Acute appendicitis is one of the most common causes of emergency abdominal surgery worldwide and represents a substantial burden on healthcare systems. Although it can occur at any age, it is most frequently diagnosed among adolescents and young adults. For more than a century, appendectomy has been considered the standard treatment because it removes the diseased appendix, provides definitive treatment, and virtually eliminates the risk of recurrence [1,2]. The introduction of laparoscopic appendectomy has further improved surgical outcomes by reducing postoperative pain, hospital stay, wound complications, and recovery time compared with open surgery [3].

Despite these advantages, appendectomy remains an invasive procedure associated with potential complications, including surgical-site infection, intra-abdominal abscess, postoperative adhesions, anesthetic complications, and injury to surrounding structures. Advances in diagnostic imaging and understanding of the disease process have also shown that acute appendicitis is not a uniform condition. It may present as uncomplicated inflammation or as complicated disease characterized by gangrene, perforation, abscess, phlegmon, or generalized peritonitis [1,2]. This distinction has increased interest in non-operative management for carefully selected patients with imaging-confirmed uncomplicated appendicitis.

Antibiotic-first therapy has emerged as a potential alternative to immediate appendectomy in clinically stable patients without evidence of perforation, abscess, generalized peritonitis, or other high-risk features. The rationale for this approach is that inflammation and infection may resolve with appropriate antimicrobial treatment, allowing patients to avoid surgery and its associated risks. Previous studies have reported satisfactory short-term treatment success, fewer immediate complications, shorter recovery periods, and earlier return to normal activities among selected patients managed with antibiotics [4,5]. However, concerns remain regarding failure of initial treatment, recurrent appendicitis, readmission, delayed appendectomy, and the possibility of progression to complicated disease.

The APPAC randomized clinical trial provided important evidence supporting antibiotic-first management in adults with computed tomography-confirmed uncomplicated appendicitis. It demonstrated that a substantial proportion of patients could be treated successfully without immediate surgery, although some subsequently required appendectomy because of treatment failure or recurrence [4,6]. Similarly, the CODA trial found that antibiotic treatment was non-inferior to appendectomy in terms of short-term general health outcomes. Nevertheless, a considerable proportion of patients initially treated with antibiotics underwent appendectomy during follow-up, particularly those with an appendicolith [7]. These findings indicate that antibiotic-first management may be appropriate for selected patients but does not provide the same certainty of definitive treatment as appendectomy.

Systematic reviews and meta-analyses have generally shown that antibiotic-first therapy may reduce immediate postoperative morbidity and facilitate faster recovery. In contrast, appendectomy offers definitive treatment with minimal risk of recurrent appendicitis [8–10]. Successful non-operative management therefore depends on accurate diagnosis, careful patient selection, reliable follow-up, and timely access to surgical intervention. Factors such as an appendicolith, severe clinical symptoms, markedly elevated inflammatory markers, or imaging findings suggestive of complicated disease may increase the likelihood of treatment failure [11]. Consequently, treatment selection should incorporate both clinical evidence and patient preferences through a shared decision-making process [12].

Although several randomized controlled trials and meta-analyses have compared antibiotic therapy with appendectomy, evidence from South Asian tertiary care hospitals remains limited. Differences in healthcare infrastructure, patient presentation, imaging availability, antimicrobial-resistance patterns, follow-up systems, and access to surgical services may influence clinical outcomes. Locally generated evidence is therefore needed to determine whether the results of major international trials are reproducible in regional clinical practice.

The present study aimed to compare antibiotic-first therapy with immediate appendectomy in adult patients with acute uncomplicated appendicitis at a tertiary care hospital in Pakistan. The primary outcomes were initial treatment success, treatment failure, recurrence, and overall complications. Secondary outcomes included length of hospital stay, time to return to normal activities, duration of analgesic use, and readmission.

