Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase II study.

BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([18F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.

Rare periorbital, pseudocystic metastasis of squamous cell carcinoma of the bladder: Case report and review of the literature.

We present the case of a man in his fifties with a history of bladder carcinoma who presented with a large periorbital cystic lesion that was found to be a metastasis. Bladder carcinomas are a very rare cause of peri-/orbital metastasis. The primary tumor in this case predominately showed squamous cell differentiation and small areas of adenoid differentiation. To our knowledge only one previous case of orbital metastasis from squamous cell carcinoma of the bladder has been reported. Cyst formation in bladder cancer metastasis has not been reported and is very rare for orbital metastases in general. The pathogenesis of metastatic cyst development is not fully understood and may vary from case to case. A biopsy of an atypical cyst is indicated.

Keratin films for ocular surface reconstruction: Wound healing in an in-vivo model.

The most commonly used tissue substitute for ocular surface reconstruction is human amniotic membrane (AM). Because of its low biomechanical strength and intransparency there is a need to search for alternatives of consistent quality. This study, further explored the biocompatibility of Keratin Film (KF) and its ability to sustain corneal epithelial wound healing. In three equal groups of 5 New Zeeland white rabbits a 4 mm superficial keratectomy was created in the right eye. Five eyes received a KF, five a human AM graft and the remaining five no implant. All eyes were treated with ofloxacin and dexamethasone eye drops and followed up for 10 days. Corneal fluorescein staining, vascularization, and transparency were assessed using slit lamp biomicroscopy according to a standardized grading score during and at the end of follow-up. The corneal-scleral-button was excised and processed for histology. After 10 days all eyes which had received a KF showed complete epithelial healing and no signs of neovascularization. In the AM group 1 eye showed a persistent epithelial defect at day 10 and 2 eyes showed neovascularization at day 7 resolving at day 10. Transparency improved progressively both in the KF group as well as in the AM group towards the end of the follow. Histology showed a multilayer epithelium firmly adherent to the KF with no evidence of keratocyte migration or inflammatory reaction in the corneal stroma. In this study on rabbit eyes KF better supported corneal epithelial wound healing than amniotic membrane.

[Beyond esthetics-Regenerative medicine for severe diseases of the adnexa oculi]. / Jenseits von Ästhetik ­ Regenerative Medizin bei schweren Erkrankungen der okulären Adnexe.

BACKGROUND: Restoration of eyelid and lacrimal functions are important steps on the way to an intact ocular surface. Clinically available substitute tissues or therapeutic options for eyelid reconstruction and lacrimal gland regeneration often reach their limits in patients with severe diseases of the adnexa oculi. Several approaches in regenerative medicine have been intensively researched and clinically tested in recent years. These range from reconstructive approaches with novel tissue matrices in the field of eyelid surgery to stem cell therapies to regenerate lacrimal gland function. MATERIAL AND METHODS: The state of the art in the current literature is presented and an overview of clinically applied or currently researched tissues for eyelid reconstruction is given. Furthermore, approaches in stem cell therapy of the lacrimal gland as well as own results are presented. RESULTS: Acellular dermis has been successfully used for eyelid reconstruction and represents a viable option in cases of limited availability of autologous tissue. In vitro grown cellular constructs or tissues with genetically modified cells have already been successfully applied in dermatology for the treatment of burns or severe genodermatoses. First studies on stem cell therapy for severe dry eye in Sjögren syndrome showed a safe and effective application of mesenchymal stem cells by injection into the lacrimal gland. CONCLUSION: Due to the limitations of currently available replacement tissues, there is a clinical need for the development of new materials for adnexa oculi reconstruction. Constructs grown in vitro with allogeneic and/or genetically engineered cells are slowly making their way into clinical practice. The efficacy and mode of action of stem cells in severe dry eye are subject matters of current clinical trials.

DMEK after penetrating keratoplasty: cohort with DMEK grafts and descemetorhexis larger than full-thickness graft.

