhanced efficacy and a favorable side effect profile of several daratumumab-based combinations in patients both ineligible and eligible for transplant, without compromising transplant ability. The combinations of daratumumab with either lenalidomide and low-dose dexamethasone or bortezomib, melphalan, and prednisone were approved for transplant-ineligible patients. The combination of daratumumab with bortezomib, thalidomide, and dexamethasone was approved for transplant-eligible patients. These combinations are expected to improve the survival outlook for patients with multiple myeloma, without an unacceptable risk of increase in adverse events, and updated information on progression-free survival and overall survival is expected from the above trials.

Feature selection based multivariate time series forecasting: An application to antibiotic resistance outbreaks prediction.

Antimicrobial resistance has become one of the most important health problems and global action plans have been proposed globally. Prevention plays a key role in these actions plan and, in this context, we propose the use of Artificial Intelligence, specifically Time Series Forecasting techniques, for predicting future outbreaks of Methicillin-resistant Staphylococcus aureus (MRSA). Infection incidence forecasting is approached as a Feature Selection based Time Series Forecasting problem using multivariate time series composed of incidence of Staphylococcus aureus Methicillin-sensible and MRSA infections, influenza incidence and total days of therapy of both of Levofloxacin and Oseltamivir antimicrobials. Data were collected from the University Hospital of Getafe (Spain) from January 2009 to January 2018, using months as time granularity. The main contributions of the work are the following: the applications of wrapper feature selection methods where the search strategy is based on multi-objective evolutionary algorithms (MOEA) along with evaluators based on the most powerful state-of-the-art regression algorithms. The performance of the feature selection methods has been measured using the root mean square error (RMSE) and mean absolute error (MAE) performance metrics. A novel multi-criteria decision-making process is proposed in order to select the most satisfactory forecasting model, using the metrics previously mentioned, as well as the slopes of model prediction lines in the 1, 2 and 3 steps-ahead predictions. The multi-criteria decision-making process is applied to the best models resulting from a ranking of databases and regression algorithms obtained through multiple statistical tests. Finally, to the best of our knowledge, this is the first time that a feature selection based multivariate time series methodology is proposed for antibiotic resistance forecasting. Final results show that the best model according to the proposed multi-criteria decision making process provides a RMSE = (0.1349, 0.1304, 0.1325) and a MAE = (0.1003, 0.096, 0.0987) for 1, 2, and 3 steps-ahead predictions.

Outcomes of Advanced Hodgkin Lymphoma after Umbilical Cord Blood Transplantation: A Eurocord and EBMT Lymphoma and Cellular Therapy & Immunobiology Working Party Study.

Allogeneic stem cell transplantation is an alternative for patients with relapsed or refractory Hodgkin lymphoma (HL), but only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 131 adults with HL who underwent UCBT in European Society for Blood and Marrow Transplantation centers from 2003 to 2015. Disease status at UCBT was complete remission (CR) in 59 patients (47%), and almost all patients had received a previous autologous stem cell transplantation. The 4-year progression-free survival (PFS) and overall survival (OS) were 26% (95% confidence interval [CI], 19% to 34%) and 46% (95% CI, 37% to 55%), respectively. Relapse incidence was 44% (95% CI, 36% to 54%), and nonrelapse mortality (NRM) was 31% (95% CI, 23% to 40%) at 4 years. In multivariate analysis refractory/relapsed disease status at UCBT was associated with increased relapse incidence (hazard ratio [HR], 3.14 [95% CI, 1.41 to 7.00], P = .005) and NRM (HR, 3.61 [95% CI, 1.58 to 8.27], P = .002) and lower PFS (HR, 3.45 [95% CI, 1.95 to 6.10], P < .001) and OS (HR, 3.10 [95% CI, 1.60 to 5.99], P = .001). Conditioning regimen with cyclophosphamide + fludarabine + 2 Gy total body irradiation (Cy+Flu+2GyTBI) was associated with decreased risk of NRM (HR, .26 [95% CI, .10 to .64], P = .004). Moreover, Cy+Flu+2GyTBI conditioning regimen was associated with a better OS (HR, .25 [95% CI, .12 to .50], P < .001) and PFS (HR, .51 [95% CI, .27 to .96], P = .04). UCBT is feasible in heavily pretreated patients with HL. The reduced-intensity conditioning regimen with Cy+Flu+2GyTBI is associated with a better OS and NRM. However, outcomes are poor in patients not in CR at UCBT.

