Characterising injuries and pathologies of common dolphin Delphinus delphis mortalities in the South Australian Sardine Fishery.

Mortality of dolphins in fishing operations is often under-estimated, as shown by studies of beach-washed carcasses. Linking evidence obtained during necropsies with fishing method is fundamental to understanding the extent of mortality and the manner in which animals die. The South Australian Sardine Fishery (SASF) has operated a purse-seine industry since 1991. This study characterised injuries, pathological changes and life history of 49 dead dolphins collected from SASF during 2006-2019. Histology examination was conducted on 25 animals. Neonates, calves and juveniles accounted for 63% of the sample. Of mature females (n = 14), 11 were pregnant or lactating, with cryptic mortality estimated to be 20% of dolphins studied. Body condition was robust in 48 dolphins. Net marks were seen on 82%, mostly on the head, trunk and peduncle. Broken/missing teeth were noted in 63%. All dolphins had subdermal haemorrhage (moderate to severe in 96%), particularly around the head. Deep haemorrhage was common, including around occipital and flipper condyles, and organs. Copious fluid was present in the thoracic (pleural) and abdominal (ascites) cavities of half of the dolphins. Within the lungs, watery fluid and froth were observed in 100 and 39%, respectively. Recent bone fractures were documented in 43% of dolphins, mostly associated with haemorrhage. Severe blunt trauma appeared to be the primary cause of death, and 10 dolphins also had other significant pathologies. Visceral organ congestion and mild cardiomyopathy were observed. Stomachs contained prey remains in 75% of cases. The results of this study may help identify unreported purse-seine mortalities washed up in South Australia and elsewhere.

Hypertrophic and keloid scars fail to progress from the CD34- /α-smooth muscle actin (α-SMA)+ immature scar phenotype and show gradient differences in α-SMA and p16 expression.

BACKGROUND: Our understanding of the pathogenesis underlying keloid scar formation is still very limited, and the morphological distinction between hypertrophic and keloid scars remains difficult. OBJECTIVES: To test whether hypertrophic and keloid scars may reflect an inability to progress from immaturity to the desired mature normotrophic scar phenotype. METHODS: Using whole-biopsy imaging and an objectively quantifiable way to analyse immunoreactivity, we have compared the immunohistopathological profiles of young immature scars with mature normotrophic scars, hypertrophic scars, and keloids with their surrounding-normal-skin. RESULTS: Abnormal scars (hypertrophic scars and keloids) maintain the immature scar phenotype, characterized by a CD34- (tumour biomarker) and α-smooth muscle actin (α-SMA)+ (myofibroblast) dermal region. This is in contrast to normal skin, surrounding-normal-skin and mature normotrophic scars that were CD34+ / α-SMA- . Immature, hypertrophic and keloid scars showed abnormal epidermal differentiation (involucrin), but only hypertrophic scars and keloids showed increased epidermal thickness. Immature scars did show increased epidermal and dermal proliferation (Ki67), which was absent from abnormal scars, where mesenchymal hypercellularity (vimentin) and senescence (p16) were predominant. Keloidal collagen and α-SMA were previously considered to distinguish between hypertrophic scars and keloids. However, α-SMA staining was present in both abnormal scar types, while keloidal collagen was present mostly in keloids. There were no obvious signs of heterogeneity within keloid scars, and the surrounding-normal-skin resembled normal skin. CONCLUSIONS: Both abnormal scar types showed a unique CD34- /α-SMA+ /p16+ scar phenotype, but the differences between hypertrophic scars and keloids observed in this study were of a gradient rather than absolute nature. This suggests that scar progression to the mature normal scar phenotype is, for as yet unknown reasons, hindered in hypertrophic and keloid scars. What's already known about this topic? Hypertrophic and keloid scars both have sustained epidermal barrier dysfunction, suggesting the persistence of an immature scar phenotype. Morphological distinction between hypertrophic and keloid scars remains a topic of debate, although α-smooth muscle actin (α-SMA) and keloidal collagen have been considered distinguishing features of hypertrophic and keloid scars, respectively. It has been suggested that keloids are not simply homogeneous growths, as heterogeneity within keloid scars and possible involvement of the surrounding-normal-skin have been reported. What does this study add? An extensive whole-biopsy imaging and quantifiable immunohistochemical assessment of immature, mature normal, hypertrophic and keloid scars, including normal skin surrounding keloids. Hypertrophic and keloid scars maintain dermal characteristics of immature scars, rather than transitioning into the normal mature phenotype. Differences between hypertrophic and keloid scars were of a gradient rather than absolute nature, with keloids showing the more extreme phenotype. There was no obvious heterogeneity within keloids, and the normal skin surrounding keloids resembled normal skin. What is the translational message? Keloids remain primarily a clinical diagnosis. A raised scar with the CD34- /α-SMA+ /p16+ phenotype with strong immunoreactivity for p16 and significant amounts of keloidal collagen, together with a thickened and strongly abnormal involucrin-stained epidermis, would sway the diagnosis towards keloid scars. A hypertrophic scar seems more likely when the CD34- /α-SMA+ /p16+ phenotype shows very strong presence of α-SMA+ in large dermal nodules, with lesser p16 staining and absent or negligible keloidal collagen.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Biology of soft tissue repair: gingival epithelium in wound healing and attachment to the tooth and abutment surface.

