Effect of incisional negative pressure therapy and conventional treatment on wound complications after orthopaedic trauma surgery: A meta-analysis of randomized controlled studies.

The results of this meta-analysis were applied to analyse the effects of Negative Pressure Wound Therapy (NPWT) and conventional dressings on post-surgical outcomes after trauma in orthopaedics. Through June 2023, a full review of the literature has been carried out with the help of 4 databases, PubMed, Embase, Cochrane Library, and the Web of Science. The quality of the literature was evaluated according to the classification and exclusion criteria established for this trial, which led to an analysis of 9 related trials. The results included the injury was deeply and superficially infected, and the wound was dehiscence. The 95% confidence interval (CI) and odds ratios (OR) were computed by means of a fixed-effect and a random-effect model. Meta-analyses were conducted with RevMan 5.3. There is no statistical significance between NPWT and routine therapy for deep wound infection (OR, 1.37; 95% CI, 0.82-2.27, p = 0.23); There was no difference in the incidence of inflammation in the wound than with conventional dressings (OR, 1.10; 95% CI, 0.84-1.45, p = 0.49); But NPWT was obviously superior to that of routine therapy in superficial wound infection (OR, 2.07; 95% CI, 1.32-3.25, p = 0.002) and wound dehiscence (OR, 2.44; 95% CI, 1.31-4.57, p = 0.005); But not with respect to wound exudate. therapy group, but no statistically significant difference was found with respect to wound exudation. (OR, 1.16; 95% CI, 0.86-1.57, p = 0.34). Given that some of the chosen trials are too small for this meta-analysis, caution should be exercised when treating their values. More high-quality research with a large sample is required in order to confirm the findings.

The outcome of sutured wounds compared with tissue adhesive for paediatric wound closure: A meta-analysis.

A meta-analysis investigation was executed to measure the outcome of sutured wounds (SWs) compared with tissue adhesive (TA) for paediatric wound closure (PWC). A comprehensive literature inspection till February 2023 was applied and 2018 interrelated investigations were reviewed. The 18 chosen investigations enclosed 1697 children with PWC in the chosen investigations' starting point, 977 of them were utilising SWs, and 906 were utilising TA. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the effect of SWs compared with TA for PWC by the dichotomous approaches and a fixed or random model. SWs had significantly higher wound cosmetic (WC) scores (mean deviation [MD], 1.70; 95% CI, 0.57-2.84, P = .003), lower wound dehiscence (WD) (OR 0.60; 95% CI, 0.06-0.43, P < .001), and lower cost (MD, -10.22; 95% CI, -10.94 to -9.50, P < .001) compared with those with TA in PWC. No significant difference was found between children utilising SWs and TA in wound infection (WI) (OR, 0.45; 95% CI, 0.15-1.30, P = .14) with no heterogeneity (I2 = 0%) in PWC. SWs had significantly higher WC scores, lower WD, and lower cost, yet, no significant difference was found in WI compared with those with TA in PWC. However, care must be exercised when dealing with its values because of the low sample size of some of the nominated investigations and the low number of selected investigations for the meta-analysis.

A systemic review and a meta-analysis on the influences of closed incisions in orthopaedic trauma surgery by negative pressure wound treatment compared with conventional dressings.

We performed a meta-analysis to evaluate the influences of closed incisions in orthopaedic trauma surgery (OTS) by negative pressure wound treatment (NPWT) compared with conventional dressings. A systematic literature search up to March 2022 was done and 14 studies included 3935 subjects with OTS at the start of the study; 2023 of them used NPWT and 1912 were conventional dressings. They were reporting relationships between the influences of closed incisions in OTS by NPWT compared with conventional dressings. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) to assess the influences of closed incisions in OTS by NPWT compared with conventional dressings using the dichotomous methods with a random or fixed-effect model. NPWT had significantly lower deep surgical site infections (SSIs) (OR, 0.65; 95% CI, 0.48-0.87, P = .004), superficial SSIs (OR, 0.34; 95% CI, 0.19-0.61, P < .001), and wound dehiscence (OR, 0.41; 95% CI, 0.21-0.80, P = .009) compared with conventional dressings in subjects with closed incisions in OTS. NPWT showed a beneficial effect on deep SSIs, superficial SSIs, and wound dehiscence compared with conventional dressings in subjects with closed incisions in OTS. Further studies are required to validate these findings.

