Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose-response trial.

INTRODUCTION: Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression. METHODS: This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks. RESULTS: We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group. DISCUSSION: Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted. TRIAL REGISTRATION NUMBER: ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep.

PURPOSE: Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization. METHODS: We characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups. RESULTS: Administration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide. CONCLUSIONS: Single local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose.

Waist Circumference is not Superior to Body Mass Index in Predicting Groin Hernia Repair in Either Men or Women.

BACKGROUND AND AIMS: A high body mass index (BMI) is considered a risk factor for ventral abdominal wall hernias but protective for the development of groin hernias. The reason for this is unclear. The surrounding abdominal fat in obesity might "protect" and limit the passage through the inguinal canal. The aim was to compare two different methods used for obesity registration in groin hernia patients and to investigate the hypothesis of high BMI/low groin hernia risk phenomenon. METHODS: This was a population-based observational study comparing BMI to waist circumference (WC) as well as their correlations to the quantity of groin hernia repair performed in either sex. Two national registers were crosslinked to a large regional register including information on WC. RESULTS: A larger WC and a higher BMI were associated with a lower risk of having groin hernia repair in both sexes. There was no difference using either WC or BMI as a risk factor for groin hernia repair in either sex. There was no advantage to using body composition based on WC rather than BMI for surgery indication. CONCLUSIONS: Overweight patients, both men and women, have a lower risk of undergoing groin hernia repair regardless of fat distribution. BMI is a well-established method for obesity registration and is recommended in the evaluation of hernia patients.

European Hernia Society guidelines on management of rectus diastasis.

BACKGROUND: The definition, classification and management of rectus diastasis (RD) are controversial in the literature and a variety of different surgical treatments have been described. This article reports on the European Hernia Society (EHS) Clinical Practice Guideline for RD. METHOD: The Guideline group consisted of eight surgeons. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument were used. A systematic literature search was done in November 2018 and updated in November 2019 and October 2020. Nine Key Questions (KQs) were formulated. RESULTS: Literature reporting on the definition, classification, symptoms, outcomes and treatments was limited in quality, leading to weak recommendations for the majority of the KQs. The main recommendation is to define RD as a separation between rectus muscles wider than 2 cm. A new classification system is suggested based on the width of muscle separation, postpregnancy status and whether or not there is a concomitant hernia. Impaired body image and core instability appear to be the most relevant symptoms. Physiotherapy may be considered before surgical management. It is suggested to use linea alba plication in patients without concomitant hernia and a mesh-based repair of RD with concomitant midline hernias. CONCLUSION: RD should be defined as a separation of rectus muscles wider than 2 cm and a new classification system is suggested.

The management of RD is controversial. These guidelines are intended to provide a consensus about the exact definition, the correct way of measurement and diagnosis, a classification system, the main symptoms, and a systematic review of non-surgical and surgical treatments to achieve the best results for patients with this pathology. The main recommendation is to define RD as a separation between rectus muscles wider than 2 cm. A new classification system is proposed. It is suggested to use linea alba plication in patients without concomitant hernia and a mesh-based repair of RD in those with concomitant midline hernias.

Reporting guideline for interventional trials of primary and incisional ventral hernia repair.

BACKGROUND: Primary and incisional ventral hernia trials collect unstandardized inconsistent data, limiting data interpretation and comparison. This study aimed to create two minimum data sets for primary and incisional ventral hernia interventional trials to standardize data collection and improve trial comparison. To support these data sets, standardized patient-reported outcome measures and trial methodology criteria were created. METHODS: To construct these data sets, nominal group technique methodology was employed, involving 15 internationally recognized abdominal wall surgeons and two patient representatives. Initially a maximum data set was created from previous systematic and panellist reviews. Thereafter, three stages of voting took place: stage 1, selection of the number of variables for data set inclusion; stage 2, selection of variables to be included; and stage 3, selection of variable definitions and detection methods. A steering committee interpreted and analysed the data. RESULTS: The maximum data set contained 245 variables. The three stages of voting commenced in October 2019 and had been completed by July 2020. The final primary ventral hernia data set included 32 variables, the incisional ventral hernia data set included 40 variables, the patient-reported outcome measures tool contained 25 questions, and 40 methodological criteria were chosen. The best known variable definitions were selected for accurate variable description. CT was selected as the optimal preoperative descriptor of hernia morphology. Standardized follow-up at 30 days, 1 year, and 5 years was selected. CONCLUSION: These minimum data sets, patient-reported outcome measures, and methodological criteria have allowed creation of a manual for investigators aiming to undertake primary ventral hernia or incisional ventral hernia interventional trials. Adopting these data sets will improve trial methods and comparisons.

