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1.
Ann Vasc Surg ; 93: 428-436, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36708765

ABSTRACT

BACKGROUND: Through-knee amputation (TKA) carries potential biomechanical advantages over above knee amputation (AKA) in patients unsuitable for a below-knee amputation. However, concerns regarding prosthetic fit, cosmesis and wound healing have tempered enthusiasm for the operation. Furthermore, there are many described surgical techniques for performing a TKA. This frustrates attempts to compare past and future comparative data, limiting the opportunity to identify which procedure is associated with the best patient centered outcomes. The aim of this systematic review is to identify all the recognized operative TKA techniques described in the literature and to develop a clear descriptive system to support future research in this area. METHODS: A systematic review was performed, searching the OVID, PubMed, and Cochrane Library databases, according to Cochrane and PRISMA guidelines. Papers of any design were included if they described an operative technique for a TKA. Key operative descriptions were captured and used to design a classification system for surgical techniques. RESULTS: A total of 906 papers were identified, of which 28 are included. The most important distinctions in operative technique were the level of division of the femur (disarticulation without bone division, transcondylar amputation, with or without shaving of the medial, lateral, and posterior condyles and supracondylar amputation), management of the patella (kept whole, partially preserved, completely removed), use of a muscular gastrocnaemius flap, and skin incisions. A 4-component classification system was developed to be able to describe TKA operative techniques. A suggested shorthand nomenclature uses the first letter of each component (FPMS; Femur, Patella, Muscular flap, Skin incision), followed by a number, to describe the operation. Patient outcomes were poorly reported, and therefore outcomes for different types of TKA are not addressed in this review. CONCLUSIONS: A novel descriptive system for describing different techniques for performing a TKA has been developed. This classification system will help in reporting, comparing, and interpreting past and future studies of patients undergoing TKA.


Subject(s)
Amputation, Surgical , Disarticulation , Humans , Disarticulation/methods , Treatment Outcome , Lower Extremity/surgery , Reoperation , Knee Joint/surgery
2.
Br J Dermatol ; 187(2): 149-158, 2022 08.
Article in English | MEDLINE | ID: mdl-34726774

ABSTRACT

This review highlights the range of therapeutic options available to clinicians treating difficult-to-heal wounds. While certain treatments are established in daily clinical practice, most therapeutic interventions lack robust and rigorous data regarding their efficacy, which would help to determine when, and for whom, they should be used. The purpose of this review is to give a broad overview of the available interventions, with a brief summary of the evidence base for each intervention.


Subject(s)
Wound Healing , Humans
4.
BJS Open ; 4(1): 16-26, 2020 02.
Article in English | MEDLINE | ID: mdl-32011813

ABSTRACT

BACKGROUND: The accuracy with which surgeons can predict outcomes following surgery has not been explored in a systematic way. The aim of this review was to determine how accurately a surgeon's 'gut feeling' or perception of risk correlates with patient outcomes and available risk scoring systems. METHODS: A systematic review was undertaken in accordance with PRISMA guidelines. A narrative synthesis was performed in accordance with the Guidance on the Conduct of Narrative Synthesis In Systematic Reviews. Studies comparing surgeons' preoperative or postoperative assessment of patient outcomes were included. Studies that made comparisons with risk scoring tools were also included. Outcomes evaluated were postoperative mortality, general and operation-specific morbidity and long-term outcomes. RESULTS: Twenty-seven studies comprising 20 898 patients undergoing general, gastrointestinal, cardiothoracic, orthopaedic, vascular, urology, endocrine and neurosurgical operations were included. Surgeons consistently overpredicted mortality rates and were outperformed by existing risk scoring tools in six of seven studies comparing area under receiver operating characteristic (ROC) curves (AUC). Surgeons' prediction of general morbidity was good, and was equivalent to, or better than, pre-existing risk prediction models. Long-term outcomes were poorly predicted by surgeons, with AUC values ranging from 0·51 to 0·75. Four of five studies found postoperative risk estimates to be more accurate than those made before surgery. CONCLUSION: Surgeons consistently overestimate mortality risk and are outperformed by pre-existing tools; prediction of longer-term outcomes is also poor. Surgeons should consider the use of risk prediction tools when available to inform clinical decision-making.


