Three-Year Outcomes of Oral Antibiotics vs Intravenous and Oral Antibiotics for Uncomplicated Acute Appendicitis: A Secondary Analysis of the APPAC II Randomized Clinical Trial.

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.

Laparoscopic cholecystectomy versus antibiotic therapy for acute cholecystitis in patients over 75 years: Randomized clinical trial and retrospective cohort study.

BACKGROUND AND OBJECTIVE: The prevalence of acute cholecystitis among elderly patients is increasing. The aim of this study was to compare laparoscopic cholecystectomy (LC) to antibiotics in elderly patients with acute cholecystitis. METHODS: A randomized multicenter clinical trial including patients over 75 years with acute calculous cholecystitis was conducted in four hospitals in Finland between January 2017 and December 2019. Patients were randomized to undergo LC or antibiotic therapy. Due to patient enrollment challenges, the trial was prematurely terminated in December 2019. To assess all eligible patients, we performed a retrospective cohort study including all patients over 75 years with acute cholecystitis during the study period. The primary outcome was morbidity. Predefined secondary outcomes included mortality, readmission rate, and length of hospital stay. RESULTS: Among 42 randomized patients (LC n = 24, antibiotics n = 18, mean age 82 years, 43% women), the complication rate was 17% (n = 4/24) after cholecystectomy and 33% (n = 6/18, 5/6 patients underwent cholecystectomy due to antibiotic treatment failure) after antibiotics (p = 0.209). In the retrospective cohort (n = 630, mean age 83 years, 49% women), 37% (236/630) of the patients were treated with cholecystectomy and 63% (394/630) with antibiotics. Readmissions were less common after surgical treatment compared with antibiotics in both randomized and retrospective cohort patients (8% vs 44%, p < 0.001% and 11 vs 32%, p < 0.001, respectively). There was no 30-day mortality within the randomized trial. In the retrospective patient cohort, overall mortality was 6% (35/630). CONCLUSIONS: LC may be superior to antibiotic therapy for acute cholecystitis in the selected group of elderly patients with acute cholecystitis.

A randomized clinical trial comparing early patient-reported pain after open anterior mesh repair versus totally extraperitoneal repair of inguinal hernia.

BACKGROUND: This was a prospective, multicentre, non-blinded, randomized clinical trial involving two parallel groups of patients. METHODS: Adult patients with symptomatic unilateral primary inguinal hernia were included in this study. Patients were enrolled and treated in five Finnish hospitals. Eligible patients were randomized by use of a computer-based program to receiving either open anterior repair (modified Lichtenstein) with glue mesh fixation or totally extraperitoneal (TEP) repair. The primary aims were to compare 30-day patient-reported pain scores and return to work after surgery between the two groups. RESULTS: A total of 202 patients were randomized: 98 patients to TEP repair and 104 patients to open repair. All randomized patients received their allocated treatment. A total of 86 patients (88 per cent) in the TEP group and 94 patients (90 per cent) in the Lichtenstein group completed the 30-day follow-up. Patients experienced less early pain (P < 0.001) and used less analgesics after TEP repair, compared to those who had modified Lichtenstein repair. Two patients in the TEP group and five in the Lichtenstein group developed superficial wound infection (P = 0⋅446). Only one reoperation was performed in the Lichtenstein group due to haematoma. CONCLUSION: TEP inguinal hernia repair is associated with less early postoperative pain compared to the open glue mesh fixation technique. TRIAL REGISTRATION: NCT03566433 (http://www.clinicaltrials.gov).

In this randomized clinical trial, we compared two different operating techniques for inguinal hernia repair. Patients were randomized to receiving either open or laparoscopic inguinal hernia repair. After the operation, patient-reported pain and functional outcomes were compared. Patients experienced less pain after laparoscopic repair.

Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis: The APPAC II Randomized Clinical Trial.

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.

Serum Plant Sterols Associate with Gallstone Disease Independent of Weight Loss and Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Gallstone disease (GD) has been associated with low serum levels of plant sterols. We evaluated the impact of laparoscopic Roux-en-Y gastric bypass (LRYGB) and non-alcoholic fatty liver disease (NAFLD) on the association of GD with low levels of serum plant sterols. METHODS: Two hundred forty-two consecutive morbidly obese patients were recruited to this prospective study. Histological analysis of liver biopsy to diagnose NAFLD was performed. Bile sample was taken during the LRYGB. Associations of GD with serum non-cholesterol sterol to cholesterol ratios, measured using gas liquid chromatography and with mRNA expression of genes participating in the cholesterol, bile, and fatty acid metabolism in the liver, were analyzed. RESULTS: Out of the 242 participants, 95 had GD. Lower weight (p = 0.002) and female sex (p = 0.0006) were associated with GD. Serum plant sterols, campesterol (p = 0.003), sitosterol (p = 0.002), and avenasterol (p = 0.015), were lower in patients with GD compared to those without GD. This association remained significant after adjustment for NAFLD, use of statin medication, and previous laparoscopic cholecystectomy (LCC). Levels of sitosterol (p = 0.001) and campesterol (p = 0.001) remained lower in obese individuals with GD also after obesity surgery. Liver mRNA expression of genes regulating cholesterol synthesis and bile metabolism was increased in individuals with GD. CONCLUSIONS: Serum plant sterols were lower in patients with GD independent of NAFLD, history of LCC, use of statin medication, and weight loss after LRYGB. Low serum plant sterols in patients with GD suggest potentially inherited alterations in sterol absorption and biliary transport in subjects susceptible for GD.

