First Study of the

New astronomical observations point to a nucleosynthesis picture that goes beyond what was accepted until recently. The intermediate "i" process was proposed as a plausible scenario to explain some of the unusual abundance patterns observed in metal-poor stars. The most important nuclear physics properties entering i-process calculations are the neutron-capture cross sections and they are almost exclusively not known experimentally. Here we provide the first experimental constraints on the ^{139}Ba(n,γ)^{140}Ba reaction rate, which is the dominant source of uncertainty for the production of lanthanum, a key indicator of i-process conditions. This is an important step towards identifying the exact astrophysical site of stars carrying the i-process signature.

Proton Shell Gaps in N=28 Nuclei from the First Complete Spectroscopy Study with FRIB Decay Station Initiator.

The first complete measurement of the ß-decay strength distribution of _{17}^{45}Cl_{28} was performed at the Facility for Rare Isotope Beams (FRIB) with the FRIB Decay Station Initiator during the second FRIB experiment. The measurement involved the detection of neutrons and γ rays in two focal planes of the FRIB Decay Station Initiator in a single experiment for the first time. This enabled an analytical consistency in extracting the ß-decay strength distribution over the large range of excitation energies, including neutron unbound states. We observe a rapid increase in the ß-decay strength distribution above the neutron separation energy in _{18}^{45}Ar_{27}. This was interpreted to be caused by the transitioning of neutrons into protons excited across the Z=20 shell gap. The SDPF-MU interaction with reduced shell gap best reproduced the data. The measurement demonstrates a new approach that is sensitive to the proton shell gap in neutron rich nuclei according to SDPF-MU calculations.

Primary prophylaxis in children with severe haemophilia A and B-Implementation over the last 20 years as illustrated in real-world data in the PedNet cohorts.

INTRODUCTION: The prophylactic regimen in children with severe haemophilia is suggested in various publications and guidelines. Few data exist on its implementation in clinical practice. AIM: To investigate the implementation of primary prophylaxis based on real-life data from PedNet during the last 20 years. METHODS: All children from the PedNet cohort (n = 1260) with severe haemophilia A (SHA) or severe haemophilia B (SHB), FVIII/IX < .01 IU/mL, born between 2000 and 2009 (Cohort I; SHA n = 662; SHB n = 88) and 2010-2019 (Cohort II; SHA n = 598; SHB n = 94) were included. RESULTS: In SHA, the median age at start of prophylaxis was 17.3 months (IQR; 12.5-26.1) in Cohort I which decreased to 13.1 months (IQR; 10.4-19.1) in Cohort II (p < .000). "Once-a-week" prophylaxis at start increased from 49% to 68% (SHA) and 38% to 70% (SHB). FVIII doses were reduced from median 43.5 (IQR; 34.6-49.0) to 30.9 IU/kg (IQR; 26.3-46.3), while dosing with FIX did not change. After 2010 approximately 60% of the patients with SHA and SHB started prophylaxis before any joint bleed. The number of CVADs needed in both cohorts was around 30%. Incidences of inhibitors were unchanged: SHA (∼31%) and SHB (∼10%). Sporadic cases were diagnosed significantly later (median 8.3 months; IQR; 3.7-11.9) and they had more joint bleeds before start of prophylaxis. CONCLUSION: Primary prophylaxis nowadays starts at an earlier age: before any joint bleed (60% of patients with SHA and SHB). Approximately 70% started on a once-weekly schedule with significantly reduced doses in SHA but unchanged in SHB.

Comprehensive Test of the Brink-Axel Hypothesis in the Energy Region of the Pygmy Dipole Resonance.

