Role of Age and Hematopoietic Cell Transplantation-Specific Comorbidity Index in Myelodysplastic Patients Undergoing an Allotransplant: A Retrospective Study from the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option for myelodysplastic syndromes (MDSs) but is severely limited by nonrelapse mortality (NRM), especially in this mostly older population. Comorbidity assessment is crucial to predict NRM and often assessed with the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). Moreover, the impact of age on NRM still remains a matter of debate. In recent years, the age at which transplants are made has been progressively increasing, and patients with comorbidities have become more common. Extricating the respective roles of age and comorbidities in toxic mortality is all the more important. This study by the European Group for Blood and Marrow Transplantation registry included 1245 adult patients who underwent a first allogeneic stem cell transplantation for MDSs between 2003 and 2014. Overall, 4-year NRM and overall survival were 32% and 47%, respectively. When considered as continuous predictors, HCT-CI score and age were associated with an increased hazard ratio (HR) for NRM. In multivariate analysis, age band (HR, 1.13; 95% CI, 1.02 to 1.25; P= .016), HCT-CI ≥3 (HR, 1.34; 95% CI, 1.04 to 1.73; P = .022), and Karnofsky Performance Status ≤80 (HR, 2.03; 95% CI, 1.52 to 2.73; P< .0001) were significantly predictive of a worse NRM. In our large cohort, both comorbidities, evaluated by the original HCT-CI score, and chronological age significantly affected NRM. Thus, age should be part of the transplant decision-making process and should be integrated in future scoring systems predicting outcomes of HSCT in MDSs.

Complications in Pediatric Regional Anesthesia: An Analysis of More than 100,000 Blocks from the Pediatric Regional Anesthesia Network.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Complications in pediatric regional anesthesia are rare, so a large sample size is necessary to quantify risk. The Pediatric Regional Anesthesia Network contains data on more than 100,000 blocks administered at more than 20 children's hospitals. This study analyzed the risk of major complications associated with regional anesthesia in children. METHODS: This is a prospective, observational study of routine clinical practice. Data were collected on every regional block placed by an anesthesiologist at participating institutions and were uploaded to a secure database. The data were audited at multiple points for accuracy. RESULTS: There were no permanent neurologic deficits reported (95% CI, 0 to 0.4:10,000). The risk of transient neurologic deficit was 2.4:10,000 (95% CI, 1.6 to 3.6:10,000) and was not different between peripheral and neuraxial blocks. The risk of severe local anesthetic systemic toxicity was 0.76:10,000 (95% CI, 0.3 to 1.6:10,000); the majority of cases occurred in infants. There was one epidural abscess reported (0.76:10,000, 95% CI, 0 to 4.8:10,000). The incidence of cutaneous infections was 0.5% (53:10,000, 95% CI, 43 to 64:10,000). There were no hematomas associated with neuraxial catheters (95% CI, 0 to 3.5:10,000), but one epidural hematoma occurred with a paravertebral catheter. No additional risk was observed with placing blocks under general anesthesia. The most common adverse events were benign catheter-related failures (4%). CONCLUSIONS: The data from this study demonstrate a level of safety in pediatric regional anesthesia that is comparable to adult practice and confirms the safety of placing blocks under general anesthesia in children.

Concurrent analysis of hospital stay durations and mortality of emerging severe acute respiratory coronavirus virus 2 (SARS-CoV-2) variants using real-time electronic health record data at a large German university hospital.

Multistate methodology proves effective in analyzing hospitalized coronavirus disease 2019 (COVID-19) patients with emerging variants in real time. An analysis of 2,548 admissions in Freiburg, Germany, showed reduced severity over time in terms of shorter hospital stays and higher discharge rates when comparing more recent phases with earlier phases of the pandemic.

Hemolytic Anemia After an Aortic Dissection Treated With a Valve-Sparing Aortic Root Replacement.

A 46-year-old man with a personal history of a repaired aortic dissection was admitted because of hemolytic anemia. The transesophageal echocardiogram displayed an accelerated flow and a residual intimal flap in the proximal descending aorta. A total arch replacement was performed, the flap was removed, and his hemolytic anemia was resolved. (Level of Difficulty: Advanced.).