ANTECEDENTES: La precisión con la cual los cirujanos pueden predecir los resultados de la cirugía no se ha estudiado de forma sistemática. El objetivo de esta revisión fue determinar con qué precisión la intuición de un cirujano o su percepción del riesgo se correlacionaba con los resultados del paciente y con los sistemas de puntuación del riesgo disponibles. MÉTODOS: Se efectuó una revisión sistemática siguiendo las directrices PRISMA. Se realizó una síntesis narrativa de acuerdo con la guía para la realización de síntesis narrativas en revisiones sistemáticas. Se incluyeron los estudios que comparaban las evaluaciones preoperatorias o postoperatorias de los cirujanos respecto a los resultados de los pacientes. También se incluyeron aquellos estudios en los que se hacían comparaciones con herramientas de puntuación de riesgo. Se evaluaron la mortalidad postoperatoria, la morbilidad global y la morbilidad específica de las intervenciones, y los resultados a largo plazo. RESULTADOS: Se incluyeron 27 estudios con 20.898 pacientes en los que se realizaron procedimientos de cirugía general, digestiva, cardiotorácica, ortopédica, vascular, urológica, endocrina y neurocirugía. Los cirujanos predijeron consistentemente mayores tasas de mortalidad, siendo superados en precisión por los sistemas de estimación del riesgo existentes en seis de los siete estudios que utilizaron el área bajo la curva (area under curve, AUC) operativa del receptor. La predicción de la morbilidad general por parte de los cirujanos fue buena y era equivalente, incluso mejor, que los modelos de predicción de riesgos preexistentes. La capacidad de los cirujanos para predecir los resultados a largo plazo fue pobre, con una AUC que oscilaba entre 0,51 y 0,75. Cuatro de cinco estudios encontraron que las estimaciones de riesgo postoperatorias fueron más precisas que las realizadas preoperatoriamente. CONCLUSIÓN: Los cirujanos sobrestiman consistentemente el riesgo de mortalidad, siendo superados en precisión por las herramientas preexistentes. La predicción de resultados a largo plazo también es muy pobre. Los cirujanos deberían considerar el uso de herramientas de predicción de riesgo cuando estén disponibles para informar en el proceso de decisión clínica.


Subject(s)
Risk Assessment , Surgeons , Surgical Procedures, Operative/adverse effects , Surgical Procedures, Operative/mortality , Humans , Morbidity , Postoperative Complications/etiology , Postoperative Complications/mortality , Risk Factors
5.
Br J Surg ; 106(8): 1035-1042, 2019 07.
Article in English | MEDLINE | ID: mdl-31095725

ABSTRACT

BACKGROUND: Chronic venous leg ulcers pose a significant burden to healthcare systems, and predicting wound healing is challenging. The aim of this study was to develop a genetic test to evaluate the propensity of a chronic ulcer to heal. METHODS: Sequential refinement and testing of a gene expression signature was conducted using three distinct cohorts of human wound tissue. The expression of candidate genes was screened using a cohort of acute and chronic wound tissue and normal skin with quantitative transcript analysis. Genes showing significant expression differences were combined and examined, using receiver operating characteristic (ROC) curve analysis, in a controlled prospective study of patients with venous leg ulcers. A refined gene signature was evaluated using a prospective, blinded study of consecutive patients with venous ulcers. RESULTS: The initial gene signature, comprising 25 genes, could identify the outcome (healing versus non-healing) of chronic venous leg ulcers (area under the curve (AUC) 0·84, 95 per cent c.i. 0·73 to 0·94). Subsequent refinement resulted in a final 14-gene signature (WD14), which performed equally well (AUC 0·88, 0·80 to 0·97). When examined in a prospective blinded study, the WD14 signature could also identify wounds likely to demonstrate signs of healing (AUC 0·73, 0·62 to 0·84). CONCLUSION: A gene signature can identify people with chronic venous leg ulcers that are unlikely to heal.