The Usefulness of Closed Incision Negative Pressure Wound Therapy After Spinal Fusion: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine if closed incision negative pressure wound therapy (ciNPWT) decreases surgical site infection (SSI) or wound dehiscence after spinal fusion. METHODS: Following PRISMA guidelines, a systematic review and meta-analysis were conducted to identify studies using ciNPWT after spinal fusion. Funnel plots and quality scores of the articles were performed to determine if the articles were at risk of bias. Forest plots were conducted to identify the treatment effect of ciNPWT after spinal fusion. RESULTS: A total of 8 studies comprising 1061 patients who received ciNPWT or a standard postoperative dressing after spinal fusion were included. The rate of SSI (ciNPWT, 4.49% [95% confidence interval (CI), 2.48-8.00] vs. control, 11.32% [95% CI, 7.51-16.70]; P = 0.0103) was significantly lower for patients treated with ciNPWT. A fixed-effects model showed no significant difference between patients who received ciNWPT or a standard postoperative dressing with respect to requiring reoperations for wound debridement (odds ratio, 1.25; 95% CI, 0.64-2.41). In addition, wound dehiscence was not significantly different between the 2 groups, although it was nonsignificantly lower in ciNWPT-treated patients (ciNPWT, 4.59% [95% CI, 2.49-8.31] vs. control: 7.48% [95% CI, 4.38-12.47]; P = 0.23). CONCLUSIONS: ciNPWT may reduce the rates of SSI after spinal fusion. The use of ciNWPT may also significantly reduce the burden associated with postoperative wound complications, but the meta-analysis was insufficiently powered to make this association. Additional studies may identify a subset of patients who benefit from ciNPWT for other wound-related complications.

Negative pressure wound therapy versus conventional wound care in cancer surgical wounds: A meta-analysis of observational studies and randomised controlled trials.

The application of negative pressure wound therapy (NPWT) in cancer surgical wounds is still controversial, despite its promising usage, because of the risks of increased tumorigenesis and metastasis. This study aimed to review the risks and benefits of NPWT in surgical wounds with the underlying malignant disease compared with conventional wound care (CWC). The first outcome was wound complications, divided into surgical site infection (SSI), seroma, hematoma, and wound dehiscence. The secondary outcome was hospital readmission. We performed a separate meta-analysis of observational studies and randomised controlled trials (RCTs) with CI 95%. Thirteen observational studies with 1923 patients and seven RCTs with 1091 patients were included. NPWT group showed significant decrease in the risk of SSI (RR = 0.45) and seroma (RR = 0.61) in observational studies with P value <0.05, as well as RCTs but were not significant (RR = 0.88 and RR = 0.68). Wound dehiscence (RR = 0.74 and RR = 1.15) and hospital readmission (RR = 0.90 and RR = 0.62) showed lower risks in NPWT group but were not significant. Hematoma (RR = 1.08 and RR = 0.87) showed no significant difference. NPWT is not contraindicated in cancer surgical wounds and can be considered a beneficial palliative treatment to promote wound healing.

Negative pressure wound therapy compared with conventional wound dressings for closed incisions in orthopaedic trauma surgery: A meta-analysis.

We performed a meta-analysis to evaluate the effect of negative pressure wound therapy compared with conventional wound dressings on closed incisions in orthopaedic trauma surgery. A systematic literature search up to October 2021 was done and 12 studies included 3555 subjects with closed incisions in orthopaedic trauma surgery at the start of the study: 1833 of them were provided with negative pressure wound therapy and 1722 were conventional wound dressings. They were reporting relationships about the effect of negative pressure wound therapy compared with conventional wound dressings on closed incisions in orthopaedic trauma surgery. We calculated the odds ratio (OR) and mean difference (MD) with 95% confidence intervals (CIs) to assess the effect of negative pressure wound therapy compared with conventional wound dressings on closed incisions in orthopaedic trauma surgery using the dichotomous and continuous methods with a random or fixed-effect model. Negative pressure wound therapy had significantly lower deep surgical site infection (OR, 0.65; 95% CI, 0.48-0.88, P = .005), superficial surgical site infection (OR, 0.23; 95% CI, 0.11-0.49, P = .31), and wound dehiscence (OR, 0.41; 95% CI, 0.21-0.80, P = .009) compared with conventional wound dressings in subjects with closed incisions in orthopaedic trauma surgery. However, negative pressure wound therapy had no significant effect on the length of hospital stay (MD, 0.29; 95% CI, -2.00- 2.58, P = .80) compared with conventional wound dressings in subjects with closed incisions in orthopaedic trauma surgery. Negative pressure wound therapy had significantly lower deep surgical site infection, superficial surgical site infection, and wound dehiscence; however, negative pressure wound therapy had no beneficial effect on the length of hospital stay compared with conventional wound dressings in subjects with closed incisions in orthopaedic trauma surgery. Further studies are required to validate these findings.