Epithelium attachment to the tooth or abutment surface is necessary to form a biological seal preventing pathogens and irritants from penetrating the body and reaching the underlying soft tissues and bone, which in turn can lead to inflammation and subsequent bone resorption. The present review investigated oral wound closure and the role of micro-environment, saliva, crevicular fluid and microbiota in wound healing. The importance of the junctional epithelium (peri-implant epithelium) attachment to the abutment surface was investigated. Current research focuses on macro-design, surface-topography, surface-chemistry, materials, coatings and wettability to enhance attachment, since these optimised surface properties are expected to promote keratinocyte attachment and spreading through hemi-desmosome formation. Detailed studies describing the extent of junctional epithelium attachment - e.g. barrier function, hemi-desmosomes, epithelium quality, composition of the external basement membrane or ability of the epithelium to resist microbial penetration and colonisation - are not yet reported in animals due to ethical considerations, scalability, expense, technical challenges and limited availability of antibodies. In vitro studies generally include relatively simple 2D culture models, which lack the complexity required to draw relevant conclusions. Additionally, human organotypic 3D mucosa models are being developed. The present review concluded that more research using these organotypic mucosa models may identify relevant parameters involved in soft-tissue-abutment interactions, which could be used to study different macro-shapes and surface modifications. Such studies would bridge the gap between clinical, animal and traditional in vitro cell culture studies supporting development of abutments aiming at improved clinical performance.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

The Histological Composition of Capsular Contracture Focussed on the Inner Layer of the Capsule: An Intra-Donor Baker-I Versus Baker-IV Comparison.

BACKGROUND: Capsular contracture remains one of the major complications after breast implantation surgery. The extent of capsular contraction is scored using the Baker scale. The aim of this study was to compare intra-individual Baker-I with Baker-IV capsules, and in particular the prevalence and histological properties of the inner capsule layer. METHODS: Twenty capsules from ten patients were included after bilateral explantation surgery due to unilateral capsular contracture (Baker-IV) after cosmetic augmentation with textured implants. All capsules underwent (immune-)histochemical analysis: haematoxylin-eosin (morphology), CD68 (macrophages), cytokeratin (epithelial cells) and vimentin (fibroblasts), and were visually scored for cell density and the presence of an inner layer and measured for thickness. RESULTS: Baker-IV (n = 10) capsules were significantly thicker compared to Baker-I (n = 10) capsules (P = 0.004). An inner layer was present in 8 Baker-I capsules. All Baker-I capsules were vimentin and CD68-positive and cytokeratin-negative. Positive vimentin was seen throughout the inner layer, and CD-68 staining was observed adjacent to the intermediate capsule layer. In contrast, only 2 Baker-IV capsules had an inner layer, of which only 1 showed the same profile as Baker-I capsules (P = 0.016). No cytokeratin positivity was seen in any capsule. In Baker-IV capsules, outer layers showed more positivity for both vimentin and CD68. CONCLUSION: The inner layer is morphologically consistent with synovial metaplasia and is more prevalent in healthy, uncontracted Baker-I capsules. This inverse relation between the presence of the inner layer and higher Baker classification or pathological contracture could indicate a protective role of the inner layer against capsular contracture formation. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Increased epidermal thickness and abnormal epidermal differentiation in keloid scars.

