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Abstract Background Based on epidemiological and clinical data acute appendicitis can present either as uncomplicated (70–80%) or complicated (20–30%) disease. Recent studies have shown that antibiotic therapy is both safe and cost-effective for a CT-scan confirmed uncomplicated acute appendicitis. However, based on the study protocols to ensure patient safety, these randomised studies used mainly broad-spectrum intravenous antibiotics requiring additional hospital resources and prolonged hospital stay. As we now know that antibiotic therapy for uncomplicated acute appendicitis is feasible and safe, further studies evaluating optimisation of the antibiotic treatment regarding both antibiotic spectrum and shorter hospital stay are needed to evaluate antibiotics as the first-line treatment for uncomplicated acute appendicitis. Methods APPAC II trial is a multicentre, open-label, non-inferiority randomised controlled trial comparing per oral (p.o.) antibiotic monotherapy with intravenous (i.v.) antibiotic therapy followed by p.o. antibiotics in the treatment of CT-scan confirmed uncomplicated acute appendicitis. Adult patients with CT-scan diagnosed uncomplicated acute appendicitis will be enrolled in nine Finnish hospitals. The intended sample size is 552 patients. Primary endpoint is the success of the randomised treatment, defined as resolution of acute appendicitis resulting in discharge from the hospital without the need for surgical intervention and no recurrent appendicitis during one-year follow-up. Secondary endpoints include post-intervention complications, late recurrence of acute appendicitis after one year, duration of hospital stay, pain, quality of life, sick leave and treatment costs. Primary endpoint will be evaluated in two stages: point estimates with 95% confidence interval (CI) will be calculated for both groups and proportion difference between groups with 95% CI will be calculated and evaluated based on 6 percentage point non-inferiority margin. Discussion To our knowledge, APPAC II trial is the first randomised controlled trial comparing per oral antibiotic monotherapy with intravenous antibiotic therapy continued by per oral antibiotics in the treatment of uncomplicated acute appendicitis. The APPAC II trial aims to add clinical evidence on the debated role of antibiotics as the first-line treatment for a CT-confirmed uncomplicated acute appendicitis as well as to optimise the non-operative treatment for uncomplicated acute appendicitis. Trial registration Clinicaltrials.gov, NCT03236961, retrospectively registered on the 2nd of August 2017.

Background: Antibiotic therapy is currently considered a safe and effective treatment alternative for computed tomography (CT)-confirmed uncomplicated acute appendicitis with recent studies reporting good results on both oral antibiotics only and outpatient management. Furthermore, there are promising pilot results on uncomplicated acute appendicitis management with symptomatic treatment (placebo). This trial aims to assess whether both antibiotics and hospitalization can be safely omitted from the treatment of uncomplicated acute appendicitis., Methods: The APPAC IV (APPendicitis Acuta IV) trial is a randomized, double-blind, multicenter noninferiority clinical trial comparing oral moxifloxacin with oral placebo in an outpatient setting with a discharge directly from the emergency room (ER). Adult patients (18-60 years) with CT-confirmed uncomplicated acute appendicitis (absence of appendicolith, abscess, perforation, tumor, appendiceal diameter ⩾15 mm on CT, or body temperature >38 °C) will be enrolled in nine Finnish hospitals. Primary outcome is treatment success at 30 days, that is, the resolution of acute appendicitis resulting in discharge from the hospital without appendectomy during the 30-day follow-up evaluated using a noninferiority design with a noninferiority margin of 6 percentage points. Noninferiority will be evaluated using one-sided 95% confidence interval of proportion difference between groups. Secondary endpoints include postintervention complications, recurrent appendicitis after the 30-day follow-up, duration of hospital stay, admission to hospital and reason for admission, readmissions to emergency department or hospitalization, VAS pain scores, quality of life, sick leave, and treatment costs. The follow-up after discharge from the ER includes a phone call at day 1, and at 3-4 days, 30 days, and 1, 3, 5, 10, and 20 years. Those eligible patients, who decline to undergo randomization, will be invited to participate in a concurrent observational cohort study with follow-up at 30 days, and 1 and 5 years., Discussion: To our knowledge, APPAC IV trial is the first large randomized, double-blind, noninferiority multicenter clinical trial aiming to compare oral antibiotics and placebo for CT-diagnosed uncomplicated acute appendicitis in an outpatient setting. The study aims to bridge the major knowledge gap on whether antibiotics and hospitalization or both can be omitted in the treatment of uncomplicated acute appendicitis., Trial Registration: The study protocol has been approved by the Clinical Trials Information System (CTIS) of the European Medicines Agency (EMA), study number: 2023-506213-21-00 and the trial has been registered in ClinicalTrials.gov, NCT06210269., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Randomised controlled trials (RCTs) have found antibiotics to be a feasible and safe alternative to appendicectomy in adults with imaging-confirmed acute appendicitis. However, patient inclusion criteria and outcome definitions vary greatly between RCTs. We aimed to compare antibiotics with appendicectomy for the treatment of acute appendicitis using individual patient data and uniform outcome definitions., Methods: In this individual patient data meta-analysis, we searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials without language restrictions between database inception and June 6, 2023, for RCTs comparing appendicectomy with antibiotics for the treatment of adults (≥18 years) with imaging-confirmed acute appendicitis. Studies without 1-year follow-up data on complications were excluded, as were patients. Corresponding authors of eligible studies were contacted and invited to share data; individual patient data were merged after validation. One-stage meta-analyses