Surgical site complications in kidney transplant recipients: incidence, risk factors and outcomes in the modern era.

BACKGROUND: Surgical site complications (SSCs) are an important source of morbidity after kidney transplantation. We assessed the incidence, risk factors, outcomes and economic impact of SSCs in a large, diverse population of kidney transplant recipients. METHODS: We conducted a single-centre, observational cohort study of adult (age ≥ 18 yr) patients who underwent kidney transplantation between Jan. 1, 2005, and Dec. 31, 2015, with a minimum of 1 year of follow-up. Cases of SSC, including infections and wound dehiscence, were determined from patient records. Inpatient and outpatient hospital costs were determined 6 and 12 months after transplantation. We used the Kaplan-Meier product-limit method to determine the cumulative probability of SSCs and other outcomes. We evaluated risk factors and clinical outcomes using Cox proportional hazard ratios. Linear regression models were used to study the effect of SSCs on graft function. RESULTS: The incidence rate of SSCs within 30 days after transplantation was 4.19 per 100 person-months. The cumulative probability of developing an SSC within 30 days after transplantation was 4.13% (95% confidence interval [CI] 3.23%-5.28%). Increased recipient body mass index (BMI) (hazard ratio [HR] 1.07, 95% CI 1.02-1.11), longer cold ischemic time (HR 1.05, 95% CI 1.01-1.09) and transplantation in 2010-2012 versus 2005-2009 (HR 2.20, 95% CI 1.19-4.04) were risk factors for SSC development. In multivariable stepwise Cox proportional hazard models, SSC was a significant risk factor for death-censored graft failure (HR 3.08, 95% CI 1.60-5.90) and total graft failure (HR 2.09, 95% CI 1.32-3.32). Cumulative median hospital costs were $2238.46 greater for patients with an SSC than for those without. CONCLUSION: Increased BMI, longer cold ischemic time and the 2010-2012 transplantation period predisposed to SSCs. The development of SSCs was associated with a higher risk of graft failure. Strategies to minimize SSCs may improve outcomes after kidney transplantation and reduce costs.

Failure of Abdominal Wall Closure: Prevention and Management.

This article reviews evidence-based techniques for abdominal closure and management strategies when abdominal wall closures fail. In particular, optimal primary fascial closure techniques, the role of prophylactic mesh, considerations for combined hernia repair, closure techniques when the fascia cannot be closed primarily, and management approaches for fascial dehiscence are reviewed.

Which determinants are considered to be important for adherence to Negative Pressure Wound Therapy: A multimethods study.

AIM: To explore the extent of patients that choose to cease Negative Pressure Wound Therapy (NPWT) prematurely in a clinical setting, and to explore the determinants of nonadherence. METHOD: This study exists out of: (1) a retrospective study to assess the number of patients who ceased NPWT prematurely; (2) a narrative review (NR) to identify determinants of nonadherence; and (3) a survey among wound care specialists to explore specific determinants of nonadherence to NPWT. RESULTS: (1) Based on the retrospective study, 20% ceased NPWT prematurely because of experienced limitations in daily activities. (2) Based on 22 studies, 23 determinants that might influence nonadherence were identified and added as questions in the survey. (3) Twenty-two percent (n = 136) wound care specialists completed the survey. Confidence with the healthcare team, consistency in therapy advices, coping with pain, former negative experiences with NPWT, a normal activity pattern, social support from family or friends, and support from the healthcare team were identified as highly relevant determinants of nonadherence to NPWT. Only religion scored distinctively lower. CONCLUSION: This study is a first step in exploring the determinants of nonadherence to NPWT. In 20% NPWT was prematurely ceased at the request of the patient, this means that this therapy may have not been the best choice of therapy for this particular patient. The identification of potential determinants of nonadherence may help healthcare professionals in their dialogue with patients. The next step should be a prognostic study to assess which determinants best predict adherence to NPWT.