BACKGROUND: The pathogenesis underlying keloid formation is still poorly understood. Research has focused mostly on dermal abnormalities, while the epidermis has not yet been studied. OBJECTIVES: To identify differences within the epidermis of mature keloid scars compared with normal skin and mature normotrophic and hypertrophic scars. METHODS: Rete ridge formation and epidermal thickness were evaluated in tissue sections. Epidermal proliferation was assessed using immunohistochemistry (Ki67, keratins 6, 16 and 17) and with an in vitro proliferation assay. Epidermal differentiation was evaluated using immunohistochemistry (keratin 10, involucrin, loricrin, filaggrin, SPRR2, SKALP), reverse-transcriptase polymerase chain reaction (involucrin) and transmission electron microscopy (stratum corneum). RESULTS: All scars showed flattening of the epidermis. A trend of increasing epidermal thickness correlating to increasing scar abnormality was observed when comparing normal skin, normotrophic scars, hypertrophic scars and keloids. No difference in epidermal proliferation was observed. Only the early differentiation marker involucrin showed abnormal expression in scars. Involucrin was restricted to the granular layer in healthy skin, but showed panepidermal expression in keloids. Normotrophic scars expressed involucrin in the granular and upper spinous layers, while hypertrophic scars resembled normotrophic scars or keloids. Abnormal differentiation was associated with ultrastructural disorganization of the stratum corneum in keloids compared with normal skin. CONCLUSIONS: Keloids showed increased epidermal thickness compared with normal skin and normotrophic and hypertrophic scars. This was not due to hyperproliferation, but possibly caused by abnormal early terminal differentiation, which affects stratum corneum formation. Our findings indicate that the epidermis is associated with keloid pathogenesis and identify involucrin as a potential diagnostic marker for abnormal scarring.

Stratum corneum profiles of inflammatory mediators in patch test reactions to common contact allergens and sodium lauryl sulfate.

BACKGROUND: Recent studies have demonstrated allergen-specific differences in the gene expression of inflammatory mediators in patch tested skin. OBJECTIVES: To determine levels of various inflammatory mediators in the stratum corneum (SC) after patch testing with common contact allergens and the skin irritant sodium lauryl sulfate (SLS). METHODS: In total, 27 individuals who had previously patch tested positive to nickel, chromium, methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) or para-phenylenediamine were retested and then patch tested with SLS and petrolatum, with petrolatum serving as the patch test control. At 72 h, the test sites were clinically graded and the SC samples collected on adhesive tape. RESULTS: The levels of 18 of the 32 quantified mediators differed significantly from that of the control patches for at least one of the tested substances. SLS and MCI/MI induced the largest number of immunomediators. Interleukin (IL)-16 levels were significantly higher in patch test reactions in all allergens than they were in the controls, while no significant difference was detected for SLS. Furthermore, a strong negative correlation was found between strength of patch test reaction and IL-1α levels. CONCLUSIONS: Cytokine profiles in the SC of patch tested skin did not show a distinct allergen-specific pattern. However, MCI/MI induced a larger and wider immune response than the other allergens, perhaps due to its potency as an irritant. The levels of IL-16 were significantly increased in patch test reactions to allergens but not to SLS; thus, they may help clinicians to differentiate between allergic contact dermatitis and irritant contact dermatitis.

Suppression of interictal spikes during phasic rapid eye movement sleep: a quantitative stereo-electroencephalography study.