An economic evaluation of the randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo (the HI-Light Vitiligo Trial).

BACKGROUND: Economic evidence for vitiligo treatments is absent. OBJECTIVES: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo. METHODS: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months' treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost-utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015. RESULTS: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188-235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151-196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment. CONCLUSIONS: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success.

Randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo: results of the HI-Light Vitiligo Trial.

BACKGROUND: Evidence for the effectiveness of vitiligo treatments is limited. OBJECTIVES: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo. METHODS: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting < 10% of skin, were randomized 1 : 1 : 1 to receive TCS (mometasone furoate 0·1% ointment + dummy NB-UVB), NB-UVB (NB-UVB + placebo TCS) or a combination (TCS + NB-UVB). TCS was applied once daily on alternating weeks; NB-UVB was administered on alternate days in escalating doses, adjusted for erythema. The primary outcome was treatment success at 9 months at a target patch assessed using the participant-reported Vitiligo Noticeability Scale, with multiple imputation for missing data. The trial was registered with number ISRCTN17160087 on 8 January 2015. RESULTS: In total 517 participants were randomized to TCS (n = 173), NB-UVB (n = 169) and combination (n = 175). Primary outcome data were available for 370 (72%) participants. The proportions with target patch treatment success were 17% (TCS), 22% (NB-UVB) and 27% (combination). Combination treatment was superior to TCS: adjusted between-group difference 10·9% (95% confidence interval 1·0%-20·9%; P = 0·032; number needed to treat = 10). NB-UVB alone was not superior to TCS: adjusted between-group difference 5·2% (95% CI - 4·4% to 14·9%; P = 0·29; number needed to treat = 19). Participants using interventions with ≥ 75% expected adherence were more likely to achieve treatment success, but the effects were lost once treatment stopped. Localized grade 3 or 4 erythema was reported in 62 (12%) participants (including three with dummy light). Skin thinning was reported in 13 (2·5%) participants (including one with placebo ointment). CONCLUSIONS: Combination treatment with home-based handheld NB-UVB plus TCS is likely to be superior to TCS alone for treatment of localized vitiligo. Combination treatment was relatively safe and well tolerated but was successful in only around one-quarter of participants.

Guidelines for treatment of umbilical and epigastric hernias from the European Hernia Society and Americas Hernia Society.

BACKGROUND: Umbilical and epigastric hernia repairs are frequently performed surgical procedures with an expected low complication rate. Nevertheless, the optimal method of repair with best short- and long-term outcomes remains debatable. The aim was to develop guidelines for the treatment of umbilical and epigastric hernias. METHODS: The guideline group consisted of surgeons from Europe and North America including members from the European Hernia Society and the Americas Hernia Society. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, the Scottish Intercollegiate Guidelines Network (SIGN) critical appraisal checklists, and the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument were used. A systematic literature search was done on 1 May 2018, and updated on 1 February 2019. RESULTS: Literature reporting specifically on umbilical and epigastric hernias was limited in quantity and quality, resulting in a majority of the recommendations being graded as weak, based on low-quality evidence. The main recommendation was to use mesh for repair of umbilical and epigastric hernias to reduce the recurrence rate. Most umbilical and epigastric hernias may be repaired by an open approach with a preperitoneal flat mesh. A laparoscopic approach may be considered if the hernia defect is large, or if the patient has an increased risk of wound morbidity. CONCLUSION: This is the first European and American guideline on the treatment of umbilical and epigastric hernias. It is recommended that symptomatic umbilical and epigastric hernias are repaired by an open approach with a preperitoneal flat mesh.

ANTECEDENTES: La reparación de las hernias umbilicales y epigástricas es un procedimiento quirúrgico frecuente con una tasa esperada de complicaciones baja. Sin embargo, sigue en discusión cuál es el mejor método de reparación óptimo para obtener los mejores resultados a corto y a largo plazo. El objetivo del estudio fue desarrollar una guía para el tratamiento de las hernias umbilicales y epigástricas. MÉTODOS: El grupo para la elaboración de la guía estuvo formado por cirujanos europeos y norteamericanos junto con miembros de la European Hernia Society (EHS) y de la America's Hernia Society (AHS). Para elaborar la guía, se siguieron las recomendaciones GRADE (Grading of Recommendations Assessment, Development and Evaluation), SIGN (Scottish Intercollegiate Guidelines Network) y AGREE (Appraisal of Guidelines for Research & Evaluation). Se realizó una búsqueda sistemática de la literatura el 1 de mayo de 2018, que luego se actualizó el 1 de febrero de 2019. RESULTADOS: Los trabajos dedicados de forma específica a las hernias umbilicales y epigástricas eran muy limitados en cantidad y calidad, por lo que la mayoría de las recomendaciones que se extrajeron fueron calificadas como débiles y basadas en una baja calidad de la evidencia. La recomendación principal era utilizar una malla en la reparación de las hernias umbilicales y epigástricas para reducir la tasa de recidiva. La mayoría de las hernias umbilicales y epigástricas pueden repararse mediante un abordaje abierto con una malla plana preperitoneal. Se puede considerar el abordaje laparoscópico si el defecto de la hernia es grande o si el paciente tiene un riesgo aumentado de morbilidad de la herida. CONCLUSIÓN: Esta es la primera guía europea y americana del tratamiento de las hernias umbilicales y epigástricas. Se sugiere reparar las hernias sintomáticas umbilicales y epigástricas mediante un abordaje abierto con una malla plana preperitoneal.