Circumferential Lipobrachioplasty Is a Safe Procedure.

BACKGROUND: Excess fat and skin in the upper arms have become troublesome with aging and especially after the advancement in methods of weight reduction. Arm contouring procedures can be divided into three groups: those dealing with skin redundancy, those dealing with the lipodystrophy, and a combination of both. This study tries to find an answer to the debate about the safety of simultaneous circumferential liposuction and brachioplasty. METHODS: Sixty-two patients (49 women and 13 men) were operated on by simultaneous circumferential suction-assisted lipectomy followed by brachioplasty. Preoperative and postoperative arm circumferences and outcomes (including complications and patient satisfaction) were evaluated starting at least 6 months after the procedure. RESULTS: Only two patients (3.2 percent) developed small areas of wound dehiscence that healed after repeated dressing and an extended period of compression garment use. One patient (1.6 percent) complained of hypertrophic scarring, which was managed by local compression and silicone sheets. The average reduction in mid arm circumference was 9 cm (range, 5 to 14 cm). Approximately 95.2 percent of the patients in the study are highly satisfied, and 4.8 percent reported a mild degree of satisfaction. CONCLUSIONS: Simultaneous circumferential arm liposuction followed by brachioplasty addresses both the lipodystrophy and arm ptosis in a single hospital admission. This combination does not increase the complication rate. The results are highly satisfactory to the patients. According to the results of this study, circumferential arm lipobrachioplasty is considered to be a safe, efficient, reliable, and feasible procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Uterine Dehiscence and Subsequent Pregnancy Management: A Review of the Literature.

IMPORTANCE: Uterine dehiscence is a separation of the uterine musculature with intact uterine serosa. Uterine dehiscence can be encountered at the time of cesarean delivery, be suspected on obstetric ultrasound, or be diagnosed in between pregnancies. Management is a conundrum for obstetricians, regardless of timing of onset. EVIDENCE ACQUISITION: A literature search was undertaken by our research librarian using the search engines PubMed, CINAHL, and Web of Science. The search term used was "uterine dehiscence." The search was limited to the English language, and there was no limit on the years searched. RESULTS: The search identified 152 articles, 32 of which are the basis for this review. Risk factors, treatment, and management in subsequent pregnancies are discussed. The number of prior cesarean deliveries is the greatest risk factor for uterine dehiscence. Unrepaired uterine dehiscence can cause symptoms outside of pregnancies and may require repair for alleviation of these symptoms. Dehiscence should also be repaired prior to subsequent pregnancies. CONCLUSION AND RELEVANCE: Planned delivery prior to the onset of labor with careful monitoring of maternal symptoms is the preferred management strategy of women with prior uterine dehiscence. Careful attention should be paid to the lower uterine segment thickness when ultrasonography is performed in women with prior cesarean delivery. RELEVANCE STATEMENT: An evidence-based review of uterine dehiscence in pregnancy and how to manage subsequent pregnancies following uterine dehiscence.

Surgical Wound Dehiscence Treatment With Low-Level Laser Therapy and Barbatimão: A Case Report.

BACKGROUND: Low-level laser therapy (LLLT) and a gel containing an extract of Barbatimão, a native Brazilian tree, have shown promising results in both preclinical and clinical wound healing studies. PURPOSE: To describe the treatment of surgical wound dehiscence with LLLT and Barbatimão gel. CASE STUDY: A 54-year-old woman without comorbidities underwent abdominoplasty at another health facility. Three (3) weeks later she presented to the authors' clinic after an episode of syncope, abrupt dyspnea, purulent exudate, and necrotic tissue in the surgical incision. She reported that wound redness, warmth, and swelling started 8 days postoperatively. The patient was admitted; on day 3 of that hospital stay, her condition improved and surgical debridement was performed. Follow-up care of wound dehiscence was provided in the outpatient clinic. The treatment involved daily application of Barbatimão gel and weekly application of LLLT. The wound healed after 84 days. CONCLUSION: This case report suggests that LLLT may be a beneficial adjunctive therapy, together with Barbatimão gel, for the treatment of surgical wound dehiscence.