This prospective comparative observational study was conducted in the Department of General Surgery, Ayub Teaching Hospital, Abbottabad, Khyber Pakhtunkhwa, Pakistan, from January 2024 to December 2024. The study was designed to compare the clinical outcomes of antibiotic-first therapy with immediate appendectomy in adult patients diagnosed with acute uncomplicated appendicitis. The sample size was calculated using the OpenEpi sample-size calculator by considering an expected treatment-success rate of 85% in the antibiotic-first group and 100% in the immediate appendectomy group, with a 95% confidence level, 80% statistical power, and a 1:1 group ratio. The calculated sample size was 112 participants, which was increased to 120 to account for possible incomplete follow-up. A non-probability consecutive sampling technique was used, and all eligible patients presenting to the surgical emergency department during the study period were enrolled after providing written informed consent. The study included patients aged 18 years or older with clinical and imaging-confirmed acute uncomplicated appendicitis. Uncomplicated appendicitis was defined as inflammation of the appendix without radiological evidence of perforation, gangrene, periappendiceal abscess, phlegmon, generalized peritonitis, or free intraperitoneal air. Patients with complicated appendicitis, appendicolith, pregnancy, hemodynamic instability, generalized peritonitis, previous appendectomy, immunosuppression, severe comorbid conditions affecting treatment selection, allergy or contraindication to the prescribed antibiotics, inability to complete follow-up, or refusal to provide consent were excluded. All patients underwent a detailed clinical assessment at presentation. Demographic and clinical information, including age, sex, duration of abdominal pain, nausea, vomiting, anorexia, fever, previous similar episodes, and relevant comorbidities, was recorded. Physical examination included assessment of vital signs, right lower-quadrant tenderness, rebound tenderness, guarding, rigidity, and signs of localized or generalized peritonitis. Laboratory investigations included complete blood count, white blood cell count, C-reactive protein level, renal function tests, liver function tests, and other investigations considered clinically necessary. The diagnosis of acute uncomplicated appendicitis was initially assessed through abdominal ultrasonography and was confirmed through contrast-enhanced computed tomography in patients with inconclusive ultrasound findings. Imaging studies were interpreted by a consultant radiologist or by a radiology resident under consultant supervision. Radiological criteria for uncomplicated appendicitis included a non-compressible appendix measuring more than 6 mm in diameter, appendiceal wall thickening, periappendiceal fat stranding, and localized inflammatory changes without evidence of perforation, abscess, phlegmon, gangrene, or free intraperitoneal air. Eligible patients were placed in either the antibiotic-first group or the immediate appendectomy group through shared decision-making involving the patient and the treating consultant surgeon. As this was an observational study, no random allocation was performed. Before treatment selection, patients were informed about the benefits and limitations of both treatment approaches. Patients selecting antibiotic-first therapy were counselled regarding the possibility of treatment failure, recurrent appendicitis, readmission, disease progression, and the potential need for delayed appendectomy. Patients in the antibiotic-first group received intravenous ceftriaxone 2 g once daily combined with metronidazole 500 mg every eight hours for 48 hours. After clinical improvement and tolerance of oral intake, treatment was changed to oral ciprofloxacin 500 mg twice daily and metronidazole 400 mg three times daily to complete a total antibiotic course of seven days. The antibiotic regimen was modified where necessary according to allergy status, renal function, clinical response, microbiological findings, and the institutional antimicrobial policy. Supportive management included intravenous fluids, analgesics, antiemetics, and gradual resumption of oral intake. Patients were reassessed at 6, 12, 24, and 48 hours after the initiation of antibiotic therapy. Clinical monitoring included abdominal pain, localized tenderness, guarding, body temperature, heart rate, oral intake, white blood cell count, C-reactive protein level, and signs of localized or generalized peritonitis. Patients in the immediate appendectomy group underwent surgical removal of the appendix during the index admission. Laparoscopic appendectomy was preferred whenever technically feasible and where the necessary facilities were available. Open appendectomy was performed when laparoscopic surgery was contraindicated, unavailable, or considered unsuitable by the operating surgeon. All surgical patients received perioperative antibiotic prophylaxis according to the hospital protocol. The surgical approach, operative findings, duration of surgery, intraoperative complications, conversion from laparoscopic to open surgery, and postoperative complications were documented. Resected appendices were sent for histopathological examination. Postoperative care included intravenous fluids, analgesia, antibiotic therapy where indicated, wound care, early mobilization, and gradual resumption of oral intake. Patients were discharged when they were clinically stable, afebrile, ambulatory, tolerating oral intake, and