Regulation of alternative splicing in human obesity loci.

OBJECTIVE: Multiple obesity susceptibility loci have been identified by genome-wide association studies, yet the mechanisms by which these loci influence obesity remain unclear. Alternative splicing could contribute to obesity by regulating the transcriptomic and proteomic diversity of genes in these loci. METHODS: Based on a database search, 72 of the 136 genes at the 13 obesity loci encoded multiple protein isoforms. Thus, alternative splicing of these genes in adipose tissue samples was analyzed from the Metabolic Syndrome in Men population-based study and from two weight loss intervention studies (surgical and very low calorie diet). RESULTS: Alternative splicing was confirmed in 11 genes with PCR capillary electrophoresis in human subcutaneous adipose tissue. Interestingly, differential splicing of TRA2B, BAG6, and MSH5 was observed between lean individuals with normoglycemia and overweight individuals with type 2 diabetes. Of these genes, we detected fat depot-dependent splicing of TRA2B and BAG6 and weight loss-induced regulation of MSH5 splicing in the intervention studies. Finally, body mass index was a major determinant of TRA2B, BAG6, and MSH5 splicing in the combined data. CONCLUSIONS: This study provides evidence for alternative splicing in obesity loci, suggesting that alternative splicing at least in part mediates the obesity-associated risk in these loci.

Clinical and laboratory findings in the diagnosis of right lower quadrant abdominal pain: outcome analysis of the APPAC trial.

BACKGROUND: The current research on acute appendicitis aims to improve the diagnostics and to clarify to whom antibiotic treatment might be the treatment of choice. METHODS: The present study is a retrospective analysis of a prospectively collected data in our randomized multicenter trial comparing surgery and antibiotic treatment for acute uncomplicated appendicitis (APPAC trial, NCTO1022567). We evaluated 1321 patients with a clinical suspicion of acute appendicitis, who underwent computed tomography (CT). Age, gender, body temperature, pain scores, the duration of symptoms, white blood cell count (WBC) and C-reactive protein (CRP) were recorded on admission. RESULTS: CT confirmed the diagnosis of acute appendicitis in 73% (n=970) and in 27% (n=351) it revealed no or other diagnosis. Acute appendicitis patients had significantly higher WBC levels than patients without appendicitis (median 12.2 and 10.0, respectively, p<0.0001), whereas CRP levels did not differ between the two groups. Ideal cut-off points were assessed with receiver operating characteristic (ROC) curves, but neither these markers or neither their combination nor any clinical characteristic could accurately differentiate between patients with acute appendicitis and those without. The proportion of patients with normal WBC count and CRP was significantly (p=0.0007) lower in patients with acute appendicitis than in patients without appendicitis. CONCLUSIONS: Both clinical findings and laboratory tests are unable to reliably distinguish between patients with acute appendicitis and those without. If both WBC count and CRP are normal, acute appendicitis is very unlikely. The current results emphasize the role of CT imaging in patients with suspected acute appendicitis.

Randomized Multicenter Trial Comparing Glue Fixation, Self-gripping Mesh, and Suture Fixation of Mesh in Lichtenstein Hernia Repair (FinnMesh Study).