Dehiscencia de la cúpula vaginal como causa de abdomen agudo / Acute abdomen due to vaginal cuff dehiscence

La dehiscencia de la cúpula vagina tras una histerectomía es una complicación poco frecuente con una mayor incidencia en casos de cirugía laparoscópica. Su diagnóstico es clínico y, en caso de acompañarse de evisceración de contenido intraabdominal, supone una auténtica emergencia quirúrgica debido al riesgo de lesión intestinal y peritonitis. Respecto a la vía de abordaje para su tratamiento continua existiendo controversia, recomendándose la laparoscopia si la situación de la paciente lo permite. Presentamos el caso de una paciente con antecedente de histerectomía total y doble anexectomía 3 meses antes con exploración compatible con abdomen agudo y TC indicativa de perforación de víscera hueca. En la cirugía por vía laparoscópica se evidenció una dehiscencia a nivel de la cúpula vaginal. (AU)

Vaginal cuff dehiscence after hysterectomy is a rare complication. It is more frequent in laparoscopic surgery and its diagnosis isclinical. In case of bowel evisceration it is a surgical emergency due to the risk of bowel injury and peritonitis. Controversy existsregarding the surgical approach. If the patient´s situation allows it, laparoscopy is recommended. We present the case of a patientwith total hysterectomy with bilateral salpingo-oophorectomy 3 months before. She presented an acute abdomen and the CT scanwas indicative of hollow viscus perforation. Laparoscopic surgery showed a vaginal cuff dehiscence. (AU)

Falla de sutura en cirugía colorrectal. Factores de riesgo y manejo terapéutico / Anastomotic failure in colorectal surgery. Risk factors and therapeutic management

Introducción: La dehiscencia anastomótica (DA) es una complicación de la cirugía colorrectal que determina alta morbimortalidad y peor pronóstico oncológico. El objetivo de este estudio es analizar su relación con factores de riesgo y describir su manejo terapéutico. Métodos: Estudio retrospectivo, observacional y analítico. Se incluyeron resecciones colorrectales de coordinación por patología neoplásica maligna con anastomosis primaria, entre enero de 2015 y noviembre de 2018. Resultados: Ciento doce pacientes cumplieron con los criterios de inclusión. La tasa de DA fue 17% y la mortalidad 15%. El tamaño tumoral se asoció de forma estadísticamente significativa con un mayor riesgo de falla de sutura. Discusión: Nuestros resultados son similares a los reportados en la literatura, destacándose una alta proporción de DA tempranas y por lo tanto de reintervención y detransitación. Conclusiones: El manejo de la DA es un reto terapéutico y debe ajustarse a muchos parámetros, siendo uno de los más importantes la experiencia del cirujano. (AU)

Introduction: Anastomotic dehiscence (AD) is a complication of colorectal surgery that determines high morbidity and mortality and a worse oncological prognosis. The objective of this study is to analyze its relationship with risk factors and describe its therapeutic management. Material and Methods: Retrospective, observational and analytical study. Colorectal resections with primary anastomosis for malignant neoplastic pathology performed between January 2015 and November 2018 were included. Results: One hundred and twelve patients met the inclusion criteria. The AD rate was 17% and mortality 15%. Tumor size was statistically significantly associated with an increased risk of AF. Discussion: Our results are similar to those reported in the literature, highlighting a high proportion of early AD and therefore of re-intervention and intestinal diversion. Conclusions: The management of AD is a therapeutic challenge, and must be adjusted to many parameters, one of the most important being the surgeon's experience. (AU)

Treatment of Superficial Incision Dehiscence after Abdominal Surgery by Z-Plasty: A Retrospective Case Series.