without evidence of an immediate postoperative complication. Initial treatment success in the antibiotic-first group was defined as clinical improvement without the need for appendectomy during the index hospital admission. Clinical improvement was determined by reduction in abdominal pain and tenderness, absence of fever and peritonitis, tolerance of oral intake, and improvement or stabilization of inflammatory markers. Initial treatment success in the appendectomy group was defined as successful surgical removal of the appendix without the need for additional emergency intervention during the index admission. Treatment failure in the antibiotic-first group was defined as the requirement for appendectomy during the initial admission because of persistent or worsening abdominal pain, increasing right lower-quadrant tenderness, development of guarding, rigidity, or generalized peritonitis, persistent fever, rising white blood cell count or C-reactive protein level, hemodynamic instability, inability to tolerate oral intake, radiological evidence of disease progression, or failure to demonstrate satisfactory clinical improvement within 48 hours of starting antibiotic therapy. The final decision to perform appendectomy in patients experiencing treatment failure was made by the treating consultant surgical team. Recurrence was defined as a new episode of clinically and radiologically confirmed acute appendicitis occurring after initial successful treatment and hospital discharge in a patient managed with antibiotic-first therapy. Complications in the antibiotic-first group included antibiotic-related adverse reactions, progression to complicated appendicitis, abscess formation, and other treatment-related adverse events. Initial treatment failure and recurrence were evaluated separately and were not included in the overall complication rate. Complications in the appendectomy group included surgical-site infection, intra-abdominal abscess, postoperative bleeding, ileus, anesthetic complications, readmission, reoperation, and other procedure-related adverse events. Length of hospital stay was calculated from the time of admission to discharge and was recorded in days. Time to return to normal activity was defined as the number of days from initiation of treatment to the resumption of routine personal, educational, occupational, or household activities without substantial restriction. Data were collected using a structured data-collection form. Baseline information included demographic characteristics, symptom duration, examination findings, laboratory results, inflammatory markers, imaging findings, appendix diameter, and relevant comorbidities. Treatment-related variables included the antibiotic regimen, duration of intravenous and oral antibiotic therapy, surgical approach, operative findings, complications, length of hospital stay, duration of analgesic use, readmission, and delayed appendectomy. Patients were followed through outpatient visits or telephone interviews at one week, one month, three months, six months, and twelve months after discharge. Follow-up assessments evaluated symptom resolution, delayed complications, recurrence, readmission, subsequent appendectomy, return to normal activities, and patient satisfaction. Patients developing recurrent abdominal symptoms underwent repeat clinical, laboratory, and radiological assessment where indicated. The primary study outcomes were initial treatment success, treatment failure during the index admission, recurrence of appendicitis during follow-up, and overall treatment-related complications. Secondary outcomes included length of hospital stay, time to return to normal activities, duration of analgesic use, readmission, delayed appendectomy, and patient satisfaction. Data were entered and analyzed using IBM SPSS Statistics version 26.0. Continuous variables were assessed for normality using the Shapiro–Wilk test. Normally distributed continuous variables were presented as mean and standard deviation, whereas non-normally distributed variables were presented as median and interquartile range. The independent-samples t-test was used to compare normally distributed continuous variables between the two groups, while the Mann–Whitney U test was used for non-normally distributed continuous variables. Categorical variables were presented as frequencies and percentages and were compared using the chi-square test or Fisher’s exact test, as appropriate. Differences in treatment success, treatment failure, recurrence, complications, and readmission were reported with 95% confidence intervals. Mean differences with 95% confidence intervals were calculated for continuous outcomes, including hospital stay, duration of analgesic use, and time to return to normal activity. All statistical tests were two-sided, and a p-value of less than 0.05 was considered statistically significant. Missing observations were managed through complete-case analysis. Ethical approval was obtained from the Institutional Review Board of Ayub Medical College and Ayub Teaching Hospital. Written informed consent was obtained from every participant before enrollment. Patients were informed about the potential benefits and risks of both treatment options, including treatment failure, recurrence, delayed appendectomy, anesthetic risks, and postoperative complications. Confidentiality was maintained by assigning study codes to participants, removing personal identifiers from the database, and restricting access to the collected information to members of the research team.