Subject(s)
Genetic Testing/methods , Leg Ulcer/genetics , Transcriptome , Wound Healing/genetics , Adult , Biopsy , Humans , Leg Ulcer/pathology , Leg Ulcer/physiopathology , ROC Curve , Reproducibility of Results , Sensitivity and Specificity
6.
Eur J Vasc Endovasc Surg ; 57(2): 311-317, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30172663

ABSTRACT

OBJECTIVE: To explain the angiosome concept and explore the practical application of the angiosome literature to a clinical scenario, in this case a tibial angioplasty for critical ischaemia. METHODS: Clinical vignette with explanation of the decisions made and subsequent clinical results based on the theory of the angiosome concept and the literature on angiosomal revascularisation; in this case the results of our group's recent update to a systematic review and meta-analysis. RESULTS: Endovascular combined or direct angiosomal revascularisation if superior to indirect revascularisation. This was borne out in the clinical scenario, where an indirect peroneal reperfusion of the AT angiosome resulted in major amputation. Open surgery is less dependent on the angiosome concept. The presence of adequate collateralisation into a foot arch seems to be the most important factor predicting success of indirect revascularisation. The evidence for both suffers from selection bias and many of the findings in the literature are wholly due to selection bias. CONCLUSION: The angiosome concept is useful during both open and endovascular tibial revascularisation. However, the runoff in the foot is critical to success and may not follow the 'classic' angiosome model in diabetes.


Subject(s)
Angioplasty/methods , Endovascular Procedures/methods , Tibia/blood supply , Clinical Decision-Making , Evidence-Based Medicine , Humans , Middle Aged , Practice Guidelines as Topic , Tibia/surgery , Treatment Outcome
7.
Eur J Vasc Endovasc Surg ; 53(4): 534-548, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28242154

ABSTRACT

OBJECTIVE: Endovascular abdominal aortic aneurysm repair (EVAR) sometimes requires internal iliac artery (IIA) coverage to achieve a landing zone in the external iliac artery. The aim of this study was to determine complication rates following IIA exclusion. MATERIALS AND METHODS: A systematic review of key journals was undertaken from January 1980 to April 2016. Studies detailing occlusion (using coils or plugs) or coverage of the IIA with outcome data were included. Weighted means were calculated for continuous variables. Meta-analysis was performed when comparative data were available. Quality was assessed using the GRADE system. RESULTS: Sixty-one non-randomised studies (2671 patients; 2748 IIAs) were analysed. Fifteen per cent of EVARs require IIA sacrifice. Buttock claudication (BC) occurred in 27.9% of patients, although 48.0% resolved after 21.8 months. BC rates were 32.6% with coils, 23.8% with plugs, and 12.9% with coverage alone, and less with unilateral (vs. bilateral) IIA treatment (OR 0.57, 95% CI 0.36-0.91). More proximal coil placement resulted in lower rates of BC (OR 0.12, 95% CI 0.03-0.48). Erectile dysfunction occurred in 10.2% of males, with higher rates after coiling. Type II endoleaks were more frequent after covering alone; however re-interventions were rare. Significant ischaemic events (bowel/gluteal/spinal ischaemia) were very rare. Plugs were quicker to place and required less radiation (p < .001) than coils. GRADE scoring was very low for all outcomes. CONCLUSION: Overall the quality of reported data on IIA sacrifice is poor. Buttock claudication and erectile dysfunction occurred frequently after IIA sacrifice. Where both options are technically possible, plugs could be considered preferential to coils, and placed as proximally in the IIA as possible.


Subject(s)
Aortic Aneurysm, Abdominal/surgery , Blood Vessel Prosthesis Implantation , Embolization, Therapeutic , Endovascular Procedures , Iliac Artery/surgery , Aortic Aneurysm, Abdominal/mortality , Blood Vessel Prosthesis , Blood Vessel Prosthesis Implantation/adverse effects , Blood Vessel Prosthesis Implantation/instrumentation , Blood Vessel Prosthesis Implantation/mortality , Chi-Square Distribution , Embolization, Therapeutic/adverse effects , Embolization, Therapeutic/instrumentation , Embolization, Therapeutic/mortality , Endovascular Procedures/adverse effects , Endovascular Procedures/instrumentation , Endovascular Procedures/mortality , Humans , Odds Ratio , Postoperative Complications/etiology , Prosthesis Design , Risk Factors , Treatment Outcome
8.
PLoS One ; 12(2): e0172023, 2017.
Article in English | MEDLINE | ID: mdl-28199363