OBJECTIVE: To explore the treatment of superficial incision dehiscence after abdominal surgery by Z-plasty combined with negative-pressure wound therapy. METHODS: A retrospective study was performed on seven patients with superficial abdominal incision dehiscence from October 2018 to February 2019. All patients were given systemic antibiotics and nutrition support. During the first stage, surgical debridement with negative-pressure wound therapy was performed. Local Z-plasty was performed in the second stage. RESULTS: The incision healed well in all patients, and no infection or necrosis occurred in the flaps. During the follow-up of 7.3 months (range, 5-10 months), no incision rupture or redehiscence occurred. CONCLUSIONS: Surgical debridement, negative-pressure wound therapy, and Z-plasty can be used to treat superficial abdominal incision dehiscence and achieve good therapeutic effect and prognosis. Z-plasty can be used as an alternative to direct suture of incisions because of its simplicity and excellent results.

Eficacia y seguridad de la terapia de vacío endoscópica para el tratamiento de perforaciones y dehiscencias anastomóticas del tracto digestivo superior / Safety and efficacy of endoscopic vacuum therapy for the treatment of perforations and anastomotic leaks of the upper gastrointestinal tract

OBJETIVO: Evaluar la eficacia y seguridad de la terapia de vacío endoscópica (TVE) en perforaciones y dehiscencias del tracto digestivo superior. PACIENTES Y MÉTODOS: Estudio retrospectivo observacional donde se incluyeron todos los pacientes que presentaron algún defecto del tracto gastrointestinal superior y que fueron sometidos a TVE en el período comprendido entre abril de 2017 y febrero de 2019 en 3 centros españoles. Para ello se utilizó el único sistema de terapia de vacío aprobado para uso endoscópico hasta la fecha (Eso-SPONGEr; B. Braun Melsungen AG, Melsungen, Alemania). RESULTADOS: Un total de 11 pacientes fueron sometidos a TVE como tratamiento de una dehiscencia de sutura anastomótica tras esofaguectomía (n=7), gastrectomía (n=2), como tratamiento de una perforación esofágica tras septomiotomía endoscópica de Zenker (n=1) y tras una perforación esofágica espontánea o síndrome de Boerhaave (n=1). La mediana del tamaño de la cavidad fue de 8×3cm. De mediana, la TVE se inició a los 7días de la cirugía inicial. La mediana de duración de la TVE fue de 28días. La mediana de esponjas colocadas fue de 7 y el intervalo de recambio de las esponjas, de 3,7días. En 10 casos (91%) se consiguió el cierre del defecto y en 9 casos (82%) la resolución clínica del cuadro infeccioso asociado. Cinco pacientes presentaron algún evento adverso: 3 estenosis anastomóticas, un episodio de dolor retrofaríngeo y un caso de neumonía de nueva aparición. La mediana de estancia hospitalaria desde el inicio de la TVE fue de 45días. Un paciente falleció debido a complicaciones sépticas secundarias a la dehiscencia de sutura. CONCLUSIÓN: La TVE tiene una eficacia superior al 90% en las perforaciones y fugas anastomóticas del tracto digestivo superior. Adicionalmente es una terapia segura, siendo los eventos adversos leves

AIM: To evaluate the efficacy and safety of endoscopic vacuum therapy (EVT) in the management of perforations and anastomotic leaks of the upper gastrointestinal tract. PATIENTS AND METHODS: This is a retrospective observational study which included patients who underwent EVT due to any upper gastrointestinal defect between April 2017 and February 2019 in three Spanish Hospitals. To this end, we used the only medical device approved to date for endoscopic use (Eso-SPONGEr; B. Braun Melsungen AG, Melsungen, Germany). RESULTS: 11 patients were referred for EVT of an anastomotic leak after esophagectomy (n=7), gastrectomy (n=2), esophageal perforation secondary to endoscopic Zenker's septomiotomy (n=1) and Boerhaave syndrome (n=1). The median size of the cavity was 8×3cm. The median delay between surgery and EVT was 7 days. The median of EVT duration was 28 days. The median number of sponges used was 7 and the mean period replacement was 3.7 days. In 10 cases (91%), the defect was successfully closed. In 9 cases (82%) clinical resolution of the septic condition was achieved. 5 patients presented some adverse event: 3 anastomotic strictures, 1 retropharyngeal pain and 1 case of new-onset pneumonia. The median hospital stay from the start of EVT was 45 days. 1 patient died owing to septic complications secondary to the anastomotic leak. CONCLUSION: EVT was successful in over 90% of perforations and anastomotic leaks of the upper gastrointestinal tract. Moreover, this is a safe therapy with only mild adverse events associated