PURPOSE: The study aims to evaluate visual outcome, central corneal thickness, and rebubbling rate in a cohort with oversized DMEK grafts after failed penetrating keratoplasty (PK). The unique feature of the study is a descemetorhexis diameter larger than the full-thickness graft, i.e., peripheral to the PK interface. METHODS: A monocentric, retrospective evaluation of all patients with endothelial graft failure after PK treated with an oversized DMEK graft and descemetorhexis outside of the PK interface (i.e., in host tissue) between January 2015 and July 2019 at the Department of Ophthalmology at the University of Düsseldorf (Germany) was performed. RESULTS: Eleven eyes of 10 patients were identified. Mean age was 69 years. On average (arithmetic mean ± standard deviation), 1.7 ± 1.0 previous PKs have been performed per eye in this cohort. The mean time between last PK and DMEK was 10.1 ± 7.3 years (range 2 to 23 years). In all cases, the graft diameter exceeded the diameter of the previous PK and descemetorhexis was performed in host tissue, that is, peripheral to the graft-host interface. Rebubbling was performed in 18.2% of the patients (n = 2 eyes) because of central graft detachment. Mean central corneal thickness showed a statistically significant improvement at 5.3 ± 3.5 months after surgery from 688.23 ± 151.01 to 527.75 ± 88 µm (p = 0.002). Visual acuity increased significantly by 5 lines from 1.24 ± 0.5 logMAR (range from 0.5 to 2) to 0.73 ± 0.76 logMAR (range from 0.1 to 2) within 3 months (p = 0.006). Excluding patients without visual potential and transplant failure, visual acuity improved significantly by 8 lines (p < 0.001), and stayed stable until the last follow-up at 15.1 ± 11.4 months (range 6 to 39 months, p < 0.001, n = 8) after surgery. CONCLUSION: DMEK can be successfully used to treat endothelial cell failure after PK, and can provide good postoperative results with regards to visual acuity. This study shows that stripping of Descemet's membrane (DM) peripheral to the PK interface is surgically feasible. Overlapping, larger DMEK grafts with more endothelial cells can be used without increasing rebubbling rates and may potentially improve long-term graft survival.

Does smoking have an impact on the immunological response to COVID-19 vaccines? Evidence from the VASCO study and need for further studies.

OBJECTIVES: The aim of this study was to investigate the possible impact of smoking on the humoral response to the BNT162b2 mRNA COVID-19 vaccine (also known as the BioNTech-Pfizer COVID-19 vaccine). STUDY DESIGN: A longitudinal sero-epidemiological study was conducted in sample of Italian healthcare workers (HCWs). METHODS: HCWs who were administered two doses of the BNT162b2 mRNA vaccine, 21 days apart, between December 2020 and January 2021, were invited to undergo multiple serology tests to identify SARS-CoV-2 S-RBD-specific immunoglobulin G (IgG) antibodies. Participants also responded to questions about their smoking status (i.e. current smokers vs non-smokers) in a survey. RESULTS: Sixty days after the completion of the vaccination cycle, serological analyses showed a difference in vaccine-induced IgG titre between current smokers and non-smokers, with median antibody titres of 211.80 AU/mL (interquartile range [IQR] 149.80-465.50) and 487.50 AU/mL (IQR 308.45-791.65) [P-value = 0.002], respectively. This significant difference in vaccine-induced IgG titres between current smokers and non-smokers remained after adjusting for age, sex, and previous infection with SARS-CoV-2. CONCLUSIONS: This study observed that vaccine-induced antibody titres decrease faster among current smokers than non-smokers. Further research to investigate the impact of smoking on the immunological response to COVID-19 and non-COVID-19 vaccines is required.

[Cooperation between the department of ophthalmology at the University of Düsseldorf (Germany) and the Fundación Visión in Asunción (Paraguay) as an example of the German hospital partnerships programm]. / Das deutsche Klinikpartnerschaftsprogramm am Beispiel der Kooperation der Klinik für Augenheilkunde des Universitätsklinikums Düsseldorf mit der Fundación Visión in Asunción (Paraguay).