The validity of the Brink-Axel hypothesis, which is especially important for numerous astrophysical calculations, is addressed for ^{116,120,124}Sn below the neutron separation energy by means of three independent experimental methods. The γ-ray strength functions (GSFs) extracted from primary γ-decay spectra following charged-particle reactions with the Oslo method and with the shape method demonstrate excellent agreement with those deduced from forward-angle inelastic proton scattering at relativistic beam energies. In addition, the GSFs are shown to be independent of excitation energies and spins of the initial and final states. The results provide a critical test of the generalized Brink-Axel hypothesis in heavy nuclei, demonstrating its applicability in the energy region of the pygmy dipole resonance.

Maintained survival outcome after reducing lymphadenectomy rates and optimizing adjuvant treatment in endometrial cancer.

OBJECTIVE: Main controversies in endometrial cancer treatment include the role of lymphadenectomy and optimal adjuvant treatment. We assessed clinical outcome in a population-based endometrial cancer cohort in relation to changes in treatment management over two decades. METHODS: All consenting endometrial cancer patients receiving primary treatment at Haukeland University Hospital from 2001 to 2019 were included (n = 1308). Clinicopathological variables were evaluated for year-to-year changes. Clinical outcome before and after discontinuing adjuvant radiotherapy and individualizing extent of lymphadenectomy was analyzed. RESULTS: The rate of lymphadenectomy was reduced from 78% in 2001-2012 to 53% in 2013-2019. The rate of patients with verified lymph node metastases was maintained (9% vs 8%, p = 0.58) and FIGO stage I patients who did not undergo lymphadenectomy had stable 3-year recurrence-free survival (88% vs 90%, p = 0.67). Adjuvant chemotherapy for completely resected FIGO stage III patients increased from 27% to 97% from 2001 to 2009 to 2010-2019, while adjuvant radiotherapy declined from 57% to 0% (p < 0.001). These patients had improved 5-year overall- and recurrence-free survival; 0.49 [95% CI: 0.37-0.65] in 2001-2009 compared to 0.61 [0.45-0.83] in 2010-2019, p = 0.04 and 0.51 [0.39-0.68] to 0.71 [0.60-0.85], p = 0.03, respectively. For stage I, II and IV, survival rates were unchanged. CONCLUSIONS: Our study demonstrates that preoperative stratification by imaging and histological assessments permits a reduction in lymphadenectomy to around 50%, and is achievable without an increase in recurrences at 3 years. In addition, our findings support that adjuvant chemotherapy alone performs equally to adjuvant radiotherapy with regard to survival, and is likely superior in advanced stage patients.

The effect of a one-year vigorous physical activity intervention on fitness, cognitive performance and mental health in young adolescents: the Fit to Study cluster randomised controlled trial.

BACKGROUND: Physical activity (PA) may positively stimulate the brain, cognition and mental health during adolescence, a period of dynamic neurobiological development. High-intensity interval training (HIIT) or vigorous PA interventions are time-efficient, scalable and can be easily implemented in existing school curricula, yet their effects on cognitive, academic and mental health outcomes are unclear. The primary aim of the Fit to Study trial was to investigate whether a pragmatic and scalable HIIT-style VPA intervention delivered during school physical education (PE) could improve attainment in maths. The primary outcome has previously been reported and was null. Here, we report the effect of the intervention on prespecified secondary outcomes, including cardiorespiratory fitness, cognitive performance, and mental health in young adolescents. METHODS: The Fit to Study cluster randomised controlled trial included Year 8 pupils (n = 18,261, aged 12-13) from 104 secondary state schools in South/Mid-England. Schools were randomised into an intervention condition (n = 52), in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year (2017-2018), or into a "PE as usual" control condition. Secondary outcomes included assessments of cardiorespiratory fitness (20-m shuttle run), cognitive performance (executive functions, relational memory and processing speed) and mental health (Strength and Difficulties Questionnaire and self-esteem measures). The primary intention-to-treat (ITT) analysis used linear models and structural equation models with cluster-robust standard errors to test for intervention effects. A complier-average causal effect (CACE) was estimated using a two-stage least squares procedure. RESULTS: The HIIT-style VPA intervention did not significantly improve cardiorespiratory fitness, cognitive performance (executive functions, relational memory or processed speed), or mental health (all p > 0.05). Subgroup analyses showed no significant moderation of intervention effects by sex, socioeconomic status or baseline fitness levels. Changes in cardiorespiratory fitness were not significantly related to changes in cognitive or mental health outcomes. The trial was marked by high drop-out and low intervention compliance. Findings from the CACE analysis were in line with those from the ITT analysis. CONCLUSION: The one-academic year HIIT-style VPA intervention delivered during regular school PE did not significantly improve fitness, cognitive performance or mental health, but these findings should be interpreted with caution given low implementation fidelity and high drop-out. Well-controlled, large-scale, school-based trials that examine the effectiveness of HIIT-style interventions to enhance cognitive and mental health outcomes are warranted. TRIAL REGISTRATION: ISRCTN registry, 15,730,512 . Trial protocol and analysis plan for primary outcome prospectively registered on 30th March 2017. ClinicalTrials.gov , NCT03286725 . Secondary measures (focus of current manuscript) retrospectively registered on 18 September 2017.