OBJECTIVE: Three different mesh fixation techniques were compared to find out how to perform a safe and cost-effective open inguinal hernioplasty in day-case setting with the best outcomes with regard to chronic pain. SUMMARY BACKGROUND DATA: Mesh fixation method may influence on the incidence of chronic pain after Lichtenstein hernioplasty. METHODS: Lichtenstein hernioplasty was performed under local anesthesia in 625 patients as day-case surgery in 8 Finnish hospitals. The patients were randomized to receive either a cyanoacrylate glue (Histoacryl, n = 216), self-gripping mesh (Parietex ProGrip, n = 202), or conventional nonabsorbable sutures (Prolene 2-0, n = 207) for mesh fixation. The incidence of wound complications, pain, recurrences, and patients discomfort was recorded on days 1, 7, 30, and 1 year after surgery. The primary endpoint was the sensation of pain measured by pain scores and the need of analgesics after 1 year of surgery. RESULTS: The type and size of inguinal hernias were similar in the 3 study groups. The duration of operation was 34 ±â€Š13, 32 ±â€Š9, and 38 ±â€Š9 minutes in the glue, self-gripping, and suture groups, respectively (P < 0.001). There were no significant differences postoperatively in pain response or need for analgesics between the study groups. Two superficial infections (0.3%), 31 wound seromas (5.0%), and 4 recurrent hernias (0.6%) were recorded during a 1-year follow-up. Some 25 patients (4.2%) needed occasionally analgesics for chronic groin pain. A feeling of a foreign object and quality of life were similar in all study groups. CONCLUSIONS: This randomized trial failed to prove that mesh fixation without sutures causes less inguinodynia than suture fixation in Lichtenstein hernioplasty. Mesh fixation without sutures is feasible without compromising postoperative outcome.

Characteristic changes in microbial community composition and expression of innate immune genes in acute appendicitis.

Appendicitis represents a common and severe gastrointestinal illness in younger individuals worldwide. The disease is characterized by an excessive inflammatory response and it is believed that bacterial overgrowth due to blockage of the appendix lumen might be involved. Despite the high incidence, only limited data on the pathophysiological changes exist; in particular, the innate immune responses involved are largely unknown. Real-time PCR analysis of tissue samples from inflamed and normal appendices demonstrated differentially regulated expression patterns of epithelial-derived antimicrobial peptides (AMP). The α-defensins human neutrophil peptides 1-3, HD5 and HD6, as well as the two ß-defensins, human ß-defensins (hBD)-2 and hBD-3, were up-regulated, whereas hBD-1 was down-regulated in acute appendicitis. Expression of upstream regulators of AMP expression, NOD-2 and TLRs 1, 2, 4, 5, 7, 8 and 10 was significantly increased as detected by real-time PCR. Finally, we confirmed the involvement of the pro-inflammatory cytokines IL-1ß and IL-8, and detected characteristic changes in microbial community composition in appendicitis tissue specimens by 16S rDNA based detection techniques. In this study, we demonstrate a differential regulation of the innate immune system along with an altered bacterial diversity in acute appendicitis.

The need for surgery in acute abdominal pain: a randomized study of abdominal computed tomography.

AIM: To assess the need for surgical treatment in patients with acute abdominal pain in a prospective randomized study. PATIENTS AND METHODS: Initially 203 patients with acute abdominal pain were randomized to the routine abdominal computed tomography CT (rCT, n=118), or selective abdominal CT group (sCT, n=85) over a period of 16 months. Ninety-three of the randomized patients (45.8%) underwent the study design and were reached for follow-up at three months. RESULTS: Diagnostic accuracy improved significantly in the rCT group (p<0.001). The surgeon's assessment of the need for surgery changed more often in the rCT group than in the sCT group (78.7% vs. 46.9%, p=0.002). The confidence to treat operatively increased significantly in the rCT vs. the sCT group (65.6% vs. 40.6%, p=0.028). The rCT was the only independent parameter for the change of the assessment of surgery. CONCLUSION: Routine CT allows for more confidence in decision making for the surgical treatment of patients with acute abdominal pain.

Seasonal variations of acute appendicitis and nonspecific abdominal pain in Finland.

AIM: To investigate whether seasonal changes had an effect on the incidence of acute appendicitis (AA) or nonspecific abdominal pain (NSAP). METHODS: We carried out a national register study of all patients with a hospital discharge diagnosis of AA and acute NSAP in Finland. Data were analyzed for the whole country and correlated to seasonal and weather parameters (temperature, humidity). Moreover, additional sub-analyses were performed for five geographically different area of Finland. RESULTS: The observation period spanned 21 years, with 186558 appendectomies, of which 137528 (74%) cases were reported as AA. The incidence of AA declined for 32% over the study period. The average incidence of the NSAP was 34/10000 per year. The mean annual temperature, but not relative humidity, showed clear geographical variations. The incidence of AA decreased significantly during the cold months of the year. No correlation was detected between temperature and incidence of NSAP. Humidity had a statistically significant impact on NSAP. CONCLUSION: The incidence of acute appendicitis is declining in Finland. We detected a clear seasonality in the incidence of AA and NSAP.

Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss.

