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Biomedical subjects

P Fitzgerald

Publications and source records attributed to P Fitzgerald.

At least 19 recordsLinked to original sources

A comparison of the SNAP II and BIS XP indices during sevoflurane and nitrous oxide anaesthesia at 1 and 1.5 MAC and at awakening.

BACKGROUND: Monitoring level of consciousness during anaesthesia, with the ability to predict the intentional or unintentional return to consciousness, is desirable. The purpose of this study was to compare two processed electroencephalographic depth of anaesthesia monitors (SNAP II and BIS XP) during sevoflurane and sevoflurane/nitrous oxide anaesthesia. METHODS: In total, 42 subjects received an interscalene block, followed by general anaesthesia with sevoflurane or sevoflurane/nitrous oxide. The indices were recorded at baseline, at 1.5 and 1.0 minimum alveolar concentration (MAC) equivalents, and during emergence. RESULTS: The SNAP and BIS indices decreased from baseline at 1.5 and 1.0 MAC equivalents, but there was no difference within groups between subjects who received nitrous oxide and those who did not. The SNAP index returned to baseline by 1 min before awakening and was higher than baseline at eye opening, but the BIS index remained below baseline at awakening. There was a bias of -1 (95% CI: -3 to 1) between the SNAP and BIS at baseline; this increased to 21 (95% CI: 19-23) during maintenance of anaesthesia and was 6 (95% CI: 4-8) at awakening. CONCLUSIONS: The SNAP index tracks loss of consciousness and emergence from sevoflurane and sevoflurane/nitrous oxide anaesthesia. There is significant bias between the SNAP and BIS indices and therefore, the indices are not interchangeable. The SNAP index returns to baseline before awakening, whereas the BIS index remains below baseline at awakening, suggesting that the SNAP index may be more sensitive to unintentional awareness.

Adolescent↗

Anxiety and performance in elite non-professional athletes.

Anxiety is one of the main motivators with regards to performance of individuals in any given task, including sporting endeavours. Our study sought to assess state anxiety levels in elite non-professional sportsmen, and to investigate if anxiety correlated with sporting performance, the IDA-Q (irritability, depression & anxiety questionnaire) was used to assess 3 mental state variables in an inter-county hurling team as well as a matched non-sporting control group, and performance was judged by completion of a standard task in 2 different settings: a non-pressurised one and a highly pressurised setting. Subjects had significantly higher anxiety scores on the IDA-Q than the controls (p = 0.019). There were no significant differences and controls in the depression and irritability scales. There was a significantly negative correlation between anxiety scores and performance on the IDA-Q; spearman r = -0.57. High anxiety levels impair sporting performance.

Anxiety↗

Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.

PURPOSE: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally. DESIGN: Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes. RESULTS: A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).

Antineoplastic Combined Chemotherapy Protocols↗

Hydroxy-methylglutaryl-coenzyme A reductase inhibition improves endothelial dysfunction in type-1 diabetes.

OBJECTIVE: We hypothesize that treatment with Pravastatin, a HMG CoA reductase inhibitor would improve flow-mediated dilation (FMD), a nitric oxide dependent phenomenon and the earliest detectable marker of endothelial dysfunction, in asymptomatic patients with type-1 diabetes. MATERIALS AND METHODS: FMD of the brachial artery in response to reactive hyperaemia was measured using high-resolution ultrasonography. Young male patients with type-1 diabetes (n=9) were compared with age matched non-diabetic controls (n=8). RESULTS: The FMD response in the control group was a median increase in diameter of 7.9 (range 3.8-12.6)%. In the diabetic group the FMD response was impaired when compared with controls with a median increase only of 4.4 (range 3.7-5.8)% (p<0.01). Following Pravastatin, 40 mg per day for one month in the diabetic group, there was a significant diameter change in response to reactive hyperaemia with a median of 8.4 (range 6.9-12.6)% (p<0.01). CONCLUSIONS: These data confirm the presence of endothelial dysfunction in young patients with type-1 diabetes. We have shown that 1-month of Pravastatin treatment normalizes FMD. This suggests that HMG CoA reductase inhibitors may have a role in the management of diabetes mellitus, even in the presence of normal serum cholesterol levels.