were conducted using a generalised, mixed-effects linear regression model, accounting for clustering of patients within studies. The primary outcome was the complication rate at 1-year follow-up, uniformly harmonised across trials using the Clavien-Dindo classification. Complications were further divided into minor (grade 1-2 or equivalent) and major (grade 3-5 or equivalent) complications. Appendicectomy rate during 1 year was a key secondary outcome but not considered a complication for the antibiotics group. Outcomes were described separately for patients with and without an appendicolith. This study is registered with PROSPERO, CRD42023391676., Findings: Of 887 potentially relevant articles, eight were eligible for inclusion, of which six RCTs could provide data for 2101 eligible patients (1050 assigned to antibiotics and 1051 assigned to appendicectomy; 830 [39·5%] women and 1271 [60·5%] men). All studies raised some bias concerns due to absence of blinding. One study was judged to have a high risk of bias due to the exclusion of eligible patients after randomisation, but these patients were eligible for inclusion in our meta-analysis. At 1 year, 57 (5·4%) of 1050 patients randomly assigned to antibiotics had a complication compared with 87 (8·3%) of 1051 patients randomly assigned to appendicectomy (odds ratio [OR] 0·49 [95% CI 0·20 to 1·20]; risk difference -4·5 percentage points [95% CI -11·6 to 2·6]). At 1 year, 1025 (97·5%) patients in the appendicectomy group had undergone appendicectomy compared with 356 (33·9%) patients in the antibiotics group. In patients with an appendicolith at pre-interventional imaging, there were more complications at 1 year among patients who received antibiotic treatment than among those who underwent appendicectomy (29 [15·0%] of 193 patients vs 12 [6·3%] of 190 patients; OR 2·82 [95% CI 1·11 to 7·18]; risk difference 13·2 percentage points [95% CI 2·3 to 24·2]). In the antibiotics group, 94 (48·7%) of 193 patients with an appendicolith underwent appendicectomy within 1 year versus 262 (30·6%) of 857 patients without an appendicolith., Interpretation: This meta-analysis showed that antibiotic treatment in adults with imaging-confirmed acute appendicitis was a safe alternative to surgery and resulted in around two-thirds of patients avoiding appendicectomy during the first year. In patients with an appendicolith, initial antibiotic treatment increased the risk of complications compared with appendicectomy, and around half of these patients assigned to antibiotics underwent step-up appendicectomy within 1 year. These data should be key components in shared decision making., Funding: None., Competing Interests: Declaration of interests We received no financial support for the research, authorship, or publication of this Article. JH reported receiving grants from the Orion Research Foundation and the Mary and Georg C Ehrnrooth Foundation. GHD reported receiving an award from the Patient-Centered Outcomes Research Institute (PCORI). SEM reported receiving financial support from the PCORI and the University of Michigan (Ann Arbor, MI, USA) for work related to the CODA trial. RRG reported receiving grants from KiKa, ZonMW, LTC, the Hartwig Foundation, the Janivho Foundation, and AR&D. PS reported receiving financial support from the Sigrid Jusélius Foundation; receiving research grants from the Academy of Finland and the European Research Council; being a lecturer for Novo Nordisk; and being a member of the data safety monitoring board of the Best RCT (Sweden) and the Magnet Study. MAB reported receiving institutional grants from J&J/Ethicon and KCI/3M, and being a speaker or instructor (payment to institution) for J&J/Ethicon, 3M, BD, Gore, TelaBio, Medtronic, GD Medical, Smith&Nephew, Angiodynamics, and Molnlycke. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Antibiotics have been reported as an efficient and safe treatment option for uncomplicated acute appendicitis without an appendicolith diagnosed using computed tomography (CT). The aim of this study was to assess the association of a CT-diagnosed appendicolith and its characteristics with appendicitis severity., Methods: A large prospective patient cohort with suspected acute appendicitis enrolled between April 2017 and November 2018 was retrospectively reviewed. The initial analysis evaluated the association of a CT-diagnosed appendicolith with complicated acute appendicitis; then, based on the availability of CT images, a subset of patients was analysed for the correlation of appendicolith characteristics with appendicitis severity. The final appendicitis assessment (uncomplicated or complicated-including perforation, gangrene, an abscess, or a tumour) was determined for all patients., Results: Out of 3512 eligible patients, 3085 patients with appendicitis were selected and 380 patients with an appendicolith and with a CT image available for reassessment were included. Out of the 3085 patients with CT-diagnosed acute appendicitis, 1101 (35.7%) patients presented with both acute appendicitis and an appendicolith and, out of these, 519 (47.1%) had complicated acute appendicitis. In the patients without an appendicolith (1984 patients), 426 (21.5%) had complicated appendicitis (P < 0.001). Re-evaluation of CT images for 380 patients showed that a larger appendicolith diameter (OR = 1.15 (95% c.i. 1.06 to 1.25); P < 0.001), appendicolith location at the base of the appendix (55.1% versus 44.9%; P = 0.008), and heterogeneous appendiceal wall enhancement around the appendicolith (68.4% versus 31.6%; P < 0.001) were associated with an increased risk of complicated acute appendicitis., Conclusion: The presence of an appendicolith in patients with acute appendicitis is correlated with the risk of complicated appendicitis. This risk is further increased by a larger appendicolith diameter or appendicolith location at the base of the appendix., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Objective: Appendicoliths are associated with a more complicated course of acute appendicitis and failure of non-operative treatment. We aimed to update the appendicolith classification originally described in 1966 and to assess the association of appendicolith characteristics with appendicitis severity., Design: This prospective predefined MAPPAC-trial (ClinicalTrials.gov NCT03257423) substudy included patients with CT diagnosed appendicitis