Inhibitor development in previously untreated patients with severe haemophilia: A comparison of included patients and outcomes between a clinical study and a registry-based study.

AIM: The aim of this study was to investigate whether a disease registry could serve as a suitable alternative to clinical studies to investigate safety of orphan drugs in children. METHODS: We used individual patient data from previously untreated patients (PUPs) with severe haemophilia A from the factor VIII (rAHF-PFM)-clinical study and the PedNet registry. The primary outcome was the patient characteristics at entry and the difference in inhibitor development between the clinical study and the registry-based study at 50 exposure days. RESULTS: Clinical study patients more often had a positive family history of inhibitors (31% vs 10%) and a high-risk F8 genotype (82% vs 63%). In the clinical study 41/55 (75%) and in the registry-based study 162/168 (96%) patients reached 50 exposure days. Inhibitors developed in 16 of the 41 patients in the clinical study (39%) vs 44 of the 162 patients in the registry-based study (27%); seven patients (7%) vs 28 patients (17%) had high-titre inhibitors. The risk of developing an inhibitor during the first 50 exposure days was similar (HR 1.04; 95% CI 0.56-1.94), when adjusted for family history of inhibitors, F8 gene mutation and intensive treatment at first exposure. CONCLUSION: In the registry-based study, patient numbers and completeness of follow-up were higher. The risk of developing an inhibitor to a single product was comparable. Although the sample size of this study was too small to conclude on differences in high- or low-titre inhibitors, this suggests that a registry could serve as a more suitable source for evaluation of high-titre inhibitors in the setting of factor VIII deficiency.

Quality of life following road traffic injury: the impact of age and gender.

PURPOSE: The impact of road traffic crashes on health is well developed, in terms of deaths and direct consequences, but it is less so in terms of long-term life consequences. Few studies have compared the general impact on Health Related Quality of Life (HRQoL) following road traffic injury (RTI) by using a variety of different injured body parts and severity levels of the injury and compared them with a sample of non-injured referent individuals. Consequently, the aim of the current study is to assess how injury severity is associated with HRQoL, and if it differs between men, women, over age and injured body parts. METHODS: This cross-sectional study identified people with a RTI in the Swedish Traffic Accident Data Acquisition System (STRADA). A frequency matched reference group was also included. Data include both register data and self-reported HRQoL data. RESULTS: A total of 1788 out of 4761 persons with an RTI (37.6%) and 2186 out of 4761 reference persons (45.9%) returned the questionnaire, giving a total response rate of 41.9% (n = 3974). The findings show different patterns of HRQoL loss, depending on sex, age, injured body part, and levels of injury severity. CONCLUSION: The results show that even relatively minor road traffic injuries can lead to a significantly lower of HRQoL, especially for women, compared to the non-injured reference group. Moreover, when the inherent reduction of HRQoL over age was considered, the results indicated that younger individuals have a larger difference from the reference group in HRQoL, independent of the injury severity, compared to the older individuals; hence, an improved understanding of age and gender differences in HRQoL following an RTI is needed to better understand the long-term consequences of injuries from a public health perspective.