Adolescent↗

A randomized controlled trial to evaluate the effectiveness and cost-effectiveness of psychodynamic counselling for general practice patients with chronic depression.

BACKGROUND: Counsellors have been employed in general practice with little evidence of effectiveness. This study examined the effectiveness and cost-effectiveness of short-term counselling in general practice for patients with chronic depression either alone or combined with anxiety. METHOD: A randomized controlled trial with an economic evaluation was carried out in Derbyshire. One hundred and forty-five patients were recruited at seven GP practices by screening using the Beck Depression Inventory. Both the experimental and control group received routine GP treatment but the experimental group were also referred to the practice counsellor. Depression, anxiety and other mental health symptoms, social and interpersonal functioning and social support were measured at baseline, 6 months and 12 months. Comprehensive costs were also estimated. RESULTS: There was an overall significant improvement in the actual scores over time, but there were no significant differences between the two groups on any of the measures at either 6 or 12 months. However fewer experimental group patients were still 'cases' on the BDI than controls at 12 months. There were no significant differences in the mean total costs, aggregate costs of services, or any service-group costs except for primary care, between the experimental and control groups over time. CONCLUSIONS: This trial demonstrates only very limited evidence of improved outcomes in those referred to counselling and increased primary care treatment costs in the short-term. Stricter referral criteria to exclude the more severely depressed in the group (BDI > or = 24) might have yielded more conclusive results.

Adolescent↗

The early increase in intestinal permeability and systemic endotoxin exposure in patients with severe acute pancreatitis is not associated with systemic bacterial translocation: molecular investigation of microbial DNA in the blood.

INTRODUCTION: Sepsis is the main cause of late mortality in patients with severe acute pancreatitis and is largely attributed to secondary infection of pancreatic necrosis with gram-negative enteric organisms. This is commonly preceded by a significant increase in intestinal colonization with such microbes and with early increases in intestinal permeability, thus suggesting a mechanism of bacterial translocation. Whilst cultures of blood specimens from these patients often remain sterile, it is conceivable that bacteria might translocate in small volumes with detrimental effects but elude detection by standard microbial culture techniques. AIMS: To investigate the incidence and frequency with which bacterial DNA may exist in the systemic circulation of patients with acute pancreatitis and to relate that to disease severity, changes in intestinal permeability, and systemic endotoxin exposure. METHODOLOGY: Blood samples were obtained at admission and on days 3 and 7 from 26 patients with acute pancreatitis (seven with severe cases) and from 10 healthy controls for DNA extraction and standard microbial cultures. Polymerase chain reaction techniques were used to amplify a gene region (16S ribosomal RNA) found in all bacteria. Levels of serum endotoxin and antibodies to endotoxin core (EndoCAb) were measured at admission, and intestinal permeability to the macromolecule polyethylene glycol 3350 was determined within 72 hours of the onset of symptoms. RESULTS: Blood cultures yielded and enterococci for one patient with a severe attack and coagulase-negative staphylococci for another patient with a mild attack. No bacterial DNA was found in any of the samples. Endotoxemia was detected in 20 patients (five with severe cases), and levels of serum IgM EndoCAb were depleted in patients with severe attacks but remained relatively unchanged during mild attacks (p = 0.033). Intestinal permeability was significantly increased in patients with severe attacks of acute pancreatitis but remained unchanged during mild attacks (p < 0.05). CONCLUSIONS: Whilst severe attacks of acute pancreatitis are associated with early derangement in gut barrier function and systemic endotoxin translocation, there is no molecular evidence for associated bacterial "translocation."

Acute Disease↗

Oral folic acid improves endothelial dysfunction in cigarette smokers.