presenting with an appendicolith. CT visible appendicoliths were harvested at surgery, measured and characterised by morphological examination complemented with micro-CT and micro-X-ray fluorescence spectroscopy. Patients were categorised into two groups: appendicolith appendicitis without other complications and appendicolith appendicitis with complications (appendiceal gangrene, perforation and/or abscess). The association of appendicolith classification and characteristics with appendicitis severity was evaluated., Results: Of 78 patients with a CT appendicolith, 41 appendicoliths were collected and classified based on the degree of hardness into three classes. The hardest appendicoliths (class 3) were less common (19.5%) presenting with a stone-hard outer layer and concentrically layered inner structure around a core. The layered inner structure was also observed in class 2 appendicoliths, but was absent in soft, class 1 appendicoliths. Appendicolith hardness or measures (maximum length, diameter and weight) were not associated with appendicitis severity. The spatial distribution of the main inorganic elements of calcium and phosphorus varied within most appendicoliths., Conclusion: This updated classification confirms categorisation of CT visible appendicoliths into three classes based on their physical and chemical characteristics. The data on clinical and aetiopathological characteristics of appendicoliths is scarce and using this systematic classification would add to this understanding., Competing Interests: Competing interests: EMu is currently working as full-time Medical Advisor for Biocodex Nordics. PS reports receiving personal fees for lectures form Merck and Orion Pharma. AJH reports receiving personal fees for lectures from BioCodex, Merck and Pfizer. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

17-Beta-estradiol (E2), a steroid hormone synthesized from cholesterol, has various impacts on health and the environment. Currently, the gold standard for its measurement in the body is a conventional blood test (mass spectrometry), but carbon-based electrochemical sensors have been proposed as an alternative due to their advantages, such as rapid analysis time and sensitivity. To improve the atomic-level understanding of the interactions at the substrate surface, we performed density functional theory (DFT) simulations to study the nature of the adsorption of E2 on pristine graphene. Bayesian Optimization Structure Search (BOSS) was employed to reduce human bias in the determination of the most favorable adsorption configurations. Two stable adsorption minimum configurations were found. Analysis of their electronic properties indicates that E2 physisorbs on graphene. Embarking upon complex carbonaceous materials, the importance of finding all possible minimum candidates with automated structure search tools is highlighted. Computational investigations facilitate tailoring substrate materials with outstanding performance and applications in neuroscientific research, fertility monitoring, and clinical trials. Combining them with experimental research carries significant potential to advance sensor design beyond the current state-of-the-art., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Importance: Current short-term evidence has shown that uncomplicated acute appendicitis can be treated successfully with oral antibiotics alone, but longer-term results are lacking., Objective: To assess the treatment effectiveness of oral antibiotic monotherapy compared with combined intravenous (IV) and oral antibiotics in computed tomography-confirmed uncomplicated acute appendicitis at a longer-term follow-up., Design, Setting, and Participants: This secondary analysis of a predefined year 3 follow-up of the Appendicitis Acuta II (APPAC II) noninferiority, multicenter randomized clinical trial compared oral moxifloxacin with combined IV ertapenem plus oral levofloxacin and metronidazole for the treatment of uncomplicated acute appendicitis. The trial was conducted at 9 university and central hospitals in Finland from April 2017 to November 2018, with the last follow-up in November 2022. Participants included patients aged 18 to 60 years, who were randomized to receive either oral antibiotics monotherapy (n = 301) or combined IV and oral antibiotics (n = 298)., Interventions: Antibiotics monotherapy consisted of oral moxifloxacin, 400 mg/d, for 7 days. Combined IV and oral antibiotics consisted of IV ertapenem sodium, 1 g/d, for 2 days plus oral levofloxacin, 500 mg/d, and metronidazole, 500 mg 3 times/d, for 5 days., Main Outcomes and Measures: The primary end point was treatment success, defined as the resolution of acute appendicitis and discharge from hospital without the need for surgical intervention and no appendicitis recurrence at the year 3 follow-up evaluated using a noninferiority design. The secondary end points included late (after 1 year) appendicitis recurrence as well as treatment-related adverse events, quality of life, length of hospital stay, and length of sick leave, which were evaluated using a superiority design., Results: After exclusions, 599 patients (mean [SD] age, 36 [12] years; 336 males [56.1%]) were randomized; after withdrawal and loss to follow-up, 582 patients (99.8%) were available for the year 3 follow-up. The treatment success at year 3 was 63.4% (1-sided 95% CI, 58.8% to ∞) in the oral antibiotic monotherapy group and 65.2% (1-sided 95% CI, 60.5% to ∞) in the combined IV and oral antibiotics group. The difference in treatment success rate between the groups at year 3 was -1.8 percentage points (1-sided 95% CI, -8.3 percentage points to ∞; P = .14 for noninferiority), with the CI limit exceeding the noninferiority margin. There were no significant differences between groups in treatment-related adverse events, quality of life, length of hospital stay, or length of sick leave., Conclusions and Relevance: This secondary analysis of the APPAC II trial found a slightly higher appendectomy rate in patients who received oral antibiotic monotherapy; however, noninferiority of oral antibiotic monotherapy compared with combined IV and oral antibiotics could not be demonstrated. The results encourage future studies to assess oral antibiotic monotherapy as a viable treatment alternative for uncomplicated acute appendicitis., Trial Registration: ClinicalTrials.gov Identifier: NCT03236961.