BACKGROUND: A hospital partnership between the University Eye Hospital Düsseldorf (UAK Düsseldorf) and Fundación Visión in Asunción has existed since 2014 based on a memorandum of understanding. Fundación Visión plays a leading role in ophthalmological treatment and prevention of blindness in Paraguay. Since 2016 a program for the promotion of international hospital partnerships of the German government has been in place. MATERIAL AND METHODS: Following a written application in 2016 the hospital partnership Düsseldorf-Asunción is funded by the Federal Ministry for Economic Cooperation in Germany. The aim of the project was to establish modern minimally invasive corneal transplantation techniques with faster postoperative rehabilitation and less follow-up in Paraguay with the help of several activities within a defined schedule. Secondary aims were to obtain first data on the prevalence of eye diseases in a typical patient cohort of the Fundación Visión and to establish an infrastructure for modern eye banking techniques in Paraguay. RESULTS: First a Paraguayan surgeon was trained to carry out Descemet membrane endothelial keratoplasty (DMEK) transplantations in Germany. At the same time, the surgical instruments required for the DMEK technique were purchased and delivered to the Fundación Visión. In September 2018 the first lamellar corneal transplantations were successfully performed in Paraguay by the team from the Fundación Visión under the supervision of an experienced surgical team from Düsseldorf. Subsequently, the split cornea approach using a donor cornea for a posterior and an anterior lamellar keratoplasty (DMEK and DALK) was also implemented in Asunción. In November 2019 epidemiological data on eye diseases were collected during a field campaign of the Fundación Visión in a rural region of Paraguay. In the course of data collection an employee of the University Eye Hospital Düsseldorf learned small incision cataract surgery. In March 2019, a technician from the Fundación Visión was trained in Düsseldorf in corneal tissue culture techniques and preparation of amniotic membrane transplants in the Lions eye bank North-Rhine/Westfalia. CONCLUSION: With the aid of a supported hospital partnership modern minimally invasive corneal transplantation techniques can be successfully transferred to the eye hospital of a developing country and in return surgical skills can be taught to surgeons from Germany who are in training. Therefore, an efficient hospital partnership is the basis for a mutual exchange and is not purely one-way traffic.

Conventional brain magnetic resonance imaging in the longitudinal evaluation of newly diagnosed systemic lupus erythematosus patients: a retrospective analysis from a single-centre cohort.

INTRODUCTION: Neuropsychiatric (NP) manifestations occur mostly in the early phases of the systemic lupus erythematosus (SLE) course. Nonspecific alterations are evident in conventional brain magnetic resonance imaging (MRI), regardless of clinically overt NP symptoms. The main aims of this study were to assess the prevalence of MRI abnormalities in newly diagnosed SLE, and to evaluate the impact of MRI changes during follow-up (FU) and the clinical course of NP symptoms. MATERIALS AND METHODS: Newly diagnosed SLE patients with a baseline brain MRI and with available repeated MRI during FU were retrospectively evaluated. White-matter lesions and atrophy were recorded, comparing NPSLE and non-NPSLE patients. Cox proportional hazard models were used to compare NP events during FU with MRI data. RESULTS: Forty-four patients were included, 22 with NP events attributed to SLE. The baseline MRI scan was abnormal in 21 patients (47.73%). New NP events occurred in 17 patients, and worsening was found in repeated MRIs in 12 (27.27%). A worsening of MRI was associated with higher occurrence of new NP events during FU (adjusted hazard ratio 3.946 (1.175-13.253)). CONCLUSION: Baseline MRI is useful in patients with an early diagnosis of SLE, allowing comparison with subsequent scans. In our study, radiological worsening of repeated brain MRI was associated with new NP events.

Eye Socket Regeneration and Reconstruction.