AIMS/HYPOTHESIS: The insulin receptor (INSR) has two protein isoforms based on alternative splicing of exon 11. INSR-A promotes cell growth whereas INSR-B predominantly regulates glucose homeostasis. In this study we investigated whether weight loss regulates INSR alternative splicing and the expression of splicing factors in adipose tissue. METHODS: To determine the relative ratio of the INSR splice variants, we implemented the PCR-capillary electrophoresis method with adipose tissue samples from two weight-loss-intervention studies, the Kuopio Obesity Surgery study (KOBS, n = 108) and a very low calorie diet (VLCD) intervention (n = 32), and from the population-based Metabolic Syndrome in Men study (METSIM, n = 49). RESULTS: Expression of INSR-B mRNA variant increased in response to weight loss induced by both bariatric surgery (p = 1 × 10(-5)) and the VLCD (p = 1 × 10(-4)). The adipose tissue expression of INSR-B correlated negatively with fasting insulin levels in the pooled data of the three studies (p = 3 × 10(-22)). Finally, expression of several splicing factors correlated negatively with the expression of the INSR-B variant. The strongest correlation was with HNRNPA1 (p = 1 × 10(-5)), a known regulator of INSR exon 11 splicing. CONCLUSIONS/INTERPRETATION: INSR splicing is regulated by weight loss and associates with insulin levels. The effect of weight loss on INSR splicing could be mediated by changes in the expression of splicing factors.

Outpatient antibiotic use and the incidence of acute appendicitis in Finland: a nationwide study from 1990-2008.

BACKGROUND: The incidence of acute appendicitis (AA) has decreased in Finland. We hypothesized that changing trends in outpatient antibiotic use might explain at least part of this declining incidence of AA. METHODS: The number of all patients with AA in Finland was extracted from the national data base from 1990 to 2008. For comparison, the incidence of acute diverticulitis of the colon (AD) was also recorded. All outpatient prescriptions of antibiotics belonging to the major groups of these drugs were also recorded. We used unit root and co-integration analyses for statistical analysis of the data in the study. RESULTS: The incidence of AA in Finland declined from 14.5 to 9.8 per 10,000 inhabitants (32%) and the incidence of AD increased by 47% between 1993 and 2007. The total outpatient use of antibiotics did not increase during this same period, but the use of antibiotics effective widely against colonic pathogens (macrolides, fluoroquinolones, and cephalosporins) increased significantly. No correlation was found between the incidence of AA, that of AD, and the use of different groups of antibiotics. CONCLUSIONS: Our nationwide registry study indicated that changes in outpatient antibiotic use do not explain the decreasing trend in AA in Finland. Other factors, such as improved diagnosis of AA, may have some role in the decreasing incidence of AA.

[Gastric bypass as weight loss operation: 10-year experience of one center and challenges of follow-up]. / Mahalaukun ohitus lihavuusleikkauksena: yhden keskuksen kymmenen vuoden kokemukset ja seurannan haasteet.

INTRODUCTION: Data about the implementation of long-term follow-up of weight loss operation patients and their nutritional status has been lacking in Finland. PATIENTS AND METHODS: We examined the postoperative complications and long-term outcome in respect of weight control, symptoms, nutritional status and medication of 173 patients having undergone gastric bypass. The data were collected from patient records and by questionnaires. RESULTS: Postoperative complications and weight loss were at the international level. The number of those using antidiabetic and antihypertensive drugs decreased. CONCLUSIONS: The results are in agreement with the international level, but follow-up treatment requires attention in Finland.

Changing incidence of acute appendicitis and nonspecific abdominal pain between 1987 and 2007 in Finland.

BACKGROUND: The incidence of acute appendicitis has declined in many countries. The aim of this study was to determine the trends in incidence of acute appendicitis (AA), appendectomies for AA, and nonspecific abdominal pain (NSAP) in Finland between 1987 and 2007. METHODS: We carried out a national register study. Demographic features were investigated. Diagnoses and procedures were classified according to the World Health Organization International Classification of Diseases. Data were analyzed for each of all five University Hospital districts (UHD) of Finland. RESULTS: During the observation period of 21 years, 186,558 appendectomies were performed in Finland, of which 137,528 (74%) cases were reported as AA. The incidence of acute appendicitis declined 32%. The diagnostic accuracy improved from 73 to 82% and was higher in men. The accuracy rate among the male patients was stable throughout the two decades; among the female patients it rose from 63 to 75%. The incidence of appendicitis was highest in patients aged 15-24 years. The average incidence of NSAP was 34/10,000/year, and it was higher in older age groups. There was a large geographical disparity in the incidence of NSAP. CONCLUSION: The incidence of acute appendicitis as well as the incidence of appendectomies is declining in Finland. The incidence of the NSAP has also been declining but we did not find any correlations between the incidences of the acute appendicitis and NSAP. There were clear geographical differences in the incidence of NSAP but not in the incidence of AA.