Background: Uncomplicated and complicated acute appendicitis seem to be two different forms of this common abdominal emergency. The contribution of appendiceal microbiota to appendicitis pathogenesis has been suggested, but differences between uncomplicated and complicated appendicitis are largely unknown. We compared the appendiceal microbiota in uncomplicated and complicated acute appendicitis., Methods: This prospective single-center clinical cohort study was conducted as part of larger multicenter MAPPAC trial enrolling adult patients with computed tomography or clinically confirmed uncomplicated or complicated acute appendicitis. The microbial composition of the appendiceal lumen was determined using 16S rRNA gene amplicon sequencing., Results: Between April 11, 2017, and March 29, 2019, 118 samples (41 uncomplicated and 77 complicated appendicitis) were available. After adjusting for age, sex, and BMI, alpha diversity in complicated appendicitis was higher (Shannon p = 0.011, Chao1 p = 0.006) compared to uncomplicated appendicitis. Microbial compositions were different between uncomplicated and complicated appendicitis (Bray-Curtis distance, P = 0.002). Species poor appendiceal microbiota composition with specific predominant bacteria was present in some patients regardless of appendicitis severity., Conclusion: Uncomplicated and complicated acute appendicitis have different appendiceal microbiome profiles further supporting the disconnection between these two different forms of acute appendicitis., Study Registration: ClinicalTrials.gov NCT03257423., Competing Interests: EM is currently working as full-time Medical Advisor for Biocodex Nordics. PS reports receiving personal fees for lectures form Merck and Orion Pharma. AJH reports receiving personal fees for lectures from BioCodex, Merck and Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declare no competing interests.

Background and Objective: The prevalence of bacteremia in acute appendicitis is unknown. We aimed to assess prevalence and predictive factors of bacteremia in adult patients with appendicitis., Methods: In this prospective propensity score-matched cohort study, patients were recruited as part of one single-center prospective observational study assessing appendicitis microbiology in concurrence with two randomized controlled trials on non-operative treatment of uncomplicated acute appendicitis. All patients evaluated for enrollment in these three trials between April 2017 and December 2018 with both a confirmed diagnosis of appendicitis and available blood culture on admission were included in this study. Potential predictive factors of bacteremia (age, sex, body mass index (BMI), body temperature, C-reactive protein (CRP), leukocyte count, comorbidities, symptom duration, and appendicitis severity) were assessed. Prevalence of bacteremia was determined by all available blood cultures followed by propensity score matching using sex, age, BMI, CRP, leukocyte count, and body temperature of the patients without available blood culture., Results: Out of the 815 patients with appendicitis, 271 patients had available blood culture and the prevalence of bacteremia was 12% (n = 33). Based on propensity score estimation, the prevalence of bacteremia in the whole prospective appendicitis cohort was 11.1%. Bacteremia was significantly more frequent in complicated acute appendicitis (15%; 29/189) compared with uncomplicated acute appendicitis (5%; 4/82) (p = 0.015). Male sex (p = 0.024) and higher body temperature (p = 0.0044) were associated with bacteremia., Conclusions: Estimated prevalence of bacteremia in patients with acute appendicitis was 11.1%. Complicated appendicitis, male sex, and higher body temperature were associated with bacteremia in acute appendicitis.