ABSTRACT

INTRODUCTION: Infra-popliteal angioplasty continues to be widely performed with minimal evidence to guide practice. Endovascular device selection is contentious and there is even uncertainty over which artery to treat for optimum reperfusion. Direct reperfusion (DR) targets the artery supplying the ischaemic tissue. Indirect reperfusion (IR) targets an artery supplying collaterals to the ischaemic area. Our unit practice for the last eight years has been to attempt to open all tibial arteries at the time of angioplasty. When successful, this results in both direct and indirect; or combined reperfusion (CR). The aim was to review the outcomes of CR and compare them with DR or IR alone. METHODS: An eight year retrospective review from a single unit of all infra-popliteal angioplasties was undertaken. Wound healing, limb salvage, amputation-free and overall survival data as well as re-intervention rates were captured for all patients. Subgroup analysis for diabetics was undertaken. Kaplan Meier curves are presented for survival outcomes. All odds and hazard ratios (HR) and p values were corrected for bias from confounders using multivariate analysis. RESULTS: 250 procedures were performed: 22 (9%) were CR; 115 (46%) DR and 113 (45%) IR. Amputation-free survival (HR 0.504, p = 0.039) and re-intervention and amputation-free survival (HR 0.414, p = 0.005) were significantly improved in patients undergoing CR compared to IR. Wound healing was similarly affected by reperfusion strategy (OR = 0.35, p = 0.047). Effects of CR over IR were similar when only diabetic patients were considered. CONCLUSIONS: Combined revascularisation can only be achieved in approximately 10% of patients. However, when successful, it results in significant improvements in wound healing and amputation-free survival over simple indirect reperfusion techniques.


Subject(s)
Angioplasty , Ischemia/therapy , Adult , Aged , Aged, 80 and over , Diabetes Complications/complications , Diabetes Complications/pathology , Disease-Free Survival , Female , Humans , Ischemia/mortality , Kaplan-Meier Estimate , Limb Salvage , Male , Middle Aged , Popliteal Artery/diagnostic imaging , Popliteal Artery/surgery , Proportional Hazards Models , Reperfusion , Retrospective Studies , Wound Healing
9.
Int J Surg ; 36 Suppl 1: S24-S30, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27565245

ABSTRACT

BACKGROUND: Surgical trainees are expected to demonstrate academic achievement in order to obtain their certificate of completion of training (CCT). These standards are set by the Joint Committee on Surgical Training (JCST) and specialty advisory committees (SAC). The standards are not equivalent across all surgical specialties and recognise different achievements as evidence. They do not recognise changes in models of research and focus on outcomes rather than process. The Association of Surgeons in Training (ASiT) and National Research Collaborative (NRC) set out to develop progressive, consistent and flexible evidence set for academic requirements at CCT. METHODS: A modified-Delphi approach was used. An expert group consisting of representatives from the ASiT and the NRC undertook iterative review of a document proposing changes to requirements. This was circulated amongst wider stakeholders. After ten iterations, an open meeting was held to discuss these proposals. Voting on statements was performed using a 5-point Likert Scale. Each statement was voted on twice, with ≥80% of votes in agreement meaning the statement was approved. The results of this vote were used to propose core and optional academic requirements for CCT. RESULTS: Online discussion concluded after ten rounds. At the consensus meeting, statements were voted on by 25 delegates from across surgical specialties and training-grades. The group strongly favoured acquisition of 'Good Clinical Practice' training and research methodology training as CCT requirements. The group agreed that higher degrees, publications in any author position (including collaborative authorship), recruiting patients to a study or multicentre audit and presentation at a national or international meeting could be used as evidence for the purpose of CCT. The group agreed on two essential 'core' requirements (GCP and methodology training) and two of a menu of four 'additional' requirements (publication with any authorship position, presentation, recruitment of patients to a multicentre study and completion of a higher degree), which should be completed in order to attain CCT. CONCLUSION: This approach has engaged stakeholders to produce a progressive set of academic requirements for CCT, which are applicable across surgical specialties. Flexibility in requirements whilst retaining a high standard of evidence is desirable.