A randomized controlled trial of a walking training with simultaneous cognitive demand (dual-task) in chronic stroke.

BACKGROUND AND PURPOSE: The aim was to evaluate the tolerability of, adherence to and efficacy of a community walking training programme with simultaneous cognitive demand (dual-task) compared to a control walking training programme without cognitive distraction. METHODS: Adult stroke survivors at least 6 months after stroke with a visibly obvious gait abnormality or reduced 2-min walk distance were included in a two-arm parallel randomized controlled trial of complex intervention with blinded assessments. Participants received a 10 week, bi-weekly, 30 min treadmill programme at an aerobic training intensity (55%-85% heart rate maximum), either with or without simultaneous cognitive demands. Outcome was measured at 0, 11 and 22 weeks. The primary assessment involved 2-min walk tests with and without cognitive distraction to investigate the dual-task effect on walking and cognition; secondary results were the Short Form Health Survey 36, EuroQol-5D-5L, the Physical Activity Scale for the Elderly (PASE) and step activity. RESULTS: Fifty stroke patients were included; 43 received allocated training and 45 completed all assessments. The experimental group (n = 26) increased their mean (SD) 2-min walking distance from 90.7 (8.2) to 103.5 (8.2) m, compared with 86.7 (8.5) to 92.8 (8.6) m in the control group, and their PASE score from 74.3 (9.1) to 89.9 (9.4), compared with 94.7 (9.4) to 77.3 (9.9) in the control group. Statistically, only the change in the PASE differed between the groups (P = 0.029), with the dual-task group improving more. There were no differences in other measures. CONCLUSIONS: Walking with specific additional cognitive distraction (dual-task training) might increase activity more over 12 weeks, but the data are not conclusive.

Clinical trials and registries in haemophilia: Opponents or collaborators? Comparison of PUP data derived from different data sources.

INTRODUCTION: The "Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products" (ClinGL) provides the requirements for the performing of clinical trials (CTs) for marketing authorization in Europe. The number of eligible previously untreated patients (PUPs) for CTs might be difficult to meet because of the concurrent development of FVIII concentrates, and additional data sources must be explored. AIM: The extent to which CTs and the PedNet registry met relevant parameters, identified in the ClinGL, as well as inhibitor incidences were investigated in patients from both sources. METHODS: Anonymized data of eight CTs in 369 PUPs performed from 1987 to 2009 were compared with each other and with 632 PUPs (born 2000-2009) from PedNet. RESULTS: Clinical trials in PUPs performed for marketing authorization were too heterogeneous in their investigated parameters; therefore, a comparison of single factor concentrates was not possible. Data collection in PedNet met relevant parameters required for PUPs in accordance with the ClinGL. The overall inhibitor incidences were comparable (CT = 30.9% vs PedNet = 30.6%) when only severe haemophilia A (HA) patients from both data sources were considered. CONCLUSIONS: Previously performed CTs in PUPs were divergent, which prevented a direct comparison of outcomes. However, this study demonstrated that data from CTs and carefully designed registries may complement each other in the establishing of sufficient safety information for single products to improve clinical insights and support regulatory decisions.

First-year results of an expanded humanitarian aid programme for haemophilia in resource-constrained countries.