INTRODUCTION: Endothelial dysfunction is an early manifestation of the atheromatous process and is evident without overt clinical signs or symptoms of the disease. Cigarette smoking has been shown to be associated with endothelial dysfunction in otherwise healthy adults. Although cessation of smoking is the ideal objective, it is not always attainable, and therefore any strategy to prevent early endothelial dysfunction is desirable. Folic acid is currently under review as a rational therapeutic agent in hyperhomocysteinemia. However, folic acid may modify endothelial function independent of its effect on homocysteine. We therefore investigated the effect of folic acid on endothelial function in young otherwise healthy cigarette smokers. METHODS: Volunteer cigarette smokers (n = 10) and control lifelong nonsmokers were enrolled in the study. Baseline folate, vitamin B12, homocysteine, and cholesterol levels were analyzed. Flow-mediated dilatation, an endothelial-dependent phenomenon, was assessed using ultrasonography. This scan was performed at baseline and following 4 weeks of folic acid supplementation (5 mg/day). RESULTS: There were no significant differences in the baseline hematological investigations between the groups. Homocysteine levels were within normal limits in both groups and did not change following folic acid supplementation. Cigarette smokers demonstrated significant endothelial dysfunction compared to controls (P < 0.005). This difference was significantly attenuated by folic acid supplementation (P < 0.005). CONCLUSION: Folic acid significantly improves endothelial function in otherwise healthy cigarette smokers. This provides a potential therapeutic tool in attenuating the atheromatous process in this group.

Administration, Oral↗

Comparison of PRE-dilatation vs direct stenting in coronary treatment using the Medtronic AVE S670 Coronary Stent System (the PREDICT trial).

Current stent delivery systems make primary stenting (stent placement without predilatation) possible, but few controlled trials have been performed to evaluate the success, safety, cost saving, and potential benefit of this approach in reducing late restenosis. The Comparison of PRE-Dilatation Versus Direct Stenting In Coronary Treatment using the Medtronic AVE S670 Coronary Stent System trial was a 399-patient study comparing results with the Medtronic-AVE S670 stent to objective performance criteria based on prior approved stents, with subrandomization to direct stenting versus stenting after balloon predilatation. Overall, results with the S670 stent showed excellent success and safety, with delivery success of 99%, a 14-day adverse event rate of 6.8% (including 6.5% non-Q-wave myocardial infarction), and favorable angiographic (20%) and clinical (12%) restenosis rates. Direct stenting was successful in 92% of cases, with a 99.5% secondary success rate including additional pretreatment of initially unsuccessful direct-stenting attempts, and no increase in complications. There were modest ( approximately 10%) savings in fluoroscopy time, contrast use, and a decrease in angioplasty balloon use (0.6 vs 1.3 balloons/case), but no reduction in clinical or angiographic restenosis. Patients treated later in the study, with a device that had less balloon extension beyond the edges of the stent, had slightly lower angiographic restenosis rates (19% vs 23%). In conclusion, the S670 stent showed excellent overall performance. Although direct stenting was safe and highly successful, it offered only modest cost savings, and no reduction in late restenosis compared with stenting after predilatation.

Catheterization↗

Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity.

Apoptosis via the mitochondrial pathway requires release of cytochrome c into the cytosol to initiate formation of an oligomeric apoptotic protease-activating factor-1 (APAF-1) apoptosome. The apoptosome recruits and activates caspase-9, which in turn activates caspase-3 and -7, which then kill the cell by proteolysis. Because inactivation of this pathway may promote oncogenesis, we examined 10 ovarian cancer cell lines for resistance to cytochrome c-dependent caspase activation using a cell-free system. Strikingly, we found that cytosolic extracts from all cell lines had diminished cytochrome c-dependent caspase activation compared with normal ovarian epithelium extracts. The resistant cell lines expressed APAF-1 and caspase-9, -3, and -7; however, each demonstrated diminished APAF-1 activity relative to the normal ovarian epithelium cell lines. A competitive APAF-1 inhibitor may account for the diminished APAF-1 activity because we did not detect dominant APAF-1 inhibitors, altered APAF-1 isoform expression, or APAF-1 deletion, degradation, or mutation. Lack of APAF-1 activity correlated in some but not all cell lines with resistance to apoptosis. These data suggest that regulation of APAF-1 activity may be important for apoptosis regulation in some ovarian cancers.