Subject(s)
Certification/standards , Education, Medical, Graduate/standards , Specialties, Surgical/education , Charities , Delphi Technique , Humans , Ireland , Societies, Medical , United Kingdom
11.
Eur J Vasc Endovasc Surg ; 50(2): 241-9, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26067167

ABSTRACT

OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the effects of using an intraoperatively placed perineural catheter (PNC) with a postoperative local anaesthetic infusion on immediate and long-term outcomes after lower limb amputation. METHODS: A systematic review of key electronic journal databases was undertaken from inception to January 2015. Studies comparing PNC use with either a control, or no PNC, were included. Meta-analysis was performed for postoperative opioid use, pain scores, mortality, and long-term incidence of stump and phantom limb pain. Sensitivity analysis was performed for opioid use. Quality of evidence was assessed using the GRADE system. RESULTS: Seven studies reporting on 416 patients undergoing lower limb amputation with PNC usage (n = 199) or not (n = 217) were included. Approximately 60% were transtibial amputations PNC use reduced postoperative opioid consumption (standardised mean difference: -0.59, 95% CI -1.10 to -0.07, p = .03), maintained on sensitivity analysis for large (p = .03) and high-quality (p = .003) studies, but was marginally lost (p = .06) on studies enrolling patients with peripheral arterial disease only. PNC treatment did not affect postoperative pain scores (p = .48), in-hospital mortality (p = .77), phantom limb pain (p = .28) or stump pain (p = .37). GRADE quality of evidence for all outcomes was very low. CONCLUSION: There is poor-quality evidence that PNC usage significantly reduces opioid consumption following lower limb amputation, without affecting other short- or long-term outcomes. Well-performed randomised studies are required.


Subject(s)
Amputation, Surgical/adverse effects , Anesthetics, Local/administration & dosage , Catheterization/instrumentation , Catheters, Indwelling , Lower Extremity/surgery , Pain, Postoperative/prevention & control , Amputation, Surgical/mortality , Analgesics, Opioid/therapeutic use , Anesthetics, Local/adverse effects , Chi-Square Distribution , Humans , Infusions, Parenteral , Odds Ratio , Pain Measurement , Pain, Postoperative/diagnosis , Pain, Postoperative/etiology , Pain, Postoperative/mortality , Phantom Limb/etiology , Phantom Limb/prevention & control , Time Factors , Treatment Outcome
12.
Hernia ; 19(6): 1035-6, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25731949
14.
Vascular ; 23(5): 555-7, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25394887

ABSTRACT

Coral reef aorta is a rare condition characterised by extreme calcific growths affecting the juxta and suprarenal aorta. It can cause symptoms due to visceral ischaemia, lower limb hypoperfusion, and distal embolisation. We present a case of a 61-year-old man with unresponsive hypertension, who was found to have an occluded right renal artery, and an extensive coral reef aorta with a marked pressure gradient across the lesion. Renal hypoperfusion secondary to aortic coral reef aorta was thought to be the cause for his hypertension. Endovascular placement of a balloon expandable uncovered stent resolved his hypertension within one month, with no adverse effects noted at subsequent follow-up. Endovascular treatment of coral reef aorta is technically possible and avoids a major vascular procedure.


Subject(s)
Angioplasty, Balloon/instrumentation , Aorta/surgery , Aortic Diseases/surgery , Atherosclerosis/surgery , Blood Vessel Prosthesis Implantation/instrumentation , Blood Vessel Prosthesis , Stents , Aorta/physiopathology , Aortic Diseases/complications , Aortic Diseases/diagnosis , Aortic Diseases/physiopathology , Aortography/methods , Arterial Pressure , Atherosclerosis/complications , Atherosclerosis/diagnosis , Atherosclerosis/physiopathology , Humans , Hypertension/etiology , Hypertension/physiopathology , Male , Middle Aged , Plaque, Atherosclerotic , Prosthesis Design , Tomography, X-Ray Computed , Treatment Outcome
15.
Eur J Vasc Endovasc Surg ; 48(1): 88-97, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24841052