Purpose: When an eye has become irreversibly blind or painful it is removed by enucleation or evisceration. The resulting anophthalmic socket usually receives a volume replacing implant and is subsequently fitted with a prosthetic shell for adequate cosmesis. Trauma, tumour or immunological pathomechanisms can induce loss of bone, orbital soft tissue volume, and conjunctival contraction or implant exposure, which result in difficult or impossible prosthesis wear. In this situation as well as in numerous diseases limited to the conjunctiva (e.g. Pterygium, or cicatrizing conjunctivitis) strategies to substitute the lost tissue are required.Methods: A review of the literature search using various electronic databases (PubMed and MEDLINE) was performed on indications, surgical techniques and materials used to restore the ocular socket.Results: Amniotic membrane and oral mucosa are still the most commonly used substitutes for the reconstruction of larger conjunctival defects and ocular socket reconstruction. However, due to limitations of clinical available grafts, synthetic scaffolds, biomaterials or tissue-engineered grafts have been described in preclinical studies but most of them have not been investigated adequately in clinical studies yet. In orbital volume replacement, porous and nonporous spheres are used and both show acceptable results. However, more clinical studies are required that directly compare the outcomes in patients with similar conditions. Dermofat graft remains a good option in case of sockets with significant orbital volume and conjunctival surface loss.Conclusion: Beyond established techniques using autologous or allogeneic tissue, various approaches of engineering tissue based on scaffolds and stem cell expansion techniques are currently under investigation and may become alternatives in socket reconstruction in the not too far future.

[Immunological tolerance of intraocular eyelashes after penetrating corneal injury]. / Immunologische Toleranz von intraokularen Zilien nach penetrierender Hornhautverletzung.

Penetrating eye injuries often lead to serious symptoms, such as severe inflammation and pain, especially if residual intraocular foreign bodies are present. This case report describes a patient who suffered a penetrating corneal injury resulting in eyelashes being displaced into the anterior chamber. Although no treatment was given the anterior chamber of the eye did not show any inflammatory reactions 2 weeks after the trauma. In addition to the accident mechanism the material of which the foreign body is composed plays a decisive role. While iron, copper and wooden foreign bodies lead to severe intraocular inflammation, keratin is immunologically well-tolerated.

Optimising pain management protocols following cardiac surgery: A protocol for a national quality improvement study.

Pain following cardiac surgery is a multifaceted phenomenon resulting from a number of mechanisms. High-levels of post-operative pain are associated with cardiovascular and respiratory complications and adequate pain management is crucial for enabling fast recovery. However, adequate pain control is complex, a challenge that stems from a combination of poor reporting of pain, significant variation amongst patients and the side-effects of strong, particularly opioid, analgesics. An initial audit at our hospital demonstrated high-levels of post-operative pain following cardiac surgery and a protocol was therefore devised by the anaesthetic department for cardiac surgical pain management. The protocol stratified patients into high- or low-risk of pain based on the presence of risk factors for pain and utilised a combination of pre-operative one-off dose of gabapentin, intra-operative opioid infusion and post-operative multimodal analgesia with paracetamol, weak and strong opioids. Additionally, patients at high-risk of pain also received patient controlled analgesia. Use of this protocol was associated with improved pain scores on the first three post-operative days. We have devised this study to test for reproducibility of the benefit experienced at our hospital at a larger multicentre level. After acquiring pre-existing post-operative pain management strategies through an initial survey, local study leads will undertake a baseline audit. Local study leads will then lead a 4-week period of protocol implementation. Trusts with official pain management protocols will be given the option to re-circulate their pre-existing protocols. Subsequently, pain scores during post-operative days 1-3 will be re-audited.

Systematic review of therapeutic nipple-sparing versus skin-sparing mastectomy.