Apoptosis↗

Development of interstitial cells of Cajal in a full-term infant without an enteric nervous system.

The relationship between the development of the enteric nervous system and interstitial cells of Cajal (ICC) in the human small intestine was investigated in a full-term infant who presented with intestinal pseudo-obstruction. Immunohistochemistry revealed absence of enteric nerves and ganglia but abundant c-Kit immunoreactivity associated with Auerbach's plexus (ICC-AP). However, c-Kit immunoreactivity associated with the deep muscular plexus (ICC-DMP) and intermuscular ICC was absent. Electron microscopy showed ICC-AP with a normal ultrastructure; ICC-DMP were seen but were severely injured, suggesting degeneration. In vitro recording of intestinal muscle showed slow wave activity as well as response to cholinergic stimulation. Fluoroscopic examination of the small bowel showed a variety of motor patterns, including rhythmic, propagating contractions. In conclusion, total absence of enteric nerves was associated with absence of normal ICC-DMP. However, a normal musculature, including a network of ICC-AP, allowed for generation of rhythmic, propagating contractile activity, suggesting the presence of functional motor activity.

Biological Clocks↗

Training general surgery residents in pediatric surgery: A Canadian survey.

BACKGROUND/PURPOSE: The training of general surgeons in pediatric surgery is an important educational role of pediatric surgeons (PS). The authored surveyed this training process and the related expectations and perceptions of competence. METHODS: The authors surveyed all practicing members of the Canadian Association of Paediatric Surgeons (CAPS) in Canada, all general surgery program directors (PD), and all final year general surgery residents (GS). Questions included exposure to pediatric surgery, expected and perceived competence in managing common pediatric general surgical problems, and trainee practice intentions. RESULTS: Response rate to date was 51% from PS, 69% from PD, and 19% from GS. Sixty-seven percent of PS considered the exposure to pediatric surgery satisfactory, yet only 1 of 7 residents planning on pursuing general surgery felt adequately prepared. Trainees were expected to be competent in the conditions polled by 65% of PS and 74% of PD, yet only 38% of the trainees actually felt competent in them. The largest discrepancies were found for infant hernia, newborn colostomy, and cryptorchidism. Presence of a fellowship program and size of training program had no impact on perceived competence. CONCLUSIONS: Training of general surgeons in pediatric surgery varies across Canadian programs. Perceived resident competence often lags behind program and faculty expectations. These data can be used for directing educational priorities in general surgery programs.

Attitude of Health Personnel↗

Photoangioplasty for human peripheral atherosclerosis: results of a phase I trial of photodynamic therapy with motexafin lutetium (Antrin).

BACKGROUND: In photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a study designed to evaluate the safety and tolerability of a new photosensitizer, Antrin (motexafin lutetium), in the endovascular treatment of atherosclerosis. METHODS AND RESULTS: An open-label, single-dose, escalating drug- and light-dose study was performed in patients with atherosclerotic peripheral arterial insufficiency. Clinical evaluation, serial quantitative angiography, and intravascular ultrasonography were performed. Therapy was well tolerated, and only minor side effects were observed. Treatment produced no deleterious vascular effects. Although this study was not designed to examine clinical efficacy, several secondary end points suggested a favorable therapeutic effect. CONCLUSIONS: This phase I study demonstrates that photoangioplasty with motexafin lutetium is well tolerated and safe. Preliminary efficacy data suggest a future role for the treatment of flow-limiting atherosclerosis.

