Chronicling novelty: nieuws! Lokale kronieken, 1500-1850

Collective identities and transnational networks in medieval and early modern Europe, 1000-180

Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome

Between 1988 and 1999, 127 patients with poor-risk acute lymphoblastic leukemia (ALL) received a matched unrelated donor transplant using marrow procured by National Marrow Donor Program (NMDP) collection centers and sent out to 46 transplant centers worldwide. Poor risk was defined by the presence of the translocations t(9;22) (n = 97), or t(4;11) (n = 25), or t(1;19) (n = 5). Sixty-four patients underwent transplantation in first remission (CR1), 16 in CR2 or CR3, and 47 patients had relapsed ALL or primary induction failure (PIF). Overall survival at 2 years from transplant was 40% for patients in CR1, 17% in CR2/3, and 5% in PIF or relapse. Treatment-related mortality (TRM) and relapse mortality, estimated as competing risk factors, were 54% and 6%, respectively, in CR1, 75% and 8% in CR2/3, and 64% and 31% in PIF or relapse. Currently 23 CR1 patients are alive and free of disease with a median follow-up of 24 months (range, 3-97). Multivariable analysis showed that CR1, shorter interval from di

Prolonged QT interval: A tricky diagnosis?

Prolonged heart-rate adjusted QT intervals on the electrocardiogram (ECG) are associated with an increased risk far coronary heart disease and sudden death. However, the diagnosis of the prolonged QT interval is hampered by lack of standards. We studied variations in the prevalence of prolonged QT, based on different common definitions, in a large nonhospitalized population, and compared our results with other studies applying the same definitions. The study population consisted of 2,200 men and 3,366 women participants of the Rotterdam Study, ≤55 years old. The QT interval was computed by our Modular ECG Analysis System (MEANS). Three different formulas to adjust QT for heart rata were used: Bazett's formula (QT(c), a linear regression equation (QT(Ir)), and the QT index (QTI). Prolonged QT occurred frequently in both men and women, and its prevalence increased with age. Women had longer heart-rate adjusted QT intervals than men (mean QT(c) 433 ms vs 422 ms), and mean values for QT(Ir) were lower than for QT(c) (mean QT(Ir) 422 ms in women and 412 ms in men). Prevalence was highest for prolonged QT(Ir) (31% in men and 26% in women) and lowest for prolonged QTI (6% in men and 9% in women). Comparison with other studies applying the same correction formulas showed large discrepancies in prevalence estimates of prolonged QT(c) and QT(Ir), and to a lesser degree of prolonged QTI, possibly due to differences in measurement techniques. Future research is needed to relate QT interval to prognosis, to obtain measurement technique specific reference values of heart-rate adjusted QT measurements, and to obtain age-and sex- specific threshold values for prolonged QT. Such data are needed to use the QT interval with confidence

Comparison of chop chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma

High-dose chemoradiotherapy combined with autologous bone marrow transplantation can cure patients with disseminated, aggressive non-Hodgkin's lymphoma in whom first-line chemotherapy has failed. In contrast, cure is rare with second-line chemotherapy. It has been suggested that patients with slow responses to the initial phase of first-line chemotherapy are at high risk for relapse. Therefore, such patients are potential candidates for early bone marrow transplantation

Increased end-expiratory pressures improve lung function in near-term newborn rabbits with elevated airway liquid volume at birth