A total of 120 patients with acute uncomplicated appendicitis were included in the study and divided into two treatment groups: antibiotic-first therapy group (n=60) and immediate appendectomy group (n=60). The baseline demographic and clinical characteristics of both groups were comparable, with no statistically significant differences observed in age, gender distribution, duration of symptoms, or baseline inflammatory markers (p > 0.05). The mean age of participants was 29.4 ± 8.6 years in the antibiotic group and 30.1 ± 9.2 years in the appendectomy group. Male predominance was observed in both groups.

Table 1: Baseline Demographic and Clinical Characteristics of Study Participants

Clinical outcomes showed that antibiotic-first therapy achieved initial treatment success in 51 patients (85%), whereas 9 patients (15%) required appendectomy due to persistent symptoms or clinical deterioration. In the immediate appendectomy group, all patients underwent successful surgical removal of the appendix. Although the definitive treatment rate was higher in the surgical group, antibiotic-first therapy avoided surgery in the majority of selected patients.

Table 2: Primary Treatment Outcomes

Patients managed with antibiotic-first therapy experienced a shorter initial hospital stay compared with patients undergoing surgery. The mean hospital stay was 1.8 ± 0.7 days in the antibiotic group compared with 3.2 ± 1.1 days in the appendectomy group (p < 0.001). Similarly, patients receiving antibiotics returned to normal daily activities earlier than surgical patients.

Table 3: Recovery and Healthcare Utilization Outcomes

Post-treatment complications were evaluated in both groups. The antibiotic-first group demonstrated fewer immediate complications, mainly related to treatment failure and recurrence. In the appendectomy group, complications included postoperative wound infection and intra-abdominal collections. However, the difference in overall complication rates was not statistically significant.

Table 4: Complications Observed in Both Treatment Groups

Figure 2: Comparison of Hospital Stay and Recovery Time

A comparative column chart demonstrating shorter hospital stay and faster return to normal activities among patients treated with antibiotic-first therapy.

Figure 3: Treatment Outcome Flow Diagram

Overall, the findings demonstrated that antibiotic-first therapy was effective in the majority of carefully selected patients with acute uncomplicated appendicitis and was associated with shorter hospitalization and faster recovery. However, immediate appendectomy provided definitive treatment with no recurrence risk. The choice of management strategy should therefore consider clinical presentation, patient preference, risk of recurrence, and availability of surgical facilities.