Background: Non-operative management of uncomplicated acute appendicitis is an option, but omission of antibiotics from the regimen has not been tested., Methods: A double-blind, placebo-controlled, superiority RCT in adults with CT-confirmed uncomplicated acute appendicitis was designed to compare placebo with antibiotics (intravenous ertapenem followed by oral levofloxacin and metronidazole). The primary endpoint was treatment success (resolution resulting in discharge without appendicectomy within 10 days); secondary outcomes included pain scores, complications, hospital stay, and return to work., Results: From May 2017 to September 2020, 72 patients with a mean(s.d.) age of 37.5 (11.1) years were recruited at five hospitals. Six were excluded after randomization (5 early consent withdrawals, 1 randomization protocol violation), 35 were assigned to receive antibiotics, and 31 to receive placebo. Enrolment challenges (including hospital pharmacy resources in an acute-care surgery setting) meant that only the lowest sample size of three predefined scenarios was achieved. The 10-day treatment success rate was 87 (95 per cent c.i. 75 to 99) per cent for placebo and 97 (92 to 100) per cent for antibiotics. This clinical difference of 10 (90 per cent c.i. -0.9 to 21) per cent was not statistically different for the primary outcome (1-sided P = 0.142), and secondary outcomes were similar., Conclusion: The lack of antibiotic superiority statistically suggests that a non-inferiority trial against placebo is warranted in adults with CT-confirmed mild appendicitis. Registration number: EudraCT 2015-003634-26 (https://eudract.ema.europa.eu/eudract-web/index.faces), NCT03234296 (http://www.clinicaltrials.gov)., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Contrast-enhanced CT is the reference standard used in diagnostic imaging for acute appendicitis in adults. The radiation dose has been of concern. This study aimed to assess whether a lower radiation dose would affect the diagnostic accuracy of CT., Methods: This was a prospective single-centre cohort study of patients (aged over 16 years) with suspected appendicitis evaluated for enrolment in concurrent APPAC II-III trials. The diagnostic accuracy of contrast-enhanced low- and standard-dose CT was compared with study protocols guiding imaging based on BMI; this enabled direct CT imaging comparison only in patients with a BMI below 30 kg/m2. The on-call CT diagnosis was compared with the final clinical diagnosis., Results: Among all 856 patients investigated, the accuracy of low-dose (454 patients) and standard-dose (402 patients) CT in identifying patients with and without appendicitis was 98·0 and 98·5 per cent respectively. In patients with a BMI under 30 kg/m2, respective values were 98·2 per cent (434 patients) and 98·6 per cent (210 patients) (P = 1·000). The corresponding accuracy for differentiating between uncomplicated and complicated acute appendicitis was 90·3 and 87·6 per cent in all patients, and 89·8 and 88·4 per cent respectively among those with a BMI below 30 kg/m2 (P = 0·663). The median radiation dose in the whole low- and standard-dose CT groups was 3 and 7 mSv respectively. In the group with BMI below 30 kg/m2, corresponding median doses were 3 and 5 mSv (P < 0·001)., Conclusion: Low- and standard-dose CT were accurate both in identifying appendicitis and in differentiating between uncomplicated and complicated acute appendicitis. Low-dose CT was associated with a significant radiation dose reduction, suggesting that it should be standard clinical practice at least in patients with a BMI below 30 kg/m2., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known., Objective: To compare oral antibiotics with combined intravenous followed by oral antibiotics in the management of computed tomography-confirmed uncomplicated acute appendicitis., Design, Setting, and Participants: The Appendicitis Acuta (APPAC) II multicenter, open-label, noninferiority randomized clinical trial was conducted from April 2017 until November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were enrolled in the trial. The last date of follow-up was November 29, 2019., Interventions: Patients randomized to receive oral monotherapy (n = 295) received oral moxifloxacin (400 mg/d) for 7 days. Patients randomized to receive intravenous antibiotics followed by oral antibiotics (n = 288) received intravenous ertapenem (1 g/d) for 2 days followed by oral levofloxacin (500 mg/d) and metronidazole (500 mg 3 times/d) for 5 days., Main Outcomes and Measures: The primary end point was treatment success (≥65%) for both groups, defined as discharge from hospital without surgery and no recurrent appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were noninferior to intravenous and oral antibiotics, with a margin of 6% for difference., Results: Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263 [44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ∞) for patients treated with oral antibiotics and 73.8% (1-sided 95% CI, 69.5% to ∞) for patients treated with intravenous followed by oral antibiotics. The difference was -3.6% ([1-sided 95% CI, -9.7% to ∞]; P = .26 for noninferiority), with the confidence limit exceeding the noninferiority margin., Conclusion and Relevance: Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics., Trial Registration: ClinicalTrials.gov Identifier: NCT03236961; EudraCT Identifier: 2015-003633-10.

