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Acute appendicitis is the most common indication for emergency surgery in children. In cases of perforation, patients require post-operative intravenous antibiotics in hospital. However, some children fail to respond adequately, resulting in prolonged hospitalization. The optimal antibiotic regimen for perforated appendicitis remains uncertain. We propose a double-blind, randomized controlled pilot trial comparing two commonly used antibiotic strategies. Eligible participants include children <18 years undergoing laparoscopic appendectomy for perforated appendicitis. Following surgery, participants will be randomized to receive either: (1) piperacillin/tazobactam; or (2) ceftriaxone and metronidazole. The sample size for the pilot study is 16 participants (i.e., 8 per group). Feasibility outcomes include recruitment rate, protocol adherence, loss to follow-up, and cost per participant. This pilot study will assess the feasibility of conducting a blinded randomized controlled trial of postoperative antibiotic therapy in children with perforated appendicitis. To date, only one randomized trial has addressed this question, but it was limited by its single-center design, lack of blinding, and susceptibility to ascertainment bias and other methodological concerns. Findings from this pilot will inform the design of a larger, multicenter study with rigorous blinding and standardized outcome assessment to determine whether piperacillin-tazobactam or ceftriaxone and metronidazole provides superior outcomes. ClinicalTrials.gov: NCT05943223.

Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12–16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m2) or doxorubicin alone (75 mg/m2) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0·2 and statistical power of 0·8. This study was registered with ClinicalTrials.gov, number NCT01185964. 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6·6 months (95% CI 4·1–8·3) with olaratumab plus doxorubicin and 4·1 months (2·8–5·4) with doxorubicin (stratified hazard ratio [HR] 0·67; 0·44–1·02, p=0·0615). Median overall survival was 26·5 months (20·9–31·7) with olaratumab plus doxorubicin and 14·7 months (9·2–17·1) with doxorubicin (stratified HR 0·46, 0·30–0·71, p=0·0003). The objective response rate was 18·2% (9·8–29·6) with olaratumab plus doxorubicin and 11·9% (5·3–22·2) with doxorubicin (p=0·3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL (geometric coefficient of variation in percentage [CV%] 26·2) to 487 μg/mL (CV% 33·0) and from 123 μg/mL (CV% 31·2) to 156 μg/mL (CV% 38·0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11·8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. Eli Lilly and Company.

\"Medieval Warfare: A Reader examines how armed conflict was experienced in the Middle Ages both on the field of battle and at home. This comprehensive collection of primary source materials some translated here for the first time traces over one thousand years of military developments including the fall of Rome, the fight for Jerusalem, the building of castles and other fortifications, the rise of gunpowder, and the negotiation of treaties. Curated by two of the leading experts in medieval military history, the readings in Medieval Warfare tell a story of terrors and tragedies, triumphs and technologies in the Middle Ages. Chronicles, poems, songs, and letters provide a comprehensive look not just at the waging of war but at the impact war had on society. By reclaiming the voices of victims and veterans that have previously been ignored, the editors stake out a powerful new perspective on the long history of military conflict and suffering.\"-- Provided by publisher.

The aim of this study was to validate the expanded and revised Gross Motor Function Classification System (GMFCS‐E&R) for children and youth with cerebral palsy using group consensus methods. Eighteen physical therapists participated in a nominal group technique to evaluate the draft version of a 12‐ to 18‐year age band. Subsequently, 30 health professionals from seven countries participated in a Delphi survey to evaluate the revised 12‐ to 18‐year and 6‐ to 12‐year age bands. Consensus was defined as agreement with a question by at least 80% of participants. After round 3 of the Delphi survey, consensus was achieved for the clarity and accuracy of the descriptions for each level and the distinctions between levels for both the 12‐ to 18‐year and 6‐ to 12‐year age bands. Participants also agreed that the distinction between capability and performance and the concept that environmental and personal factors influence methods of mobility were useful for classification of gross motor function. The results provide evidence of content validity of the GMFCS‐E&R. The GMFCS‐E&R has utility for communication, clinical decision making, databases, registries, and clinical research.

Acute appendicitis is the most common indication for emergency surgery in children. In cases of perforation, patients require post-operative intravenous antibiotics in hospital. However, some children fail to respond adequately, resulting in prolonged hospitalization. The optimal antibiotic regimen for perforated appendicitis remains uncertain. We propose a double-blind, randomized controlled pilot trial comparing two commonly used antibiotic strategies. Eligible participants include children <18 years undergoing laparoscopic appendectomy for perforated appendicitis. Following surgery, participants will be randomized to receive either: (1) piperacillin/tazobactam; or (2) ceftriaxone and metronidazole. The sample size for the pilot study is 16 participants (i.e., 8 per group). Feasibility outcomes include recruitment rate, protocol adherence, loss to follow-up, and cost per participant. This pilot study will assess the feasibility of conducting a blinded randomized controlled trial of postoperative antibiotic therapy in children with perforated appendicitis. To date, only one randomized trial has addressed this question, but it was limited by its single-center design, lack of blinding, and susceptibility to ascertainment bias and other methodological concerns. Findings from this pilot will inform the design of a larger, multicenter study with rigorous blinding and standardized outcome assessment to determine whether piperacillin-tazobactam or ceftriaxone and metronidazole provides superior outcomes.

This study examined the distribution of alcohol consumption in Australia, identifying the heaviest drinking 10% of the population and examining their sociodemographic characteristics and their alcohol consumption and purchasing practices. Data came from the 2016 National Drug Strategy Household Survey and the 2013 International Alcohol Control Study. The heaviest drinking 10% of the population identified based on estimates of annual alcohol consumption. Logistic regression was then used to assess the factors that distinguished these heaviest drinkers from the rest of the drinking population. The heaviest drinking 10% of the population consumed 54.4% of all alcohol consumed. These heavy drinkers were more likely to be men and to live in regional and remote areas. They were more likely to drink cask wine and full‐strength beer and to purchase cheaper alcohol than other drinkers. Australian alcohol consumption is heavily skewed. Alcohol consumption practices appear to differentiate the heaviest drinkers from others more clearly than sociodemographic factors. Public health interventions that reduce drinking among the heaviest 10% of drinkers in Australia have the potential to markedly reduce per‐capita consumption and reduce alcohol‐related harm. Interventions focused on cheap alcohol may be effective with these drinkers.

The Northern Territory (NT) Government introduced a minimum unit price (MUP) of $1.30 per standard drink (10g pure alcohol) explicitly aimed at reducing the consumption of cheap wine products from October 2018. We aimed to assess the impact of the NT MUP on estimates of beverage‐specific population‐adjusted alcohol consumption using wholesale alcohol supply data. Interrupted time series analyses were conducted to examine MUP effects on trends in estimated per capita alcohol consumption (PCAC) for cask wine, total wine and total alcohol, across the NT and in the Darwin/Palmerston region. Significant step decreases were found for cask wine and total wine PCAC in Darwin/Palmerston and across the Northern Territory. PCAC of cask wine decreased by 50.6% in the NT, and by 48.8% in Darwin/Palmerston compared to the prior year. PCAC for other beverages (e.g. beer) were largely unaffected by MUP. Overall, PCAC across the Territory declined, but not in Darwin/Palmerston. With minimal implementation costs, the Northern Territory Government's MUP policy successfully targeted and reduced cask wine and total wine consumption. Cask wine, in particular, almost halved in Darwin/Palmerston where the impact of the MUP was able to be determined and considering other interventions. Implementation of a minimum unit price for retail alcohol sales is a cost‐effective way to reduce the consumption of high alcohol content and high‐risk products, such as cheap cask wine.