INTRODUCTION: The gaps in haemophilia treatment around the world are enormous; approximately 60% of an estimated 475 000 individuals are not identified. Of the 187 000 diagnosed, 30% (57 000) access clotting factor replacement therapy. Since 1996, humanitarian aid distributed by the World Federation of Hemophilia (WFH) has played a minor, yet vital role providing life-saving clotting factor to countries in emergency situations. Donated amounts have been small and sporadic, often salvaging short-dated products, providing little opportunity to leverage donations with governments. In 2015, a prospective donation programme of 100 million I.U. per year of extended half-life factor VIII and IX over 10 years was established, necessitating the development of new logistics and training programmes by WFH. AIM: To measure the impact of a greatly expanded haemophilia humanitarian aid program. MATERIALS AND METHODS: In 2016, the first full year of the expanded programme, WFH, distributed products to 58 countries with factor VIII usage <1 I.U. per capita, a level incompatible with long-term survival and far below the 4 I.U. FVIII per capita minimum established in Europe. RESULTS: The scope of the programme and utilization data for 2016 indicate primarily use for acute bleeding, orthopaedic and emergency surgeries. Compared to 2014, 2016 data showed substantial increases in patients served (5.9-fold, from 2119 to 14 579), surgeries performed (37-fold) and bleeds treated (6.9-fold). Patients on prophylaxis rose from 0 to 852, including 458 children under 10 years old. DISCUSSION: The expanded humanitarian aid programme impacts an estimated 10% of individuals with haemophilia previously unable to access treatment. CONCLUSION: This programme represents an unprecedented public-private partnership to deliver medicines to individuals with no access. Further, the programme offers the prospective opportunity to engage governments to take more responsiblity for increasing training, medical management, and product supply in 58 resource constrained countries.

Vaccinations are not associated with inhibitor development in boys with severe haemophilia A.

BACKGROUND: Inhibitor development in previously untreated patients (PUPs) with severe haemophilia A is a multifactorial event. It is unknown whether paediatric vaccinations given in close proximity to factor VIII (FVIII) are associated with inhibitor development. OBJECTIVE: To assess whether paediatric vaccinations in close proximity to FVIII within the first 75 exposure days (EDs) are associated with inhibitor development in PUPs with severe haemophilia A. METHODS: We included 375 PUPs with severe haemophilia A (<0.01 IU/mL) from the PedNet Registry who had received vaccinations between the first and 75th ED or inhibitor development. Inhibitor risk was compared between patients who did and who did not receive vaccinations within 24, 72 or 120 hours of FVIII infusion. Unadjusted and adjusted hazard ratios were calculated for any or repeated vaccinations in close proximity to FVIII, using Cox regression. RESULTS: Inhibitor development occurred in 77 of 375 patients (20.5%). Overall inhibitor development appeared similar or lower in patients receiving vaccinations in close proximity to FVIII as compared to patients receiving vaccinations without FVIII: for 24 hours, this was 19.2% and 21.4% (P = .186), for 72 hours, 16.4% and 27.3% (P = .023) and for 120 hours, 18.3% and 25.0% (P = .085), respectively. CONCLUSION: We found no association between vaccinations given in close proximity to FVIII exposure within the first 75 EDs and inhibitor development. Our data do not support avoiding administration of FVIII at time of routine vaccinations.

Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial.

OBJECTIVE: The Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-4a trial is a randomized trial for women with high-intermediate risk endometrial cancer (EC), comparing individualized adjuvant treatment based on a molecular-integrated risk profile to standard adjuvant treatment; vaginal brachytherapy. To evaluate patient acceptability and pathology logistics of determining the risk profile, a pilot phase was included in the study. METHODS: PORTEC-4a is ongoing and the first 50 patients enrolled were included in the pilot phase. Primary endpoints of the pilot phase were patient acceptance, evaluated by analyzing the screening logs of the participating centers, and logistical feasibility of determination of the risk profile within 2 weeks, evaluated by analyzing the pathology database. RESULTS: In the first year, 145 eligible women were informed about the trial at 13 centers, of whom 50 (35%) provided informed consent. Patient accrual ranged from 0 to 57% per center. Most common reasons for not participating were: not willing to participate in any trial (43.2%) and not willing to risk receiving no adjuvant treatment (32.6%). Analysis of the pathology database showed an average time between randomization and determination of the molecular-integrated risk profile of 10.2 days (1-23 days). In 5 of the 32 patients (15.6%), pathology review took >2 weeks. CONCLUSIONS: The PORTEC-4a trial design was proven feasible with a satisfactory patient acceptance rate and an optimized workflow of the determination of the molecular-integrated risk profile. PORTEC-4a is the first randomized trial to investigate use of a molecular-integrated risk profile to determine adjuvant treatment in EC.