Importance: Long-term results support antibiotics for uncomplicated acute appendicitis as an alternative to appendectomy. To our knowledge, treatment-related long-term patient satisfaction and quality of life (QOL) are not known., Objective: To determine patient satisfaction and QOL after antibiotic therapy and appendectomy for treating uncomplicated acute appendicitis., Interventions: Open appendectomy vs antibiotics with intravenous ertapenem, 1 g once daily, for 3 days followed by 7 days of oral levofloxacin, 500 mg once daily, and metronidazole, 500 mg 3 times per day., Design, Setting, and Participants: This observational follow-up of the Appendicitis Acuta (APPAC) multicenter randomized clinical trial comparing appendectomy with antibiotics included 530 patients age 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis who were randomized to undergo appendectomy (273 [52%]) or receive antibiotics (257 [49%]). The trial was conducted from November 2009 to June 2012; the last follow-up was May 9, 2018. The data were analyzed in February 2019., Main Outcomes and Measures: In this analysis, post hoc secondary end points of postintervention QOL (EQ-5D-5L) and patient satisfaction and treatment preference were evaluated., Results: Of the 530 patients enrolled in the trial (appendectomy group: 273 [174 men (64%)] with a median age of 35 years; (antibiotic group: 257 [155 men (60%)] with a median age of 33 years), 423 patients (80%) were available for phone interview at a median follow-up of 7 years; 206 patients (80%) took antibiotics and 217 (79%) underwent appendectomy. Of the 206 patients taking antibiotics, 81 (39%) had undergone appendectomy. The QOL between appendectomy and antibiotic group patients was similar (median health index value, 1.0 in both groups; 95% CI, 0.86-1.0; P = .96). Patients who underwent appendectomy were more satisfied in the treatment than patients taking antibiotics (68% very satisfied, 21% satisfied, 6% indifferent, 4% unsatisfied, and 1% very unsatisfied in the appendectomy group and 53% very satisfied, 21% satisfied, 13% indifferent, 7% unsatisfied, and 6% very unsatisfied in the antibiotic group; P < .001) and in a subgroup analysis this difference was based on the antibiotic group patients undergoing appendectomy. There was no difference in patient satisfaction after successful antibiotic treatment compared with appendectomy (cumulative odds ratio [COR], 7.8; 95% CI, 0.5-1.3; P < .36). Patients with appendectomy or with successful antibiotic therapy were more satisfied than antibiotic group patients who later underwent appendectomy (COR, 7.7; 95% CI, 4.6-12.9; P < .001; COR, 9.7; 95% CI, 5.4-15.3; P < .001, respectively). Of the 81 patients taking antibiotics who underwent appendectomy, 27 (33%) would again choose antibiotics as their primary treatment., Conclusions and Relevance: In this analysis, long-term QOL was similar after appendectomy and antibiotic therapy for the treatment of uncomplicated acute appendicitis. Patients taking antibiotics who later underwent appendectomy were less satisfied than patients with successful antibiotics or appendectomy., Trial Registration: Clinicaltrials.gov Identifier: NCT01022567.

Objective: To compare diagnostic accuracy of contrast enhanced low-dose computed tomography (CT) accomplished in the OPTICAP trial phantom phase to standard CT in patients with suspected acute appendicitis., Background: Increasing use of CT as the gold standard in diagnosing acute appendicitis has raised concerns regarding radiation exposure. Unenhanced low-dose CT protocols have shown similar diagnostic accuracy with standard CT for diagnosing appendicitis. To our knowledge, there are no other trials in which the same patient with suspected acute appendicitis underwent both standard and low-dose CT allowing interpatient comparison., Methods: OPTICAP is an interpatient protocol sequence randomized noninferiority single-center trial performed at Turku University Hospital between November, 2015 and August, 2016. Sixty patients with suspected acute appendicitis and body mass index <30 kg/m were enrolled to undergo both standard and low-dose contrast enhanced CT scans, which were categorized as normal, uncomplicated or complicated appendicitis by 2 radiologists in blinded manner. All patients with CT confirmed appendicitis underwent appendectomy to obtain histopathology., Results: The low-dose protocol was not inferior to standard protocol in terms of diagnostic accuracy; 79% [95% confidence interval (CI) 66%-89%) accurate diagnosis in low-dose and 80% (95% CI 67%-90%) in standard CT by primary radiologist. Accuracy to categorize appendicitis severity was 79% for both protocols. The mean radiation dose of low-dose CT was significantly lower compared with standard CT (3.33 and 4.44 mSv, respectively)., Conclusion: Diagnostic accuracy of contrast enhanced low-dose CT was not inferior to standard CT in diagnosing acute appendicitis or distinguishing between uncomplicated and complicated acute appendicitis in patients with a high likelihood of acute appendicitis. Low-dose CT enabled significant radiation dose reduction.

Introduction: Based on the epidemiological and clinical data, acute appendicitis can present either as uncomplicated or complicated. The aetiology of these different appendicitis forms remains unknown. Antibiotic therapy has been shown to be safe, efficient and cost-effective for CT-confirmed uncomplicated acute appendicitis. Despite appendicitis being one of the most common surgical emergencies, there are very few reports on appendicitis aetiology and pathophysiology focusing on the differences between uncomplicated and complicated appendicitis. Microbiology APPendicitis ACuta (MAPPAC) trial aims to evaluate these microbiological and immunological aspects including immune response in the aetiology of these different forms also assessing both antibiotics non-responders and appendicitis recurrence. In addition, MAPPAC aims to determine antibiotic and placebo effects on gut microbiota composition and antimicrobial resistance., Methods and Analysis: MAPPAC is a prospective clinical trial with both single-centre and multicentre arm conducted in close synergy with