In this prospective comparative observational study, the efficacy and safety of antibiotic-first therapy and immediate appendectomy were assessed in people with acute uncomplicated appendicitis. Results showed that antibiotic-initiated treatment was successful in most of the included patients both with regard to quick recovery and shorter hospitalisation. Immediate appendectomy, however, continued to be the definitive treatment option with complete resolution of the disease and no risk of recurrence. The results are adding to the evidence that acute uncomplicated appendicitis is no longer necessarily a case for emergency surgery in all patients, but one to be individually managed. The traditional treatment of acute appendicitis is appendectomy, which was previously considered to be the “gold standard” because it also means that the inflamed appendix is removed and there is no risk of recurrence. But the paradigm of surgery has been challenged by the development of imaging diagnostic modalities and understanding of the disease process. In the present study, 85% of the patients treated with antibiotics had successful conservative treatment, which is in line with previous studies that have demonstrated favorable outcome in carefully selected patients with uncomplicated appendicitis treated with conservative management [17]. The efficacy of antibiotic-first treatment found in this study is consistent with those reported in previous RCTs and observational studies. Treatment with antibiotics has been found to be effective in achieving satisfactory short-term results, especially in those who do not have appendicolith, perforation, or systemic infection. One of the greatest benefits of non-operative treatment is that it avoids the risks of surgery, such as post-operative discomfort, risks associated with anaesthetic and wound infection. This has been described in many comparative studies showing reduced initial complications and quicker healing in patients treated with antibiotics [18]. While there are benefits to antibiotic-first treatment, the present study also found some key drawbacks. The failure rate was about 15%, requiring delayed appendectomy, and a certain number of patients that had been treated conservatively had recurrence during the follow-up. These findings reinforce the fact that the risk of subsequent surgery does not go away with antibiotic treatment. The recurrence rate of previous long term studies has been between approximately 20-30% after antibiotic treatment, so appropriate patient counselling in choosing non-operative management is important [19]. The current study obtained 100% of definitive treatment, which is consistent with appendectomy being the most effective treatment modality for acute uncomplicated appendicitis. Surgery did not result in a shorter hospital stay or a shorter recovery period, but it did prevent recurrence and offered one definitive treatment. The same has been demonstrated in multicenter studies where appendectomy was found to be highly effective and might be the preferred procedure in patients seeking definitive surgery rather than no surgery [20]. One of the significant discoveries of this study was that patients who were treated with antibiotic first therapy had a shorter hospital stay and quicker return to their daily lives. The use of avoidance of anesthesia and surgical recovery may have played a role in the better short-term recovery outcomes. Prior systematic reviews have shown that non-operative treatment can result in less health care utilization, less post-operative morbidity, and earlier return to normal activities than appendectomy [21]. But the advantages must be weighed against the likelihood of reoccurrence of symptoms and the requirement to attend further health services. Patient selection is an important determinant of therapy success, with antibiotic-first therapy. At this time, there are indications that non-operative treatment is the best alternative for those who have imaging evidence of uncomplicated appendicitis, stable clinical status and lack of high-risk factors such as appendicolith, gangrenous changes or a significant inflammatory response. Rarely used antibiotic therapy can make disease more complicated and make it harder to get the correct surgical treatment [22]. Thus, proper diagnosis with clinical examination, together with appropriate imaging techniques, is crucial. The findings of this study also emphasize that surgeon–patient communication and collaboration in decision-making is important. The treatment of acute appendicitis has now evolved from a uniform treatment strategy to a patient-centred approach that depends on clinical status, personal preference, lifestyle and the patient's tolerance of the risk of recurrence. Antibiotics may be preferred over surgery in some patients for a more temporary and less definitive solution, while others may opt for appendectomy to get a more permanent and definitive answer. This personalized approach is consistent with the principles of modern surgery, which underpin the evidence-based and preference-sensitive care paradigm [23]. At least from a healthcare system perspective, the use of antibiotic-first treatment can be an economic benefit due to fewer operative needs, less use of hospital resources, and decreased surgical workload. However, the long-term cost effectiveness could still be affected by the recurrence rates, follow-up needs, antibiotic costs, and delayed appendectomy rates. The economic analyses conducted recently indicate that in some patient groups, antibiotic treatment is cost-effective, while depending on the healthcare system and patient, there is no such thing as uniformity in the results [24]. There are several clinical implications to the present study. It provides guidance for the safe use of antibiotic-first therapy for selected patients with uncomplicated appendicitis, and acknowledges that appendectomy is a critical treatment option in patients who fail conservative treatment or who wish to have definitive treatment. Further trials are needed to enhance patient selection, find predictive biomarkers of treatment response, and to follow patients beyond 5 years. There are a few limitations of this study. Results may be biased due to the small number of participants, limited number of centers, and short follow-up period. Further, variations in antibiotic regimes and surgeon preference may impact results. Further large-scale, multicenter randomized trials are needed to more clearly define the best uses of antibiotic therapy first in a variety of healthcare settings. Finally, the current study highlights that this regimen of antibiotic-first treatment is a suitable regimen for the selected patients with AUA, and its use has benefits in terms of recovery and with the avoidance of surgery. However, an immediate appendectomy has the fewest risks of recurrence. Antibiotic-first management should be used in addition to surgery and should be viewed as an evidence-based treatment option in a modern treatment framework individualised approach.

Antibiotic-first therapy appears to be a safe and effective management option for carefully selected adult patients with acute uncomplicated appendicitis. In this study, most patients treated with antibiotics achieved successful initial recovery without immediate surgery and experienced shorter hospital stays, earlier return to normal activities, and reduced analgesic requirements. However, antibiotic treatment was associated with a risk of initial treatment failure and recurrent appendicitis, and some patients subsequently required appendectomy.

Immediate appendectomy remained the most definitive treatment strategy, providing complete removal of the diseased appendix and eliminating the risk of recurrent appendicitis. Nevertheless, surgical treatment was associated with a longer initial recovery period and the possibility of postoperative complications.

These findings support an individualized and patient-centered approach to the management of acute uncomplicated appendicitis. Treatment decisions should be based on clinical stability, imaging findings, the absence of high-risk features, patient preference, availability of reliable follow-up, and timely access to surgical intervention. Antibiotic-first therapy should not be considered a complete replacement for appendectomy but rather an evidence-based alternative for appropriately selected patients.

Further large-scale, multicenter prospective studies with standardized diagnostic criteria, uniform antibiotic protocols, and longer follow-up periods are required to determine long-term recurrence rates, identify predictors of treatment success, and evaluate quality of life and cost-effectiveness.