ABSTRACT

OBJECTIVE: The aim of this systematic review was to evaluate outcomes of direct revascularisation (DR) versus indirect revascularisation (IR) of infrapopliteal arteries to the affected angiosome for critical limb ischaemia. Both open and endovascular techniques were included. METHODS: A systematic review of key electronic journal databases was undertaken from inception to 22 March 2014. Studies comparing DR versus IR in patients with localised tissue loss were included. Meta-analysis was performed for wound healing, limb salvage, mortality, and re-intervention rates, with numerous sensitivity analyses. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Fifteen cohort studies reporting on 1,868 individual limbs were included (endovascular revascularisation, 1,284 limbs; surgical revascularisation, 508 limbs; both methods, 76 limbs). GRADE quality of evidence was low or very low for all outcomes. DR resulted in improved wound healing rates compared with IR (odds ratio [OR] 0.40, 95% confidence interval [CI] 0.29-0.54) and improved limb salvage rates (OR 0.24, 95% CI 0.13-0.45), although this latter effect was lost on high-quality study sensitivity analysis. Wound healing and limb salvage was improved for both open and endovascular intervention. There was no effect on mortality (OR 0.77, 95% CI 0.50-1.19) or reintervention rates (OR: 0.44, 95% CI 0.10-1.88). CONCLUSION: DR of the tibial vessels appears to result in improved wound healing and limb salvage rates compared with IR, with no effect on mortality or reintervention rates. However, the quality of evidence on which these conclusions are based on is low.


Subject(s)
Endovascular Procedures , Peripheral Arterial Disease/therapy , Popliteal Artery/surgery , Tibial Arteries/surgery , Vascular Surgical Procedures , Chi-Square Distribution , Endovascular Procedures/adverse effects , Endovascular Procedures/mortality , Humans , Limb Salvage , Odds Ratio , Peripheral Arterial Disease/diagnosis , Peripheral Arterial Disease/mortality , Risk Factors , Time Factors , Treatment Outcome , Vascular Surgical Procedures/adverse effects , Vascular Surgical Procedures/mortality , Wound Healing
20.
Ann R Coll Surg Engl ; 95(4): 291-6, 2013 May.
Article in English | MEDLINE | ID: mdl-23676816

ABSTRACT

INTRODUCTION: Chronic, non-healing wounds are often characterised by an excessive, and detrimental, inflammatory response. We review our experience of using a combined topical steroid, antibiotic and antifungal preparation in the treatment of chronic wounds displaying abnormal and excessive inflammation. METHODS: A retrospective review was undertaken of all patients being treated with a topical preparation containing a steroid (clobetasone butyrate 0.05%), antibiotic and antifungal at a tertiary wound healing centre over a ten-year period. Patients were selected as the primary treating physician felt the wounds were displaying excessive inflammation. Healing rates were calculated for before and during this treatment period for each patient. Changes in symptom burden (pain, odour and exudate levels) following topical application were also calculated. RESULTS: Overall, 34 ulcers were identified from 25 individual patients (mean age: 65 years, range: 37-97 years) and 331 clinic visits were analysed, spanning a total time of 14,670 days (7,721 days 'before treatment' time, 6,949 days 'during treatment' time). Following treatment, 24 ulcers demonstrated faster rates of healing, 3 ulcers showed no significant change in healing rates and 7 were healing more slowly (p=0.0006). Treatment generally reduced the burden of pain and exudate, without affecting odour. CONCLUSIONS: In normal wound healing, inflammation represents a transient but essential phase of tissue repair. In selected cases, direct application of a steroid containing agent has been shown to improve healing rates, presumably by curtailing this phase. Further evaluation is required to establish the role of preparations containing topical steroids without antimicrobials in the management of chronic wounds.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Antifungal Agents/administration & dosage , Glucocorticoids/administration & dosage , Wound Healing/drug effects , Administration, Topical , Adult , Aged , Aged, 80 and over , Chronic Disease , Clobetasol/administration & dosage , Clobetasol/analogs & derivatives , Drug Combinations , Female , Humans , Inflammation/drug therapy , Male , Middle Aged , Nystatin/administration & dosage , Ointments , Oxytetracycline/administration & dosage , Retrospective Studies
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