concurrent trials APPendicitis ACuta II (APPAC II) (per oral (p.o.) vs intravenous+p.o. antibiotics, NCT03236961) and APPAC III (double-blind trial placebo vs antibiotics, NCT03234296) randomised clinical trials. Based on the enrolment for these trials, patients with CT-confirmed uncomplicated acute appendicitis are recruited also to the MAPPAC study. In addition to these conservatively treated randomised patients with uncomplicated acute appendicitis, MAPPAC will recruit patients with uncomplicated and complicated appendicitis undergoing appendectomy. Rectal and appendiceal swabs, appendicolith, faecal and serum samples, appendiceal biopsies and clinical data are collected during the hospital stay for microbiological and immunological analyses in both study arms with the longitudinal study arm collecting faecal samples also during follow-up up to 12 months after appendicitis treatment., Ethics and Dissemination: This study has been approved by the Ethics Committee of the Hospital District of Southwest Finland (Turku University Hospital, approval number ATMK:142/1800/2016) and the Finnish Medicines Agency. Results of the trial will be published in peer-reviewed journals., Trial Registration Number: NCT03257423., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis has been established at long-term follow-up with the majority of recurrences shown to occur within the first year. Overall costs of antibiotics are significantly lower compared with appendectomy at short-term follow-up, but long-term durability of these cost savings is unclear. The study objective was to compare the long-term overall costs of antibiotic therapy versus appendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitis ACuta) trial at 5 years., Methods and Findings: This multicentre, non-inferiority randomized clinical trial randomly assigned 530 adult patients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotic treatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis. Between November 2009 and June 2012, 273 patients were randomized to appendectomy and 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher (p<0.001) (€5716; 95% CI: €5510 to €5925) compared with antibiotic therapy (€4171; 95% CI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899; p<0.001) in the antibiotic group. At 5 years, the majority (61%, n = 156) of antibiotic group patients did not undergo appendectomy., Conclusions: At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. As the majority of appendicitis recurrences occur within the first year after the initial antibiotic treatment, these results suggest that treating uncomplicated acute appendicitis with antibiotics instead of appendectomy results in lower overall costs even at longer-term follow-up., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: P.S. has received personal fees for lectures from Merck, Lilly, and Orion Pharma. All other authors have declared that no competing interests exist.

Introduction: Recent studies show that antibiotic therapy is safe and feasible for CT-confirmed uncomplicated acute appendicitis. Spontaneous resolution of acute appendicitis has already been observed over a hundred years ago. In CT-confirmed uncomplicated acute diverticulitis (left-sided appendicitis), studies have shown no benefit from antibiotics compared with symptomatic treatment, but this shift from antibiotics to symptomatic treatment has not yet been widely implemented in clinical practice. Recently, symptomatic treatment of uncomplicated acute appendicitis has been demonstrated in a Korean open-label study. However, a double-blinded placebo-controlled study to illustrate the role of antibiotics and spontaneous resolution of uncomplicated acute appendicitis is still lacking., Methods and Analysis: The APPAC III (APPendicitis ACuta III) trial is a multicentre, double-blind, placebo-controlled, superiority randomised study comparing antibiotic therapy with placebo in the treatment CT scan-confirmed uncomplicated acute appendicitis aiming to evaluate the role of antibiotics in the resolution of uncomplicated acute appendicitis. Adult patients (18-60 years) with CT scan-confirmed uncomplicated acute appendicitis (the absence of appendicolith, abscess, perforation and tumour) will be enrolled in five Finnish university hospitals.Primary endpoint is success of the randomised treatment, defined as resolution of acute appendicitis resulting in discharge from the hospital without surgical intervention within 10 days after initiating randomised treatment (treatment efficacy). Secondary endpoints include postintervention complications, recurrent symptoms after treatment up to 1 year, late recurrence of acute appendicitis after 1 year, duration of hospital stay, sick leave, treatment costs and quality of life. A decrease of 15 percentage points in success rate is considered clinically important difference. The superiority of antibiotic treatment compared with placebo will be analysed using Fisher's one-sided test and CI will be calculated for proportion difference., Ethics and Dissemination: This protocol has been approved by the Ethics Committee of Turku University Hospital and the Finnish Medicines Agency (FIMEA). The findings will be disseminated in peer-reviewed academic journals., Trial Registration Number: NCT03234296; Pre-results., Competing Interests: Competing interests: PS has received lecture fees from Merck, Lilly and Orion Pharma., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim was to evaluate effects of voltage, noise input (NI) and iterative reconstruction (IR) on radiation dose and image quality in order to establish a contrast enhanced low-dose protocol for assessment of acute appendicitis. An anthropomorphic abdominal phantom mimicking contrast enhanced abdomen was scanned with 80, 100 and 120 kV, standard and strong IR and 11 NIs (66 protocols). A total of 14 test tubes of increasing iodine dilutions and one tube with an appendicolith were evaluated within the phantom. The dose, HUs, noise, contrast-to-noise ratio (CNR) and figure of merit (FOM) were determined. Visual quality scores were assessed by two readers. A clinically used voltage-IR combination (120 kV, standard IR) was used as a