T-cell replete haploidentical stem cell transplantation attenuates the prognostic impact of FLT3-ITD in acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Acute myeloid leukemia (AML) patients harboring the FLT3-ITD mutation are considered a high risk patient subset preferentially allocated for allogeneic stem cell transplantation in first remission. Whether FLT3-ITD retains a prognostic role in haploidentical stem cell transplantation (haplo-SCT) is unknown. To analyze the prognostic impact of FLT3-ITD in haplo-SCT, we performed a retrospective analysis of the multicenter registry of the acute leukemia working party of the European Society for Blood and Marrow Transplantation. We included all adult AML patients with known FLT3 status who underwent a first T-cell replete related haplo-HCT in first complete remission from 2005 to 2016. We evaluated 293 patients of whom 202 were FLT3wt and 91 were FLT3-ITD mutated. FLT3-ITD patients were more likely to be NPM1 mutated as well as be in the intermediate risk cytogenetic risk category. In multivariate analysis, patients with FLT3-ITD had comparable rates of relapse incidence [Hazard ratio (HR) = 1.34, confidence interval (CI) 95%, 0.67-2.7; P = .9] and leukemia-free survival (HR = 0.99, CI 95%, 0.62-1.57; P = .9) to those of FLT3wt patients. Overall survival, the incidence of nonrelapse mortality, and graft versus host disease-free/relapse-free survival were not significantly impacted by FLT3-ITD status. Furthermore, relapse and overall survival were comparable between FLT3-ITD patients transplanted from various donor pools, namely matched siblings, unrelated donors, haplo-SCT). Finally, subset analysis of patients with intermediate risk cytogenetics confirmed the absence of a prognostic impact of FLT3-ITD also for this patient segment. In AML patients undergoing T-cell replete haplo-SCT, the FLT3-ITD mutation possibly does not retain its prognostic significance.

Single-unit analysis of the human posterior hypothalamus and red nucleus during deep brain stimulation for aggressivity.

OBJECTIVE Deep brain stimulation (DBS) of the posterior hypothalamus (PH) has been reported to be effective for aggressive behavior in a number of isolated cases. Few of these case studies have analyzed single-unit recordings in the human PH and none have quantitatively analyzed single units in the red nucleus (RN). The authors report on the properties of ongoing neuronal discharges in bilateral trajectories targeting the PH and the effectiveness of DBS of the PH as a treatment for aggressive behavior. METHODS DBS electrodes were surgically implanted in the PH of 1 awake patient with Sotos syndrome and 3 other anesthetized patients with treatment-resistant aggressivity. Intraoperative extracellular recordings were obtained from the ventral thalamus, PH, and RN and analyzed offline to discriminate single units and measure firing rates and firing patterns. Target location was based on the stereotactic coordinates used by Sano et al. in their 1970 study and the location of the dorsal border of the RN. RESULTS A total of 138 units were analyzed from the 4 patients. Most of the PH units had a slow, irregular discharge (mean [± SD] 4.5 ± 2.7 Hz, n = 68) but some units also had a higher discharge rate (16.7 ± 4.7 Hz, n = 15). Two populations of neurons were observed in the ventral thalamic region as well, one with a high firing rate (mean 16.5 ± 6.5 Hz, n = 5) and one with a low firing rate (mean 4.6 ± 2.8 Hz, n = 6). RN units had a regular firing rate with a mean of 20.4 ± 9.9 Hz and displayed periods of oscillatory activity in the beta range. PH units displayed a prolonged period of inhibition following microstimulation compared with RN units that were not inhibited. Patients under anesthesia showed a trend for lower firing rates in the PH but not in the RN. All 4 patients displayed a reduction in their aggressive behavior after surgery. CONCLUSIONS During PH DBS, microelectrode recordings can provide an additional mechanism to help identify the PH target and surrounding structures to be avoided such as the RN. PH units can be distinguished from ventral thalamic units based on their response to focal microstimulation. The RN has a characteristic higher firing rate and a pattern of beta oscillations in the spike trains. The effect of the anesthetic administered should be considered when using microelectrode recordings. The results of this study, along with previous reports, suggest that PH DBS may be an effective treatment for aggression.

Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial.

BACKGROUND: The standard of care for smouldering multiple myeloma is observation. We did the QuiRedex study to compare early treatment with lenalidomide plus dexamethasone with observation in patients with high-risk smouldering multiple myeloma. Here we report the long-term follow-up results of the trial. METHODS: We did this open-label, randomised, controlled phase 3 study at 19 centres in Spain and three centres in Portugal. Patients aged 18 years or older with high-risk smouldering multiple myeloma were randomly assigned (1:1), via a computerised random number generator, to receive either early treatment with lenalidomide plus dexamethasone or observation, with dynamic balancing to maintain treatment balance within the two groups. Randomisation was stratified by time from diagnosis of smouldering multiple myeloma to study enrolment (≤6 months vs >6 months). Patients in the treatment group received nine 4-week induction cycles (lenalidomide 25 mg per day on days 1-21, plus dexamethasone 20 mg per day on days-1-4 and days 12-15), followed by maintenance therapy (lenalidomide 10 mg per day on days 1-21 of each 28-day cycle) up to 2 years. Group allocation was not masked from study investigators or patients. The primary endpoint was time from randomisation to progression to symptomatic myeloma. The primary analysis was based on the per-protocol population, restricted to patients who fulfilled the protocol in terms of eligibility. Safety assessments were based on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00480363. FINDINGS: Between Nov 8, 2007, and June 9, 2010, 125 patients were enrolled and underwent randomisation. 119 patients comprised the per-protocol population and were randomly assigned to receive either lenalidomide plus dexamethasone (n=57) or observation (n=62). The cutoff date for this update was June 30, 2015. Median follow-up for surviving patients was 75 months (IQR 67-85). Lenalidomide plus dexamethasone continued to provide a benefit on time to progression compared with observation (median time to progression not reached [95% CI 47 months-not reached] vs 23 months [16-31]; hazard ratio [HR] 0·24 [95% CI 0·14-0·41]; p<0·0001). Progression to multiple myeloma occurred in 53 (86%) of 62 patients in the observation group compared with 22 (39%) of 57 patients in the treatment group. At data cutoff, ten (18%) patients had died in the treatment group and 22 (36%) patients had died in the observation group; median overall survival from the time of study entry had not been reached in either group (95% CI 65 months-not reached vs 53 months-not reached; HR 0·43 [95% CI 0·21-0·92], p=0·024). Survival in patients who had received subsequent treatments at the time of progression to active disease did not differ between groups (HR 1·34 [95% CI 0·54-3·30]; p=0·50). The most frequently reported grade 3 adverse events in patients given lenalidomide plus dexamethasone were infection (four [6%]), asthenia (four [6%]), neutropenia (three [5%]), and skin rash (two [3%]); these events all occurred during induction therapy. No grade 4 adverse events occurred, but one (2%) patient in the lenalidomide plus dexamethasone group died from a respiratory infection during induction therapy The frequency of second primary malignancies was higher in patients in the treatment group than in those in the observation group (six [10%] of 62 patients vs one [2%] of 63 patients), but the cumulative risk of development did not differ significantly between the groups (p=0·070). INTERPRETATION: This study is, to our knowledge, the first randomised trial in which early treatment has been assessed in selected patients with high-risk smouldering multiple myeloma. Positive results from ongoing trials would support the use of early treatment for patients with high-risk disease in the near future. FUNDING: Pethema (Spanish Program for the Treatment of Hematologic Diseases).