Proximal humeral fractures in Sweden-a registry-based study.

Proximal humeral fracture is the third most common osteoporotic fracture. To our knowledge, this is the first nationwide population-based registry study in adults that includes both inpatient and outpatient visits. Thus, we were able to report the true incidence rates and trends in the treatment of proximal humeral fractures. INTRODUCTION: Proximal humeral fractures are among the most common osteoporotic fractures. Valid epidemiologic population-based data, including both inpatient and outpatient visits, however, are lacking. METHODS: To investigate the Swedish national incidence rates and treatment trends of proximal humeral fractures, we obtained data from the Swedish Hospital Discharge Register between 2001 and 2012. All adult patients (≥18 years of age) in the Swedish Hospital Discharge Register were included. Outpatient visits have been included in the register since 2001. RESULTS: We identified 98,770 patients (women n = 72,063; 73 %) with proximal humeral fractures between 2001 and 2012. In 2001, the sex-specific incidence of proximal humeral fractures was 134.5 per 100,000 person-years for women and 49.2 for men. In 2012, the corresponding values were 174.6 for women and 68.1 for men, increasing 30 % in women and 39 % in men. A total of 17,013 surgical procedures were conducted between 2001 and 2012. Open reduction and internal fixation with a plate was the most common procedure (n = 5050, 30 %), followed by endoprosthetic implantation (n = 3962, 23 %) and intramedullary nailing (n = 3376, 20 %). The proportion of surgically treated patients increased from 12.1 % in 2001 to 16.8 % in 2012 for women and from 15.1 % in 2001 to 17.1 % in 2012 for men. CONCLUSION: The Swedish national incidence of proximal humeral fractures has been increasing, although it seems to have peaked in the elderly population during 2008-2010. The rate of surgical treatment has increased substantially, particularly open reduction and internal fixation with a plate. To our knowledge, this is the first nationwide epidemiologic study for Sweden reporting the incidence of proximal humeral fractures and including all inpatient and outpatient visits.

A randomised, phase II study of repeated rhenium-188-HEDP combined with docetaxel and prednisone versus docetaxel and prednisone alone in castration-resistant prostate cancer (CRPC) metastatic to bone; the Taxium II trial.

BACKGROUND: Rhenium-188-HEDP is a beta-emitting radiopharmaceutical used for palliation of metastatic bone pain. We investigated whether the addition of rhenium-188-HEDP to docetaxel/prednisone improved efficacy of chemotherapy in patients with CRPC. METHODS: Patients with progressive CRPC and osteoblastic bone metastases were randomised for first-line docetaxel 75 mg/m2 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital. RESULTS: Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median number of cycles of docetaxel was 9 in the control group and 8 in the experimental group. Median follow-up was 18.4 months. Two patients from the experimental group did not start treatment after randomisation. In the intention to treat analysis no differences in PFS, survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (33.8 months (95%CI 31.75-35.85)) than in the control group (21.0 months (95%CI 13.61-28.39); p 0.012). Also median PFS in patients with a baseline phosphatase >220U/L was significantly better with combination treatment (9.0 months (95%CI 3.92-14.08) versus 6.2 months (95%CI 3.08-9.32); log rank p 0.005). As expected, thrombocytopenia (grade I/II) was reported more frequently in the experimental group (25% versus 0%). CONCLUSION: Combined treatment with rhenium-188-HEDP and docetaxel did not prolong PFS in patients with CRPC. The observed survival benefit in the per-protocol analysis warrants further studies in the combined treatment of chemotherapy and radiopharmaceuticals.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study).

BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.

Registries supporting new drug applications.

PURPOSE: Knowledge of the benefits and risks of new drugs is incomplete at the time of marketing approval. Registries offer the possibility for additional, post-approval, data collection. For all new drugs, which were approved in the European Union between 2007 and 2010, we reviewed the frequency, the type, and the reason for requiring a registry. METHODS: The European Public Assessment Reports, published on the website of the European Medicine Agency, were reviewed for drugs approved by the Committee for Medicinal Products for Human Use. We searched for key characteristics of these drugs, including therapeutic area (ATC1 level), level of innovation (the score is an algorithm based on availability of treatment and therapeutic effect), and procedural characteristics. In addition, we identified if these registries were defined by disease (disease registry) or exposure to a single drug (drug registry). RESULTS: Out of 116 new drugs approved in the predefined period, for 43 (37%), 1 to 6 registry studies were identified, with a total of 73 registries. Of these 46 were disease registries and 27 (single) drug registries. For 9 drugs, the registry was a specific obligation imposed by the regulators. The level of innovation and the orphan status of the drugs were determinants positively predicting post-approval registries (OR 10.3 [95% CI 1.0-103.9] and OR 2.8 [95% CI 1.0-7.5], respectively). CONCLUSIONS: The majority of registries required by regulators are existing disease registries. Registries are an important and frequently used tool for post-approval data collection for orphan and innovative drugs.

Effect of Antibiotic Prophylaxis on Surgical Site Infections Following Removal of Orthopedic Implants Used for Treatment of Foot, Ankle, and Lower Leg Fractures: A Randomized Clinical Trial.

Importance: Following clean (class I, not contaminated) surgical procedures, the rate of surgical site infection (SSI) should be less than approximately 2%. However, an infection rate of 12.2% has been reported following removal of orthopedic implants used for treatment of fractures below the knee. Objective: To evaluate the effect of a single dose of preoperative antibiotic prophylaxis on the incidence of SSIs following removal of orthopedic implants used for treatment of fractures below the knee. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial including 500 patients aged 18 to 75 years with previous surgical treatment for fractures below the knee who were undergoing removal of orthopedic implants from 19 hospitals (17 teaching and 2 academic) in the Netherlands (November 2014-September 2016), with a follow-up of 6 months (final follow-up, March 28, 2017). Exclusion criteria were an active infection or fistula, antibiotic treatment, reimplantation of osteosynthesis material in the same session, allergy for cephalosporins, known kidney disease, immunosuppressant use, or pregnancy. Interventions: A single preoperative intravenous dose of 1000 mg of cefazolin (cefazolin group, n = 228) or sodium chloride (0.9%; saline group, n = 242). Main Outcomes and Measures: Primary outcome was SSI within 30 days as measured by the criteria from the US Centers for Disease Control and Prevention. Secondary outcome measures were functional outcome, health-related quality of life, and patient satisfaction. Results: Among 477 randomized patients (mean age, 44 years [SD, 15]; women, 274 [57%]; median time from orthopedic implant placement, 11 months [interquartile range, 7-16]), 470 patients completed the study. Sixty-six patients developed an SSI (14.0%): 30 patients (13.2%) in the cefazolin group vs 36 in the saline group (14.9%) (absolute risk difference, -1.7 [95% CI, -8.0 to 4.6], P = .60). Conclusions and Relevance: Among patients undergoing surgery for removal of orthopedic implants used for treatment of fractures below the knee, a single preoperative dose of intravenous cefazolin compared with saline did not reduce the risk of surgical site infection within 30 days following implant removal. Trial Registration: clinicaltrials.gov Identifier: NCT02225821.

Factor VIII products and inhibitor development in severe hemophilia A.

BACKGROUND: For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS: We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS: Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS: Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).