Background: The use of nipple-sparing mastectomy (NSM) is increasing, despite unproven oncological safety in the therapeutic setting. The aim of this systematic review was to determine the safety and efficacy of NSM compared with skin-sparing mastectomy (SSM). Methods: A literature search of all original studies including RCTs, cohort studies and case-control studies comparing women undergoing therapeutic NSM or SSM for breast cancer was undertaken. Primary outcomes were oncological outcomes; secondary outcomes were clinical, aesthetic, patient-reported and quality-of-life outcomes. Data analysis was undertaken to explore the relationship between NSM and SSM, and preselected outcomes. Heterogeneity was assessed using the Cochrane tests. Results: A total of 690 articles were identified, of which 14 were included. There was no statistically significant difference in 5-year disease-free survival and mortality for NSM and SSM groups, where data were available. Local recurrence rates were also similar for NSM and SSM (3·9 versus 3·3 per cent respectively; P = 0·45). NSM had a partial or complete nipple necrosis rate of 15·0 per cent, and a higher complication rate than SSM (22·6 versus 14·0 per cent respectively). The higher overall complication rate was due to the rate of nipple necrosis in the NSM group (15·0 per cent). Conclusion: In carefully selected cases, NSM is a viable choice for women with breast cancer who need to have a mastectomy. More research is needed to help further refine which surgical approaches to NSM optimize outcomes.

Intestinal anti-transglutaminase 2 immunoglobulin A deposits in children at risk for coeliac disease (CD): data from the PreventCD study.

In coeliac disease (CD), anti-tissue transglutaminase 2 immunoglobulin (Ig)A antibodies (anti-TG2) are produced and deposited in the intestine. PreventCD (www.preventcd.com) is a European multi-centre study, which investigates the influence of infant nutrition and that of genetic, immunological and other environmental factors on the risk of developing CD. The aim of the current study was to evaluate the appearance of intestinal anti-TG2 deposits in very early intestinal biopsies from at-risk infants and their predictive value for villous atrophy. Sixty-five small bowel biopsies, performed in 62 children, were investigated for the presence of intestinal anti-TG2 extracellular IgA deposits by using double immunofluorescence. The biopsies were performed in the presence of elevated serum levels of CD-associated antibodies and/or symptoms suggesting disease. Deposits of anti-TG2 IgA were present in 53 of 53 CD patients and three of three potential CD patients. In potential CD patients, mucosal deposits showed a patchy distribution characterized by some areas completely negative, whereas active CD patients had uniformly present and evident mucosal deposits. Only one of six patients without CD (negative for serum anti-TG2 and with normal mucosa) had intestinal deposits with a patchy distribution and a weak staining. Two of the 53 CD patients received a definitive diagnosis of CD after a second or third biopsy; mucosal deposits of anti-TG2 IgA were evaluated in all samples. Before developing villous atrophy, both patients had anti-TG2 deposits in normal mucosal architecture, antibodies in one patient being absent in serum. We demonstrated that in CD the intestinal deposits of anti-TG2 are a constant presence and appear very early in the natural history of disease.

Impact of the SCARE guideline on the reporting of surgical case reports: A before and after study.

INTRODUCTION: The SCARE guideline was developed in 2016 through an expert Delphi consensus exercise. It aimed to improve the quality of reporting of surgical case reports. The aim of this study was to assess the impact of introducing the SCARE guideline for surgical on reporting of case reports submitted to a single journal. METHODS: A total of 20 case reports published in the International Journal of Surgery Case Reports (IJSCR) and Annals of Medicine and Surgery (AMS) in July and August 2016, prior to the introduction of the SCARE guideline (the pre-SCARE period), were randomly identified and scored against the SCARE criteria. Two independent teams performed the scoring giving a total score out of a theoretical maximum of 34 for each case report, the 'SCARE score' (expressed as a percentage). The scores for the two teams were then compared and consensus was reached to achieve a final sore set. This process was repeated for the January and February 2017 issues of the journal, post implementation of the guideline (the post-SCARE period). SCARE scores were compared between the pre- and post-SCARE periods. RESULTS: The mean pre-SCARE score was 75.0% (standard deviation ± 6.29, Range 62-84), and the mean post-SCARE score was 82.6% (standard deviation ± 8.02, range 66-99), a 10% relative increase in compliance which was statistically significant (P < 0.001). The Cohen's Kappa score between teams A and B was 0.871, implying very substantial agreement. CONCLUSION: Implementation of the SCARE guideline resulted in a 10% improvement in the reporting quality of surgical case reports published in a single journal. Adherence to SCARE reporting guidelines by authors, reviewers and editors should be improved to boost reporting quality. Journals should develop their policies, submission processes and guide for authors to incorporate the guideline.