Predictors and outcomes of pacemaker implantation in patients with cardiac amyloidosis.

OBJECTIVE: We sought to investigate prevalence, incidence and prognostic implications of permanent pacemaker (PPM) implantation in patients with cardiac amyloidosis (CA), thereby identifying the predictors of time to PPM implantation. METHODS: Seven hundred eighty-seven patients with CA (602 men, median age 74 years, 571 transthyretin amyloidosis (ATTR), 216 light-chain amyloidosis (AL)) evaluated at two European referral centres were retrospectively included. Clinical, laboratory and instrumental data were analysed. The associations between PPM implantation and mortality, heart failure (HF) or a composite endpoint of mortality, cardiac transplantation and HF were analysed. RESULTS: 81 (10.3%) patients had a PPM before initial evaluation. Over a median follow-up time of 21.7 months (IQR 9.6-45.2), 81 (10.3%) additional patients (18 with AL (22.2%) and 63 with ATTR (77.8%)) underwent PPM implantation with a median time to implantation of 15.6 months (IQR 4.2-40), complete atrioventricular block was the most common indication (49.4%). Independent predictors of PPM implantation were QRS duration (HR 1.03, 95% CI 1.02 to 1.03, p<0.001) and interventricular septum (IVS) thickness (HR 1.1, 95% CI 1.03 to 1.17, p=0.003). The model to estimate the probability of PPM at 12 months and containing both factors showed a C-statistic of 0.71 and a calibration of slope of 0.98. CONCLUSIONS: Conduction system disease requiring PPM is a common complication in CA that affects up to 20.6% of patients. QRS duration and IVS thickness are independently associated with PPM implantation. A PPM implantation at 12 months model was devised and validated to identify patients with CA at higher risk of requiring a PPM and who require closer follow-up.

Low-level exposure to HIV induces virus-specific T cell responses and immune activation in exposed HIV-seronegative individuals.

HIV-specific T cells response and T cell activation are frequently seen in exposed seronegative individuals (ESN). In this study, we report HIV-specific response and level of T cell activation in ESN partners of HIV-infected patients presenting low or undetectable levels of HIV-RNA. We evaluated 24 HIV-serodiscordant couples. ESN were classified into three categories of exposure to HIV (very low, low, and moderate-high), considering levels of HIV-RNA in their infected partner and frequency of sexual high-risk practices within the last 12 mo. HIV-specific T cell responses and activation levels in T cell subsets were evaluated by flow cytometry. We reported that 54% of ESN had detectable HIV-specific T cells response, being the highest prevalence seen in the low exposure group (64%). Several T cell subsets were significantly increased in ESN when compared with controls: CD4(+)CD38(+) (p = 0.006), CD4(+)HLA-DR(-)CD38(+) (p = 0.02), CD4(+)CD45RA(+)CD27(+)HLA-DR(-)CD38(+) (p = 0.002), CD8(+)CD45RA(+)CD27(+)CD38(-)HLA-DR(+) (p = 0.02), and CD8(+)CD45RA(+)CD27(-)CD38(+)HLA-DR(+) (p = 0.03). Activation of CD8(+) T cells was increased in ESN with detectable HIV T cell responses compared with ESN lacking these responses (p = 0.04). Taken together, these results suggest that persistent but low sexual HIV exposure is able to induce virus-specific T cells response and immune activation in a high proportion of ESN, suggesting that virus exposure may occur even in conditions of maximal viral suppression in the HIV-infected partner.

The expansion ability but not the quality of HIV-specific CD8(+) T cells is associated with protective human leucocyte antigen class I alleles in long-term non-progressors.