Recommendations

Antibiotic-first therapy may be considered for carefully selected, clinically stable adult patients with imaging-confirmed acute uncomplicated appendicitis who have no evidence of perforation, abscess, phlegmon, generalized peritonitis, hemodynamic instability, or other features associated with complicated disease. Before adopting non-operative management, healthcare institutions should develop standardized protocols defining patient-selection criteria, diagnostic requirements, antibiotic regimens, monitoring schedules, treatment-failure criteria, discharge conditions, and indications for immediate or delayed appendectomy.

A standardized imaging pathway should be established to accurately distinguish uncomplicated from complicated appendicitis. Ultrasonography may be used as an initial investigation where appropriate, while computed tomography should be considered in patients with inconclusive clinical or ultrasound findings. Imaging should specifically assess for perforation, abscess, phlegmon, free intraperitoneal air, gangrenous changes, and the presence of an appendicolith, as these findings may affect the likelihood of successful non-operative management.

Institutions offering antibiotic-first treatment should adopt an evidence-based antibiotic protocol specifying the appropriate antimicrobial agent, dosage, route of administration, treatment duration, and criteria for switching from intravenous to oral therapy. Antibiotic selection should be guided by local antimicrobial-susceptibility patterns, patient allergy status, renal function, institutional policies, and antimicrobial-stewardship principles. Patients should undergo regular clinical assessment during the initial treatment period, including monitoring of abdominal pain, tenderness, temperature, vital signs, oral intake, white blood cell count, C-reactive protein level, and signs of disease progression.

Clear and objective criteria for treatment failure should be included in institutional protocols. Patients with persistent or worsening abdominal pain, increasing tenderness, fever, rising inflammatory markers, inability to tolerate oral intake, hemodynamic deterioration, generalized peritonitis, or imaging evidence of disease progression should be promptly evaluated for appendectomy. Surgical facilities and experienced surgical teams should remain readily available to manage patients who fail conservative treatment or develop recurrent appendicitis.

Shared decision-making should be an essential part of treatment selection. Patients should receive balanced information regarding the potential benefits of avoiding immediate surgery, shorter initial recovery, and reduced exposure to operative risks. They should also be informed that antibiotic treatment does not eliminate the risk of treatment failure, readmission, recurrence, or the possible need for appendectomy at a later stage. Patient preference, lifestyle, ability to comply with follow-up, distance from healthcare facilities, and access to emergency surgical services should be considered when selecting the treatment approach.

Patients successfully managed with antibiotics should be enrolled in a structured follow-up program to identify recurrence or delayed complications at an early stage. Follow-up may include scheduled outpatient visits, telephone assessments, and clear written instructions to seek urgent medical care if recurrent right lower-quadrant pain, fever, vomiting, worsening tenderness, or other concerning symptoms develop. A reliable system should also be established for rapid reassessment and surgical referral when recurrence is suspected.

Immediate appendectomy should remain the preferred treatment for patients with complicated appendicitis, clinical instability, generalized peritonitis, failure of antibiotic therapy, unreliable follow-up, or a strong preference for definitive treatment. It should also be considered in patients with clinical or imaging features associated with a high risk of non-operative treatment failure.

Further multicenter prospective studies with larger sample sizes, standardized imaging criteria, uniform antibiotic regimens, and longer follow-up periods are recommended. Future research should evaluate long-term recurrence, predictors of treatment failure, quality of life, patient satisfaction, cost-effectiveness, antimicrobial resistance, healthcare utilization, and the outcomes of delayed appendectomy. Regional studies are particularly important to determine whether antibiotic-first management can be safely and effectively implemented in different healthcare settings.

Authors’ Contributions

Dr. Bahri Room, Dr. Abid Ali Khan, and Dr. Misbah Ullah contributed equally to this work. They were jointly involved in the conceptualization and design of the study, patient recruitment, clinical assessment, data collection, interpretation of the findings, and drafting and critical revision of the manuscript. Dr. Muhammad Ali contributed to patient monitoring, follow-up assessments, data documentation, and editing and reviewing the manuscript. Dr. Javed Ahmad provided clinical supervision, methodological guidance, validation of the clinical and surgical data, interpretation of the results, and substantive intellectual review of the manuscript. All authors read and approved the final manuscript and agreed to be accountable for all aspects of the work.

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