Impact of the PROCESS guideline on the reporting of surgical case series: A before and after study.

INTRODUCTION: The PROCESS guideline was developed in 2016 through expert Delphi consensus. It aimed to improve the quality of reporting of surgical case series. This study assessed the impact of the introduction of the PROCESS guideline on reporting for surgical case series submitted to three journals. METHODS: 20 case series published in the International Journal of Surgery Case Reports (IJSCR), the International Journal of Surgery (IJS) or the Annals of Medicine and Surgery (AMS) in September to December 2016, prior to the introduction of the PROCESS guideline (the pre-PROCESS period), were randomly identified and scored against the PROCESS criteria. Two authors independently scored each article a total score out of 29, the 'PROCESS score' (expressed as a percentage). Scores for the two researchers were compared and consensus was reached to achieve a final score set. The process was repeated for the January 2017 to April 2017 issues of the three journals, post PROCESS implementation (the post-PROCESS period). RESULTS: The mean PROCESS score was 80% (range 66-90%) for the pre-PROCESS period and 84% (range 72-95%) for the post-PROCESS period, a 4% relative increase [STATS]. The Cohen's Kappa score between researchers was 0.907 implying very substantial agreement. CONCLUSION: Implementation of the PROCESS guideline resulted in a 5% improvement in the reporting quality of surgical case series published in three journals. Further research is needed to identify and successfully navigate existing barriers to greater compliance. Authors, reviewers and editors should adhere to the guidelines to boost reporting quality. Journals should develop their policies and guide for authors to incorporate the guideline and mandate compliance.

[Peri-ocular Necrotising Fasciitis - Case Report and Overview]. / Periokuläre nekrotisierende Fasziitis ­ Fallbericht und Überblick.

Peri-ocular necrotising fasciitis is a very rare ophthalmological clinical picture and is potentially fatal. This disease is caused by bacterial infection of the fasciae, which rapidly spreads. The present article reports a typical case of the disease and gives an overview of the typical clinical signs and symptoms of peri-ocular necrotising fasciitis.

An assessment of the compliance of Randomised controlled trials published in craniofacial surgery journals with the CONSORT statement: A systematic review protocol.

INTRODUCTION: The role of clinical trials in medicine is expanding, particularly in surgery. Randomised controlled trials (RCTs) represent the gold standard evidence for high-quality assessment of healthcare interventions. The Consolidated Standards of Reporting Trials (CONSORT) guidance has been published to maximise RCT reporting transparency. This paper outlines the study protocol for a systematic review that will assess the current compliance of RCTs published within craniofacial surgery with the CONSORT criteria. The aims are to identify areas where reporting can be improved to ensure craniofacial surgery is guided by high-quality evidence. METHODS AND ANALYSIS: This protocol is compliant with the Preferred Reporting Items for Systematic Review and meta-Analysis protocols (PRISMA-P) guidelines. Craniofacial surgery RCTs will be identified by searching within craniofacial surgery journals. Five journals from the Thomson Reuters Impact Factor Report 2016 included 'cranio' in their title and were included. MEDLINE PubMed will be used to search all RCTs published in these journals. The search strategy is described within this protocol. It will be limited to articles written in English, conducted on humans, and published in the last five years. Two independent researchers will assess each study for inclusion and will perform the data extraction. The researchers will assess compliance of each RCT with the 25-item CONSORT Statement checklist as the primary outcome. Discrepancies will be resolved through consensus or third author arbitration. Secondary outcomes to be extracted include the pathology and interventions examined, and indices of RCT quality. The systematic review will be compliant with PRISMA guidelines. The review has been registered a priori with the Registry of Systematic Reviews/meta-analyses (UIN: reviewregistry219). ETHICS AND DISSEMINATION: This systematic review will be conducted in line with the Cochrane Handbook for Systematic Reviews and Interventions. The intent is to publish in a peer-reviewed journal and present the data at relevant conferences.