Studies in long-term non-progressors (LTNP) have suggested that the quality of the CD8(+) response may involve protective human leucocyte antigen (HLA) class I alleles. However, studies examining the expansion ability of different functional CD8(+) T cells and their association with HLA class I alleles are lacking. LTNP, untreated typical progressors (TP) and patients successfully on highly active retroviral therapy (HAART) during 1 year (HP) were included. HLA class I typing was performed using a sequence-specific primer assay. Functional subsets of Gag- and Nef-specific CD8(+) cells were analysed based on the production of macrophage inflammatory protein (MIP)-1ß, tumour necrosis factor (TNF)-α and interleukin (IL)-2. Their expansion abilities were evaluated after 10-day culture in the presence of Gag and Nef human immunodeficiency virus (HIV) peptides. No differences were seen when comparing quantitative and qualitative HIV-specific CD8(+) T cell responses according to the presence/absence of protective HLA alleles (B*58 and B*27 supertypes) in each group. However, LTNP with protective HLA alleles showed a higher expansion ability of Gag-specific MIP(+) TNF(+) IL-2(+) T cells and Nef-specific MIP(+) TNF(+) IL-2(+) . HLA-B*5701+LTNP displayed a higher expansion ability of Gag and Nef-specific MIP(+) TNF(-) IL-2(+) T cells than HLA-B*5701-LTNP. This was not so for HLA-B*2705. No differences were seen in the expansion ability according to the presence/absence of protective HLA alleles in TP and HP. The expansion ability of polyfunctional CD8(+) T cells is modulated by HLA class I alleles and targeted protein. LTNP with HLA class I protective alleles (mainly B*5701) display better expansion ability of polyfunctional HIV-specific CD8(+) T cells than the rest, suggesting that factors other than HLA-B*5701 must contribute to the control of viral replication in other LTNP. Furthermore, these attributes of HIV-specific CD8(+) T are not restored by HAART; thus, adjuvant therapies and vaccines that induce and/or normalize the expansion ability of HIV-specific T cells are required.

Impact of Gag sequence variability on level, phenotype, and function of anti-HIV Gag-specific CD8(+) cytotoxic T lymphocytes in untreated chronically HIV-infected patients.

The role of cytotoxic T lymphocyte responses in controlling viral replication during chronic HIV infection remains controversial. Viral escape mutations driven by immune pressure have been postulated to be an important mechanism contributing to the evasion of CD8(+) T cell responses. To explore this issue in more detail, HIV-1 p17 sequence variability was examined in chronically HIV-infected patients, in parallel with the level, phenotype, and function of HIV-SL9-specific CD8(+) T cell. Thirty-one HLA-A*0201(+) (A2(+)) and 10 HLAA* 02() (A2()) patients were included. The phenotype of SL9-specific CD8(+) T cell and their ability to produce IFN-gamma were analyzed by multiparameter flow cytometry. The HIV Gag p17 was sequenced and the mean variability score for each residue within SL9 and the two epitope flanking regions were calculated using Shannon entropy. The mean variability of SL9 and the proportion of patients with amino acid changes within SL9 were similar in A2(+) and A2() patients. Patients without Tet(+) cells had a significantly higher prevalence of aminoacid changes in SL9 than patients with Tet(+) cells. Interestingly, in patients with Tet(+) cells, the Y79F mutation within SL9 tended to be associated with lower levels of Tet(+) cells. We did not find any association between amino acid changes within SL9 and the differentiation stage of Tet(+) cells, or with IFN-gamma production. A similar analysis within the epitope flanking sequences did not reveal differences in the variability of these regions. These results suggest that viral mutations driven by immune selection pressure may play an important role in evading the immunological response in chronically HIV-infected individuals.

Immunological and virological effects of structured treatment interruptions following exposure to hydroxyurea plus didanosine.

Both hydroxyurea (HU) and structured treatment interruptions (STI) have been investigated as therapeutic approaches to enhance immune responses in chronically HIV-infected individuals. HIV-specific T cell responses as well as T cell activation were analyzed longitudinally in 31 HIV-infected individuals who had been treated for the prior 12 months with didanosine (ddI) plus HU and thereafter completed three STI cycles consisting of 2 months off and 2 months on ddI-HU. Similar increases in plasma HIV-RNA were seen in each of the three cycles off therapy, whereas CD4 counts remained fairly stable along the study period. T cell activation paralleled the evolution of plasma HIV-RNA during the first STI cycle and waned afterward. At baseline most patients presented a high level of CD8+ responses to different HIV peptide pools and 23% of them had CD4+ responses to Gag and/or Env. The level of CD8+ responses against each pool was stable and did not increase during STI cycles, while CD4 responses tended to decline. However, the contribution of Nef-specific response to the total CD8 response tended to increase. In a multivariate model, both a higher baseline plasma HIV-RNA and a higher level of Nef-specific response contribution to the total CD8+ response were independently associated with lower plasma HIV-RNA increases during each of the three STI cycles. Nef-specific CD8+ responses might contribute to a better virological control of HIV replication following treatment interruptions in HIV-infected individuals and might be boosted by the immunomodulatory effect of HU.