reference. Overall, 100 kV with standard IR (p = 0.002) and 80 kV with both IRs (p < 0.001) showed higher CNR than the reference, but noise was most pronounced at 80 kV (p < 0.001). The highest FOM was found in the 100 kV protocols (p < 0.001). The reference and 100 kV with standard IR had highest image quality scores, where the 100 kV protocol enabled a distinct dose reduction. Lowering the voltage seems to be a more favorable tool than IR changes in optimizing the dose in contrast enhanced abdominal CT., Trial Registration: ClinicalTrials.gov number, NCT01022567., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: An increasing amount of evidence supports antibiotic therapy for treating uncomplicated acute appendicitis. The objective of this study was to compare the costs of antibiotics alone versus appendicectomy in treating uncomplicated acute appendicitis within the randomized controlled APPAC (APPendicitis ACuta) trial., Methods: The APPAC multicentre, non-inferiority RCT was conducted on patients with CT-confirmed uncomplicated acute appendicitis. Patients were assigned randomly to appendicectomy or antibiotic treatment. All costs were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis during the 1-year follow-up. The cost estimates were based on cost levels for the year 2012., Results: Some 273 patients were assigned to the appendicectomy group and 257 to antibiotic treatment. Most patients randomized to antibiotic treatment did not require appendicectomy during the 1-year follow-up. In the operative group, overall societal costs (€5989·2, 95 per cent c.i. 5787·3 to 6191·1) were 1·6 times higher (€2244·8, 1940·5 to 2549·1) than those in the antibiotic group (€3744·4, 3514·6 to 3974·2). In both groups, productivity losses represented a slightly higher proportion of overall societal costs than all treatment costs together, with diagnostics and medicines having a minor role. Those in the operative group were prescribed significantly more sick leave than those in the antibiotic group (mean(s.d.) 17·0(8·3) (95 per cent c.i. 16·0 to 18·0) versus 9·2(6·9) (8·3 to 10·0) days respectively; P < 0·001). When the age and sex of the patient as well as the hospital were controlled for simultaneously, the operative treatment generated significantly more costs in all models., Conclusion: Patients receiving antibiotic therapy for uncomplicated appendicitis incurred lower costs than those who had surgery., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background and Aims: Uptake of the positron emission tomography (PET) tracer 2-deoxy-2-[ 18 F]-fluoro-d- glucose ([ 18 F]FDG) into macrophages is a sensitive marker of inflammation in atherosclerosis. To assess the anti-inflammatory effects of statins, we studied whether atorvastatin therapy reduces aortic [ 18 F]FDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 (Ldlr -/- Apob 100/100 )., Methods: Thirty-six Ldlr -/- Apob 100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then allocated to receive a HFD (n = 13), chow diet (Chow, n = 12), or HFD with added atorvastatin (HFD + A, n = 11), for another 12 weeks. In addition to aortic histopathology, [ 18 F]FDG uptake was studied in vivo using PET/computed tomography (CT), and ex vivo by gamma counting of excised aorta., Results: Total cholesterol levels were lower in the Chow and HFD + A groups than in the HFD group (10 ± 3.2, 23 ± 4.9 and 34 ± 9.2 mmol/l, respectively), with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. Compared to the HFD group, [ 18 F]FDG uptake in the aorta (normalized for blood) was lower in the Chow group in both in vivo (2.1 ± 0.21 vs. 1.7 ± 0.25, p = 0.018) and ex vivo (5.2 ± 2.3 vs. 2.8 ± 0.87, p = 0.011) analyses, whereas atorvastatin had no effect on uptake (2.1 ± 0.42 in vivo and 3.9 ± 1.8 ex vivo). [ 18 F]FDG uptake correlated with plasma total cholesterol levels., Conclusions: Atorvastatin therapy did not show cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr -/- Apob 100/100 mice, as determined by histology and [ 18 F]FDG PET, whereas a cholesterol-lowering diet intervention was effective., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Twenty-four females (mean age 38 years) with varying amounts of vocal training read aloud from a book for 45 min (70 dB at 40 cm distance). Symptoms of the throat and voice were ascertained with a questionnaire before, during and after the test. Fundamental frequency (F(0)) and sound pressure level (SPL) were measured. The alpha ratio describing the spectrum slope was calculated: SPL in the range 1-5 kHz minus SPL in the range 50 Hz-1 kHz. All measurements were made for the 1st, 5th, 15th, 30th and the 45th min of loading and for text reading before and after it. F(0), SPL and alpha values rose during the test, which may indicate adaptation to loading. During the first 5 min, however, these parameters showed a decreasing tendency, possibly reflecting warm-up. Subjects with more vocal training had a lower F(0) in the loading test. SPL seemed to reflect variation of symptoms during loading. Changes in acoustic parameters did not distinguish between subjects with most and fewest symptoms of fatigue in this test., (Copyright 2004 S. Karger AG, Basel.)

A method for microbial isomerization of oat linoleic acid to conjugated linoleic acid (CLA) was developed. The method includes hydrolysis of oat lipids in aqueous flour slurries by the endogenous oat lipase. Then, the flour slurry containing free linoleic acid is utilized as a substrate for the isomerization reaction carried out by resting cells of Propionibacterium freudenreichii ssp. shermanii. The isomerization reaction progressed most effectively when, after the lipid hydrolysis period, the pH of the slightly acidic oat slurry was elevated to 8.0-8.5 and maintained at this range. With slurries containing 5% (w/v) oat flour, the amounts of CLA formed per dry matter were up to 10.1 mg/g corresponding to 102 mg/g lipids or 0.44 mg/mL slurry. Increments in the flour content up to 15% increased the volumetric production of CLA to 0.85 mg/mL. The proportion of the cis-9,trans-11 isomer was 80% of the total CLA formed. CLA could be concentrated into the solid material of the oat slurry by acidification.