Humans↗

Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis.

BACKGROUND: Treatment of in-stent restenosis presents a critical limitation of intracoronary stent implantation. Ionizing radiation has been shown to decrease neointimal formation within stents in animal models and in initial clinical trials. We studied the effects of intracoronary gamma-radiation therapy versus placebo on the clinical and angiographic outcomes of patients with in-stent restenosis. METHODS AND RESULTS: One hundred thirty patients with in-stent restenosis underwent successful coronary intervention and were then blindly randomized to receive either intracoronary gamma-radiation with (192)Ir (15 Gy) or placebo. Four independent core laboratories blinded to the treatment protocol analyzed the angiographic and intravascular ultrasound end points of restenosis. Procedural success and in-hospital and 30-day complications were similar among the groups. At 6 months, patients assigned to radiation therapy required less target lesion revascularization and target vessel revascularization (9 [13.8%] and 17 [26.2%], respectively) compared with patients assigned to placebo (41 [63.1%, P=0.0001] and 44 [67.7%, P=0.0001], respectively). Binary angiographic restenosis was lower in the irradiated group (19% versus 58% for placebo, P=0.001). Freedom from major cardiac events was lower in the radiation group (29.2% versus 67.7% for placebo, P<0.001). CONCLUSIONS: Intracoronary gamma-radiation used as adjunct therapy for patients with in-stent restenosis significantly reduces both angiographic and clinical restenosis.

Aged↗

p53 induces apoptosis by caspase activation through mitochondrial cytochrome c release.

The p53 tumor suppressor gene is critically involved in cell cycle regulation, DNA repair, and programmed cell death. Several lines of evidence suggest that p53 death signals lead to caspase activation; however, the mechanism of caspase activation by p53 still is unclear. Expressing wild type p53 by means of an adenoviral expression vector, we were able to induce apoptotic cell death, as characterized by morphological changes, phosphatidylserine externalization, and internucleosomal DNA fragmentation, in p53(null) Saos-2 cells. This cell death was accompanied by caspase activation as well as by cleavage of caspase substrates and was preceded by mitochondrial cytochrome c release. The addition of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-fmk) directly after transduction almost completely prevented p53-induced apoptotic cell death but did not inhibit mitochondrial cytochrome c release. In contrast, N-acetylcysteine, even at high concentrations, could not prevent induction of programmed cell death by p53 expression. Cytosolic extracts from Saos-2 cells transduced with p53, but not from Saos-2 cells transduced with the empty adenoviral vector, contained a cytochrome c-releasing activity in vitro, which was still active in the presence of zVAD-fmk. When Bax was immunodepleted from the cytosolic extracts of p53-expressing cells before incubation with isolated mitochondria, the in vitro cytochrome c release was abolished. Thus, we could demonstrate in cells and in vitro that p53 activates the apoptotic machinery through induction of the release of cytochrome c from the mitochondrial intermembrane space. Furthermore, we provide in vitro evidence for the requirement of cytosolic Bax for this cytochrome c-releasing activity of p53 in Saos-2 cells.

Acetylcysteine↗

The PRESTO (Prevention of restenosis with tranilast and its outcomes) protocol: a double-blind, placebo-controlled trial.