Enhanced HIV-specific immune responses in chronically HIV-infected patients receiving didanosine plus hydroxyurea.

BACKGROUND: The role of hydroxyurea (HU) in the treatment of HIV infection remains controversial. HU potentiates didanosine (ddI) antiviral activity and might exert immunomodulatory effects. PATIENTS AND METHODS: Immunologic parameters were examined in HIV-infected patients enrolled in a simplification trial in which ddI-HU was provided to subjects who had been on complete virus suppression under highly active antiretroviral therapy (HAART) for longer than 6 months. A total of 84 of these patients showed plasma viraemia repeatedly below 5000 HIV-RNA copies/ml, and were the main study population. A group of 22 patients who continued on HAART and another of 22 drug-naive HIV-positive individuals were taken as controls. RESULTS: At 12 months, the levels of naive and memory T-cell subsets were similar in patients on ddI-HU and under HAART, whereas immune activation tended to be lower in the former group. The frequency of HIV-specific CD8+ T cells (CTL) directed against 125 peptides derived from Gag, Pol, Env, Nef and HIV regulatory proteins was similar among patients on ddI-HU and untreated controls, and significantly higher than in patients under HAART. This higher CTL response in patients on ddI-HU was seen even when considering only subjects with undetectable viral load. HIV-specific CD4+ T-cell responses were absent in almost all patients on HAART, whereas they were present in up to 19% of patients on ddI-HU. CONCLUSION: Treatment with ddI-HU provides higher levels of HIV-specific CD8+ and CD4+ T-cell responses than standard triple drug regimens. Thus, hydroxyurea might exert a beneficial immunomodulatory effect in HIV infection.

CD38 expression on CD8 T lymphocytes as a marker of residual virus replication in chronically HIV-infected patients receiving antiretroviral therapy.

The level of CD8+ CD38+ T lymphocytes in blood correlates with disease progression in HIV-infected individuals, independently of the CD4 count. Effective antiretroviral therapy reduces this lymphocyte subset in parallel with plasma viremia, although CD38 expression on CD8+ cells does not normalize completely in most subjects, and might reflect residual HIV replication. The expression of CD38 on CD8+ cells (as number of CD38 molecules per CD8+ cell) was measured quantitatively by flow cytometry in 200 individuals, of whom 170 were HIV positive and 30 were HIV-uninfected controls. Forty-six HIV-infected subjects were on antiretroviral therapy and had undetectable viral load. The remaining 124 HIV-positive persons were not on therapy and had detectable plasma viremia. The mean level of CD38 on CD8+ cells was higher in HIV-positive, untreated patients than in subjects on antiviral therapy and controls (5023, 2029, and 1978 molecules per CD8+ cell, respectively, p < 0.01). In HIV-positive, untreated subjects, the higher CD38 expression mainly occurred on CD45RO+ CD8+ cells. The level of CD38 strongly correlated with plasma HIV-RNA (r = 0.63, p < 0.001). The levels of CD38 on CD8+ cells declined steadily in HIV-positive subjects after beginning antiretroviral therapy. A few individuals presented viral blips whereas being on antiviral treatment, levels of CD38 on CD8+ cells increased transiently in parallel with episodes of viral replication. Levels of CD38 on CD8+ cells are increased in chronic HIV infection, and strongly correlate with plasma viremia. The slow decline of CD38 expression on CD8+ cells over time in subjects with undetectable plasma viremia while being on antiretroviral therapy suggests that CD38 expression on CD8+ cells could be used as a marker of residual virus replication.

Differences in cellular activation and apoptosis in HIV-infected patients receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors.