Tonic and phasic rapid eye movement (REM) sleep seem to represent two different brain states exerting different effects on epileptic activity. In particular, interictal spikes are suppressed strongly during phasic REM sleep. The reason for this effect is not understood completely. A different level of synchronization in phasic and tonic REM sleep has been postulated, yet never measured directly. Here we assessed the interictal spike rate across non-REM (NREM) sleep, phasic and tonic REM sleep in nine patients affected by drug resistant focal epilepsy: five with type II focal cortical dysplasia and four with hippocampal sclerosis. Moreover, we applied different quantitative measures to evaluate the level of synchronization at the local and global scale during phasic and tonic REM sleep. We found a lower spike rate in phasic REM sleep, both within and outside the seizure onset zone. This effect seems to be independent from the histopathological substrate and from the brain region, where epileptic activity is produced (temporal versus extra-temporal). A higher level of synchronization was observed during tonic REM sleep both on a large (global) and small (local) spatial scale. Phasic REM sleep appears to be an interesting model for understanding the mechanisms of suppression of epileptic activity.

Preliminary performance data of the RHE/IL-18 assay performed on SkinEthic™ RHE for the identification of contact sensitizers.

OBJECTIVE: The purpose of this study was to evaluate the performances of the RHE/IL-18 assay using the SkinEthic™ RHE model for the identification of contact sensitizers. METHODS: A set of 18 substances and mixtures was tested on this epidermal model, following the RHE/IL-18 protocol. The final results of the assay were obtained following 5 interpretation schemes, to determine the optimal prediction model for this assay with this specific test system. The data were analysed with a special focus on the basal level of IL-18 release and on the performance obtained with respect to three different gold standards: LLNA, HRIPT and an integrated reference, constructed from all available results. RESULTS: No important differences were found in the performance levels depending on the three gold standards. The performances obtained with the SkinEthic™ RHE model support that this model may be considered as an alternative to different reconstructed epidermis models (EpiDERM™ , EpiCS™ and VUMC-EE) for the performance of RHE/IL-18 assays. CONCLUSION: The prediction model to be used was refined, and more substances have to be tested in order to gather enough data for this evaluation and to determine the right criteria applicable for this assay using the SkinEthic™ RHE test system.

Fluid boundaries between wake and sleep: experimental evidence from Stereo-EEG recordings.

Sleep and waking have been traditionally considered global behavioural states regulated by subcortical neuromodulatory circuits in a top-down fashion. Over the last years, we have been experiencing a paradigm shift towards a view that both wake and sleep are in essence local processes. Here we review recent clinical and basic research works supporting this view by taking advantage of stereotactic electroencephalography (Stereo-EEG, SEEG) recordings performed in epileptic patients. Specifically, we will discuss a growing body of evidence showing how electrophysiological features of sleep and wakefulness are coexisting across diffuse brain areas in pathological and physiological sleep as well as during state transitions (sleep onset and awakenings). Finally, we will discuss their implication for sleep medicine to extent that, reconsidering the classical definition of wakefulness and sleep as separate and mutually exclusive states may offer new insight for the understanding of parasomnias and other dissociated states.

Renal transplantation in systemic amyloidosis-importance of amyloid fibril type and precursor protein abundance.

Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty-nine percent of patients with end-stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A-I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post-RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history.

Timing of supplementation alters grazing behavior and milk production response in dairy cows.

Offering feed supplements to grazing dairy cows results in substitution of pasture; however, previous data indicate that the time at which concentrate supplements are offered might affect the level of substitution. These data indicated that cows grazed more intensely presunset, regardless of the amount of supplement offered. It was, therefore, hypothesized that substitution rate would be less, and response to supplement greater if cows received their supplement at the p.m. rather than the a.m. milking. Forty-eight multiparous, nonpregnant, Holstein-Friesian cows, approximately 60 d in milk, were randomly allocated to 1 of 3 treatments in an incomplete crossover arrangement. Treatments were pasture only, pasture + 3 kg of concentrate supplement dry matter (DM) offered during the a.m. milking (AM-SUP), and pasture + 3 kg of concentrate supplement DM offered during the p.m. milking (PM-SUP). Time spent grazing and calculated pasture DM intake did not differ between the AM-SUP and PM-SUP cows. However, a tendency (0.18 kg of milk/kg of concentrate DM) was observed for an increased marginal milk response (kg of milk/kg of DM supplement) for the AM-SUP cows when compared with PM-SUP cows. Irrespective of when supplements were offered, supplementation reduced total grazing time by a similar amount, and the reduction in time spent grazing was evident throughout the day. Cows in the PM-SUP group ruminated for longer and cows in the AM-SUP group spent more time idle compared with the pasture only groups. Cows in the AM-SUP group grazed for less time during the major a.m. grazing bout following a.m. milking compared with PM-SUP cows; in comparison, the major p.m. grazing bout following p.m. milking was unaffected by supplementation. The results indicated possible improvements in marginal milk response to supplements from altering the timing of delivery.

Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation.

OBJECTIVES: Lysozyme amyloidosis (ALys) is a form of hereditary systemic non-neuropathic amyloidosis, which is inherited in an autosomal dominant fashion. Lysozyme, which is the amyloidogenic precursor protein in ALys, is a ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and macrophages. The aim of this study is to describe the phenotype and outcome of patients with ALys including the role of solid organ transplantation. DESIGN: Retrospective evaluation of patients with ALys. SETTING: UK National Amyloidosis Centre. PATIENTS: All 16 patients with ALys followed at the centre. RESULTS: A family history of amyloidosis was present in every affected individual. Although the phenotype was broadly similar amongst those from the same kindred, there were marked phenotypic differences between kindreds who possessed the same amyloidogenic mutation. Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically visible amyloidotic lesions were present in nine of 10 patients who underwent GI endoscopy. All symptomatic ALys individuals had hepatic amyloid. Four patients received orthotopic liver transplants (OLT), three for spontaneous hepatic rupture and one case, who had extensive hepatic amyloid and a strong family history of hepatic rupture, pre-emptively. All of the liver grafts were functioning at censor 1.7, 5.8, 9.0 and 11.0 years after OLT. Five patients had progressive amyloidotic renal dysfunction culminating in end-stage renal failure, three of whom underwent renal transplantation (RTx). There was no evidence of renal allograft dysfunction at censor 6.6, 1.8 and 0.8 years after RTx. CONCLUSIONS: Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which has a slow natural history. There was a clear family history in all cases within this cohort, demonstrating a high clinical penetrance in the presence of an amyloidogenic lysozyme mutation. There is currently no amyloid-specific therapy for the condition which is managed symptomatically. OLT and RTx appear to be successful treatments for patients with liver rupture or end-stage renal disease, respectively, with excellent outcomes in terms of medium-term graft function and patient survival.

Efficacy of topical treatments for cutaneous warts: a meta-analysis and pooled analysis of randomized controlled trials.

Many topical treatments for cutaneous warts exist and previous reviews of trials did not follow intention-to-treat (ITT) principles for analysis. We aimed to perform a meta-analysis and pooled analysis of randomized controlled trials (RCTs) of topical treatment for cutaneous warts using ITT principles. Systematic electronic searches (Cochrane library, Medline, Embase, Clinical trial registers) were conducted in May 2009. Included trials reported completed cure of warts and data were extracted from these trials. We performed random-effects meta-analysis and assessed heterogeneity using the I(2) statistic and conducted a pooled analysis of each treatment. We found 77 relevant studies of which the majority were of low methodological quality. Salicylic acid (SA) was superior to placebo with a risk ratio (RR) for cure of 1·60 [95% confidence interval (CI) 1·15-2·24]. Cryotherapy was not statistically better than placebo, RR 0·89 (95% CI 0·27-2·92), but aggressive cryotherapy was significantly better than gentle cryotherapy with a RR of 2·06 (95% 1·20-3·52). Combined therapy of SA and cryotherapy had a higher cure rate than either SA or cryotherapy alone. The results of the pooled analysis found a cure rate of 23% (5-73%) in placebo trials, 52% (0-87%) in SA trials, 49% (0-69%) in cryotherapy trials, 54% (45-75%) in aggressive cryotherapy trials and 58% (38-78%) in the combined cryotherapy and SA trials. Aside from the use of SA and aggressive cryotherapy there is insufficient evidence from RCTs to support the use of other therapies. Higher quality evidence is needed to evaluate other therapies.