BACKGROUND: Tranilast is a unique drug in clinical development for the prevention of restenosis after percutaneous transluminal coronary revascularization (PTCR). Tranilast interferes with proliferation and migration of vascular medial smooth muscle cells induced by platelet-derived growth factor and transforming growth factor beta1. Collagen synthesis in vascular medial smooth muscle cells is inhibited by tranilast, which also inhibits the release or production of cyclooxygenase-2 and restores cytokine-induced nitric oxide production. These mechanisms may contribute to the reduction of angiographic restenosis after coronary intervention previously reported in clinical studies. METHODS: The primary objective of this multicenter study of 11,500 patients is to compare the composite clinical event rate of death, myocardial infarction, or the need for ischemia-driven target vessel revascularization of tranilast (300 and 450 mg twice daily) for 1 or 3 months with that of placebo in patients undergoing PTCR with or without stenting for single or multiple vessels over a 9-month period. The lesions can be de novo or restenotic. All revascularization procedures and the use of glycoprotein IIb/IIIa agents are permitted. The inclusion criteria are meant to allow an "all comer" approach for generalization of results to the broadest possible PTCR population. A subset population (n = 2000) will undergo 9-month follow-up angiography, 1000 of which will also undergo intravascular ultrasound (n = 1000). This study is the first tranilast trial to be conducted in a Western population to confirm the improved angiographic findings reported in Japanese patients and to determine if the clinical sequelae of restenosis are also reduced. CONCLUSION: This multicenter study is the largest restenosis trial planned to date. It will test whether tranilast, a drug with multiple actions aimed at affecting proliferation and migration of vascular smooth muscle cells, can reduce clinical, angiographic, and intravascular ultrasound assessments of restenosis.

Adolescent↗

A five year outbreak of methicillin-susceptible Staphylococcus aureus phage type 53,85 in a regional neonatal unit.

We identified a 5-year outbreak of a methicillin-susceptible Staphylococcus aureus (MSSA) strain, affecting 202 babies on a neonatal unit, by routine weekly phage typing all S. aureus isolates. Multiple staged control measures including strict emphasis on hand hygiene, environmental and staff surveillance sampling, and application of topical hexachlorophane powder failed to end the outbreak. S. aureus PT 53,85 (SA5385) was found on opened packs of Stomahesive, used as a neonatal skin protectant. Only following the implementation of aseptic handling of Stomahesive, and the use of topical mupirocin for staff nasal carriers of SA5385, and for babies colonized or infected with S. aureus, did the isolation rate of SA5385 decline. DNA fingerprinting indicated that > or =, 95% of SA5385 isolates were clonal. In vitro death rates of SA5385 on Stomahesive with human serum were significantly lower than on Stomahesive alone (P = 0.04), and on cotton sheet with serum (P = 0.04), highlighting the potential of this material as a survival niche. Phage typing remains a valuable, inexpensive and simple method for monitoring nosocomial MSSA infection.

Bacteriophage Typing↗

Review of closed dressings after laser resurfacing.

BACKGROUND: Laser skin resurfacing has become an accepted technique for the treatment of facial rhytides and associated solar skin damage. Achieving a successful result is directly related to proper postoperative wound care during the reepithelialization process. There are open and closed approaches to the treatment of the post-laser resurfacing patient with distinct advantages and disadvantages. OBJECTIVE: To review the most commonly used closed dressings after facial laser skin resurfacing and compare their advantages and disadvantages. To compare clinical findings with a group of patients treated exclusively with an open technique. METHODS: Review of composite foams, polymer film, polymer mesh, and hydrogel products and prospective observations of clinical outcomes of patients treated with each dressing category after facial laser skin resurfacing. We perform a retrospective chart review of a group of patients treated exclusively with an open technique comparing crust formation, comfort, and pruritus with the prospective group of patients treated with closed dressings. RESULTS: The closed dressings available today each have unique structural configurations and adhesive properties intended to maintain an occlusive wound environment. Patient acceptance of these dressings was favorable, with improved comfort compared to the open dressing group. Complications of bacterial infections and contact dermatitis were not observed when closed dressings were used with a protocol for dressing changes performed at 48 hours. Rates of reepithelialization did not vary according to dressing category. Crust formation and postoperative pruritus occurred less frequently when closed occlusive dressings were worn by patients. CONCLUSIONS: When used properly, these dressings improve patient comfort, simplify their postoperative wound care, and do not increase the risk of infection or contact dermatitis. Overall satisfaction was highest with perforated mesh and polymer dressings for full-face wounds.

Adult↗