Approximately 53% of near-term newborns admitted to intensive care experience respiratory distress. These newborns are commonly delivered by cesarean section and have elevated airway liquid volumes at birth, which can cause respiratory morbidity. We investigated the effect of providing respiratory support with a positive end-expiratory pressure (PEEP) of 8 cmH(2)O on lung function in newborn rabbit kittens with elevated airway liquid volumes at birth. Near-term rabbits (30 days; term = 32 days) with airway liquid volumes that corresponded to vaginal delivery (similar to 7 mL/kg, control, n = 11) or cesarean section (similar to 37 mL/kg; elevated liquid (EL), n = 11] were mechanically ventilated (tidal volume= 8 mL/kg). The PEEP was changed after lung aeration from 0 to 8 to 0 cmH(2)O (control, n = 6; EL, n = 6), and in a separate group of kittens, PEEP was changed after lung aeration from 8 to 0 to 8 cmH(2)O (control, n = 5; EL, n = 5). Lung function (ventilator parameters, compliance, lung gas volumes, and distribution of gas within the lung) was evaluated using plethysmography and synchrotron-based phase-contrast X-ray imaging. EL kittens initially receiving 0 cmH(2)O PEEP had reduced functional residual capacities and lung compliance, requiring higher inflation pressures to aerate the lung compared with control kittens. Commencing ventilation with 8 cmH(2)O PEEP mitigated the adverse effects of EL, increasing lung compliance, functional residual capacity, and the uniformity and distribution of lung aeration, but did not normalize aeration of the distal airways. Respiratory support with PEEP supports lung function in near-term newborn rabbits with elevated airway liquid volumes at birth who are at a greater risk of suffering respiratory distress.NEW & NOTEWORTHY Term babies born by cesarean section have elevated airway liquid volumes, which predisposes them to respiratory distress. Treatments targeting molecular mechanisms to clear lung liquid are ineffective for term newborn respiratory distress. We showed that respiratory support with an end-expiratory pressure supports lung function in near-term rabbits with elevated airway liquid volumes at birth. This study provides further physiological understanding of lung function in newborns with elevated airway liquid volumes at risk of respiratory distress.Developmen

Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma

We examined the feasibility of achieving a rapid response in patients with previously untreated multiple myeloma by administering vincristine 0.4 mR and doxorubicin 9 mg/m2 as a rapid intravenous infusion for 4 d together with intermittent high-dose dexamethasone 40 mg (VAD) for remission induction treatment in patients who were scheduled to receive high-dose therapy. 139 patients (86 male, 53 female; median age 53 years, range 32-65 years; Durie and Salmon stage IIA: 42, IIB: one, IIIA: 89, IIIB: seven) were included in a prospective multicentre study in which VAD was administered as remission induction treatment and was followed by intensified treatment. The response was evaluated according to the criteria of the Eastern Cooperative Oncology Group (ECOG). The results of treatment were evaluable in 134 patients. Five patients died before evaluation. 86 patients (62%) achieved a partial response (PR) and seven patients (5%) achieved a complete response (CR), which equates to a response rate of 67%. The main side-effect was mild neurotoxicity, which was observed in 18% of the patients. Fever or infections were reported in 27% of the patients. VAD administered as an outpatient regimen, based on rapid intravenous infusion, is an effective induction regimen for untreated myeloma with a 67% response rate and acceptable toxicity

Two Days Versus Five Days of Postoperative Antibiotics for Complex Appendicitis:Cost Analysis of a Randomized, Noninferiority Trial