The mechanism of CD4(+) T cell depletion seen in HIV infection is largely mediated by increased apoptosis of these cells. The benefit of protease inhibitor (PI)-based antiretroviral therapy to CD4(+) T cell recovery seems to involve more than its antiviral activity, and a direct antiapoptotic effect of PIs has been proposed to explain it. To test this hypothesis we have analyzed directly, ex vivo, the effects of two different highly active antiretroviral therapy (HAART) regimens on the levels of activation and apoptosis of T lymphocytes. A total of 126 subjects (43 receiving PIs, 35 receiving NNRTIs, 27 untreated HIV carriers, and 21 uninfected control subjects) was included in the study. Apoptosis was measured in blood lymphocytes by flow cytometry, using annexin V labeling. A broad panel of monoclonal antibodies was used to characterize the different CD4(+) and CD8(+) lymphocyte subsets. Apoptosis was significantly increased in HIV-untreated subjects, whereas apoptosis levels did not differ when comparing HIV-positive subjects undergoing HAART and uninfected control subjects. Likewise, markers of activation were elevated in HIV-positive untreated patients, and declined in subjects receiving treatment. However, activated-memory CD8(+) T cells remained significantly higher in treated patients with respect to uninfected control subjects. No differences in the level of apoptosis or in immune activation markers were recognized when comparing subjects receiving PIs and those receiving NNRTIs. Antiretroviral therapy reduces apoptosis of CD4(+) and CD8(+) lymphocytes to normal levels without differences when comparing subjects receiving PI and NNRTI triple combinations. Despite complete suppression of viral replication, activated memory CD8(+) T cells remain significantly elevated in subjects receiving HAART, suggesting the persistence of residual HIV replication. If PIs provide a positive effect on CD4(+) counts beyond an antiviral effect, mechanisms other than apoptosis should be involved.

Emergence and long-lasting persistence of linezolid-resistant Enterococcus faecium-ST117 in an oncohematologic patient after a nine-day course of linezolid.

We report the emergence and long-lasting persistence of linezolid resistance in an ampicillin-resistant Enterococcus faecium strain in the intestine of a neutropenic oncohematologic patient receiving chemotherapy. The patient was first colonized by an epidemic ampicillin-resistant E. faecium (ARE)-ST117 clustering into lineage 78. This clone exhibited resistance to levofloxacin, erythromycin and high-level resistance to streptomycin and gentamicin. After receiving treatment with several broad spectrum antibiotics for febrile neutropenia, a 9-day course of oral linezolid was administered once the patient developed bacteraemia by the same ARE colonizing clone. Linezolid-resistant ARE was detected 17 days later in the follow-up fecal samples and persisted 41 days after suppression of linezolid therapy. Resistance to linezolid was associated with G2576T transversion in the 23S rRNA and the presence of cfr gene was not detected. The persistence of G2576T-ARE strains, especially in oncohematologic patients with injured intestinal membranes, could increase the risk of bacteraemia.

The effect of antiepileptic drugs on coagulation and bleeding in the perioperative period of epilepsy surgery: the Cleveland Clinic experience.

Antiepileptic drugs (AED) are known to cause coagulation disturbances. We retrospectively analyzed the effect of AED on coagulation parameters in children who underwent craniotomy for epilepsy surgery. A total of 84 children were included. Perioperative coagulation parameters, the number and type of AED, estimated blood loss and the amount of blood products transfused were recorded. The most commonly used AED was lamotrigine. Of all patients, 7.1% were taking valproate. None of the patients showed significantly abnormal prothrombin time, activated partial thromboplastin time, or platelet count preoperatively. Thirty-eight percent of patients were transfused with allogeneic red blood cells and 4.7% of all patients showed significant coagulopathy intraoperatively and postoperatively. We concluded that the number of AED does not appear to be associated with preoperative coagulation disorders or blood transfusion requirements. However, caution should be taken in patients taking AED who undergo complex brain epilepsy surgery due to the potential for significant blood loss.

Longitudinal assessment of interleukin 7 plasma levels in HIV-infected patients in the absence of and under antiretroviral therapy.

BACKGROUND: Cross-sectional studies in HIV-positive patients have suggested that interleukin 7 (IL-7) may increase in parallel to CD4 decline during the natural course of HIV infection. We tested this hypothesis in a longitudinal study examining the evolution of IL-7 and CD4 counts in 2 different scenarios. METHODS: IL-7 and CD4 counts were regularly monitored in 30 drug-naive patients during a follow-up period of 46 ± 14 months in the absence of therapy and in 42 patients who started highly active antiretroviral therapy and maintained undetectable viremia for 2 years. Multivariate linear regression analysis was used to ascertain what factors were associated with IL-7 variations during follow-up. RESULTS: In antiretroviral therapy-naive patients, CD4 counts significantly decreased (P < 0.0001), whereas plasma HIV-RNA and IL-7 levels remained fairly stable. In patients on highly active antiretroviral therapy, CD4 counts significantly increased (P < 0.0001) and IL-7 tended to decrease (P = 0.1). There was no correlation between CD4 and IL-7 variations either in the naive or in the treated population. The only parameter significantly associated with IL-7 variation during follow-up was its baseline level that showed a negative correlation. CONCLUSIONS: In HIV patients with low or moderate degree of immunodeficiency, CD4 counts and plasma IL-7 levels do not evolve in parallel, suggesting that other factors different from CD4 counts must be involved in the upregulation of IL-7 observed in HIV infection.

Down-regulation of interleukin-7 receptor (CD127) in HIV infection is associated with T cell activation and is a main factor influencing restoration of CD4(+) cells after antiretroviral therapy.

BACKGROUND: Factors influencing the depletion of CD4(+) cells and the restoration of CD4(+) cells after antiretroviral therapy are not completely understood. Recently, attention has been paid to interleukin (IL)-7 and its receptor (CD127). We analyzed the influence of T cell activation and of suppression of viremia with antiretroviral therapy on this system, as well as its role in CD4(+) cell restoration after long-term antiretroviral therapy. METHODS: IL-7 levels and CD127 expression on several subsets of CD4(+) and CD8(+) T lymphocytes and the activation status (CD38) of these cells were examined at baseline and during 24 months of complete viral suppression under highly active antiretroviral therapy (HAART). RESULTS: A total of 42 individuals with human immunodeficiency virus (HIV) infection and 10 age-matched, uninfected control subjects were examined. Before HAART, IL-7 levels were increased and CD127 expression was decreased. Down-regulation of CD127 was mainly associated with T cell activation and reverted only partially after suppression of detectable plasma HIV RNA with HAART. In a multivariate analysis, CD127 expression on CD8(+) T cells was the main determinant of the extent of CD4(+) cell gains after successful HAART. CONCLUSIONS: The IL-7-CD127 system is impaired in HIV-infected patients. CD127 down-regulation is associated with T cell activation and with CD4(+) cell restoration after HAART.

No major differences in the functional profile of HIV Gag and Nef-specific CD8+ responses between long-term nonprogressors and typical progressors.

The mechanism explaining the failure of HIV-specific CD8(+) T cell responses to successfully control HIV replication remains elusive. A total of 83 drug-naive HIV-infected individuals, 27 of whom were long-term nonprogressors (LTNP), was examined. The ability of CD8(+) T lymphocytes to produce three different cytokines (MIP-1beta, TNF-alpha, IL-2) in response to HIV Gag and Nef peptides and to polyclonal stimuli and the ability of HIV-specific CD8(+) T cells to expand in vitro were evaluated by multiparameter flow cytometry. In response to polyclonal stimulation, LTNP presented significantly higher levels of several CD8(+) T cell subsets than progressors. While most patients presented detectable Gag and Nef-specific CD8(+) responses, no significant differences in any of the CD8(+) functional T cell subsets were recognized when comparing LTNP and progressors. HIV responses were dominated by cells producing only MIP-1beta or TNF-alpha, being similar in LTNP and progressors. However, expansion of HIV-specific CD8(+) T cells was more frequent in LTNP than progressors, especially for cells producing MIP-1beta. LTNP show higher levels of CD8(+) responses against polyclonal stimuli than progressors. However, HIV-specific CD8(+) responses do not differ between them except for a more preserved ability of cells from LTNP to expand in vitro.