Objective: To compare costs for 2 days versus 5 days of postoperative antibiotics within the antibiotics after an aPPendectomy In Complex appendicitis trial. Background: Recent studies suggest that restrictive antibiotic use leads to a significant reduction in hospital stays without compromising patient safety. Its potential effect on societal costs remains underexplored. Methods: This was a pragmatic, open-label, multicenter clinical trial powered for noninferiority. Patients with complex appendicitis (age ≥ 8 years) were randomly allocated to 2 days or 5 days of intravenous antibiotics after appendectomy. Patient inclusion lasted from June 2017 to June 2021 in 15 Dutch hospitals. The final follow-up was on September 1, 2021. The primary trial endpoint was a composite endpoint of infectious complications and mortality within 90 days. In the present study, the main outcome measures were overall societal costs (comprising direct health care costs and costs related to productivity loss) and cost-effectiveness. Direct health care costs were recorded based on data in the electronic patient files, complemented by a telephone follow-up at 90 days. In addition, data on loss of productivity were acquired through the validated Productivity Cost Questionnaire at 4 weeks after surgery. Cost estimates were based on prices for the year 2019. Results: In total, 1005 patients were evaluated in the "intention-to-treat" analysis: 502 patients were allocated to the 2-day group and 503 to the 5-day group. The mean difference in overall societal costs was - €625 (95% CI: -€ 958 to -€ 278) to the advantage of the 2-day group. This difference was largely explained by reduced hospital stay. Productivity losses were similar between the study groups. Restricting postoperative antibiotics to 2 days was cost-effective, with estimated cost savings of €31,117 per additional infectious complication. Conclusions: Two days of postoperative antibiotics for complex appendicitis results in a statistically significant and relevant cost reduction, as compared with 5 days. Findings apply to laparoscopic appendectomy in a well-resourced health care setting.</p

Two Days Versus Five Days of Postoperative Antibiotics for Complex Appendicitis:Cost Analysis of a Randomized, Noninferiority Trial

Objective: To compare costs for 2 days versus 5 days of postoperative antibiotics within the antibiotics after an aPPendectomy In Complex appendicitis trial. Background: Recent studies suggest that restrictive antibiotic use leads to a significant reduction in hospital stays without compromising patient safety. Its potential effect on societal costs remains underexplored. Methods: This was a pragmatic, open-label, multicenter clinical trial powered for noninferiority. Patients with complex appendicitis (age ≥ 8 years) were randomly allocated to 2 days or 5 days of intravenous antibiotics after appendectomy. Patient inclusion lasted from June 2017 to June 2021 in 15 Dutch hospitals. The final follow-up was on September 1, 2021. The primary trial endpoint was a composite endpoint of infectious complications and mortality within 90 days. In the present study, the main outcome measures were overall societal costs (comprising direct health care costs and costs related to productivity loss) and cost-effectiveness. Direct health care costs were recorded based on data in the electronic patient files, complemented by a telephone follow-up at 90 days. In addition, data on loss of productivity were acquired through the validated Productivity Cost Questionnaire at 4 weeks after surgery. Cost estimates were based on prices for the year 2019. Results: In total, 1005 patients were evaluated in the "intention-to-treat" analysis: 502 patients were allocated to the 2-day group and 503 to the 5-day group. The mean difference in overall societal costs was - €625 (95% CI: -€ 958 to -€ 278) to the advantage of the 2-day group. This difference was largely explained by reduced hospital stay. Productivity losses were similar between the study groups. Restricting postoperative antibiotics to 2 days was cost-effective, with estimated cost savings of €31,117 per additional infectious complication. Conclusions: Two days of postoperative antibiotics for complex appendicitis results in a statistically significant and relevant cost reduction, as compared with 5 days. Findings apply to laparoscopic appendectomy in a well-resourced health care setting.</p

Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element

Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unknown. We identify a novel mechanism by which cis-elements promote long-range interactions, inducing conformational changes critical for diversification of the TCRβ antigen receptor locus (Tcrb). Association between distal Vβ gene segments and the highly expressed DβJβ clusters, termed the recombination center (RC), is independent of enhancer function and recruitment of V(D)J recombinase. Instead, we find that tissue-specific folding of Tcrb relies on two distinct architectural elements located upstream of the RC. The first, a CTCF-containing element, directly tethers distal portions of the Vβ array to the RC. The second element is a chromatin barrier that protects the tether from hyperactive RC chromatin. When the second element is removed, active RC chromatin spreads upstream, forcing the tether to serve as a new barrier. Acquisition of barrier function by the CTCF element disrupts contacts between distal Vβ gene segments and significantly alters Tcrb repertoires. Our findings reveal a separation of function for RC-flanking regions, in which anchors for long-range recombination must be cordoned off from hyperactive RC landscapes by chromatin barriers