International classification of abdominal wall planes (ICAP) to describe mesh insertion for ventral hernia repair.

BACKGROUND: Nomenclature for mesh insertion during ventral hernia repair is inconsistent and confusing. Several terms, including 'inlay', 'sublay' and 'underlay', can refer to the same anatomical planes in the indexed literature. This frustrates comparisons of surgical practice and may invalidate meta-analyses comparing surgical outcomes. The aim of this study was to establish an international classification of abdominal wall planes. METHODS: A Delphi study was conducted involving 20 internationally recognized abdominal wall surgeons. Different terms describing anterior abdominal wall planes were identified via literature review and expert consensus. The initial list comprised 59 possible terms. Panellists completed a questionnaire that suggested a list of options for individual abdominal wall planes. Consensus on a term was predefined as occurring if selected by at least 80 per cent of panellists. Terms scoring less than 20 per cent were removed. RESULTS: Voting started August 2018 and was completed by January 2019. In round 1, 43 terms (73 per cent) were selected by less than 20 per cent of panellists and 37 new terms were suggested, leaving 53 terms for round 2. Four planes reached consensus in round 2, with the terms 'onlay', 'inlay', 'preperitoneal' and 'intraperitoneal'. Thirty-five terms (66 per cent) were selected by less than 20 per cent of panellists and were removed. After round 3, consensus was achieved for 'anterectus', 'interoblique', 'retro-oblique' and 'retromuscular'. Default consensus was achieved for the 'retrorectus' and 'transversalis fascial' planes. CONCLUSION: Consensus concerning abdominal wall planes was agreed by 20 internationally recognized surgeons. Adoption should improve communication and comparison among surgeons and research studies.

ANTECEDENTES: La nomenclatura de la inserción de una malla para la reparación de una hernia incisional ventral (ventral hernia, VH) es inconsistente y confusa. En la literatura indexada se usan varios términos, tales como 'inlay', 'sublay', y 'underlay' que pueden referirse a los mismos planos anatómicos. Este hecho frustra las comparaciones de técnicas quirúrgicas e invalida los metaanálisis que comparan resultados quirúrgicos en función del plano de inserción de la malla. En consecuencia, el objetivo de este estudio fue establecer una clasificación internacional de los planos de la pared abdominal (International Classification of Abdominal Wall Planes, ICAP). MÉTODOS: Se realizó un estudio Delphi, en el que participaron 20 cirujanos de pared abdominal reconocidos internacionalmente. Se identificaron diferentes términos que describían los planos de la pared abdominal anterior mediante la revisión de la literatura y el consenso de expertos. La lista inicial incluía 59 términos posibles. Los panelistas completaron un cuestionario que sugería una lista de opciones para los planos individuales de la pared abdominal. El consenso sobre un término fue predefinido cuando dicho término había sido seleccionado por ≥ 80% de panelistas. Se eliminaron los términos con una puntuación < 20%. RESULTADOS: La votación comenzó en agosto de 2018 y se completó en enero de 2019. Durante la Ronda 1, 43 (73%) términos fueron seleccionados por < 20% de los panelistas y se sugirieron 37 términos nuevos, dejando 53 términos para la Ronda 2. Cuatro planos alcanzaron un consenso en la Ronda 2 con los términos 'onlay', 'inlay', 'pre-peritoneal' e 'intra-peritoneal'. Treinta y cinco (66%) términos fueron seleccionados por < 20% de los panelistas y fueron eliminados. Después de la Ronda 3, se logró un consenso para 'anterectus' (ante-recto), 'interoblique' (inter-oblicuo), 'retrooblique' (retro-oblicuo) y 'retromuscular'. Se alcanzó un consenso por defecto para los planos 'retrorectus' (retro-recto) y 'transversalis fascial' (fascial transverso). CONCLUSIÓN: La ICAP ha sido desarrollada por el consenso de 20 cirujanos reconocidos internacionalmente. Su implementación debería mejorar la comunicación y la comparación entre cirujanos y estudios de investigación.

Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship.

Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF). While effective slowing fibrosis progression, as an oral medicine nintedanib is limited. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, the nintedanib pharmacokinetic/pharmacodynamic relationship was dissected. Pharmacokinetic analysis indicated oral-delivered nintedanib plasma exposure and lung tissue partitioning were not dose-proportional and resulting lung levels were substantially higher than blood. Although initial-oral absorbed nintedanib efficiently partitioned into the lung, only a quickly eliminated fraction appeared available to epithelial lining fluid (ELF). Because IPF disease appears to initiate and progress near the epithelial surface, this observation suggests short duration nintedanib exposure (oral portion efficiently partitioned to ELF) is sufficient for IPF efficacy. To test this hypothesis, exposure duration required for nintedanib activity was explored. In vitro, IPF-cellular matrix (IPF-CM) increased primary normal human fibroblast (nHLF) aggregate size and reduced nHLF cell count. IPF-CM also increased nHLF ACTA2 and COL1A expression. Whether short duration (inhalation pharmacokinetic mimic) or continuous exposure (oral pharmacokinetic mimic), nintedanib (1-100 nM) reversed these effects. In vivo, intubated silica produced a strong pulmonary fibrotic response. Once-daily (QD) 0.021, 0.21 and 2.1 mg/kg intranasal (IN; short duration inhaled exposure) and twice-daily (BID) 30 mg/kg oral (PO; long duration oral exposure) showed that at equivalent-delivered lung exposure, QD short duration inhaled nintedanib (0.21 mg/kg IN vs. 30 mg/kg PO) exhibited equivalent-to-superior activity as BID oral (reduced silica-induced elastance, alpha-smooth muscle actin, interleukin-1 beta (IL-1ß) and soluble collagen). Comparatively, the increased inhaled lung dose (2.1 mg/kg IN vs. 30 mg/kg PO) exhibited increased effect by further reducing silica-induced elastance, IL-1ß and soluble collagen. Neither oral nor inhaled nintedanib reduced silica-induced parenchymal collagen. Both QD inhaled and BID oral nintedanib reduced silica-induced bronchoalveolar lavage fluid macrophage and neutrophil counts with oral achieving significance. In summary, pharmacokinetic elements important for nintedanib activity can be delivered using infrequent, small inhaled doses to achieve oral equivalent-to-superior pulmonary activity.

Nebulized Amikacin and Fosfomycin for Severe Pseudomonas aeruginosa Pneumonia: An Experimental Study.

OBJECTIVES: Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem. DESIGN: Prospective randomized animal study. SETTING: Animal Research, University of Barcelona, Spain. SUBJECTS: Thirty female pigs. INTERVENTIONS: The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance. MEASUREMENTS AND MAIN RESULTS: We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004). CONCLUSIONS: Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

Randomized clinical trial of open suture repair versus totally extraperitoneal repair for treatment of sportsman's hernia.

BACKGROUND: Sportsman's hernia/athletic pubalgia is a recognized cause of chronic groin pain in athletes. Both open and laparoscopic surgical repairs have been described for treatment, but there are no comparative studies. The hypothesis here was that relief of pain would be achieved earlier in patients treated with open minimal suture repair than totally extraperitoneal repair. METHODS: A randomized multicentre trial in four European countries was conducted to compare open minimal suture repair with totally extraperitoneal repair. The primary endpoint was complete relief of pain (visual analogue scale (VAS) score 20 or less on a scale from 0 to 100 mm) at 1 month. Secondary endpoints included complications, time to return to sporting activity, and number of patients returning to sport within 1 year. RESULTS: A total of 65 athletes (92 per cent men) with a median age of 29 years were enrolled (31 open repair, 34 totally extraperitoneal repair). By 4 weeks after surgery, median preoperative VAS scores had dropped from 70-80 to 10-20 in both groups (P < 0·001). Relief of pain (VAS score 20 or less) during sports activity 4 weeks after surgery was achieved in 14 of 31 patients after open repair and 24 of 34 after totally extraperitoneal repair (P = 0·047). Return to full sporting activity was achieved by 16 and 18 patients respectively after 1 month (P = 0·992), and by 25 versus 31 after 3 months (P = 0·408). CONCLUSION: Totally extraperitoneal repair was less painful than open repair in the first month, but otherwise both procedures were similarly effective in treating chronic pain due to sportsman's hernia. Registration number: NCT02297711 ( http://www.clinical.trials.gov).

Randomized clinical trial comparing total extraperitoneal with Lichtenstein inguinal hernia repair (TEPLICH trial).

BACKGROUND: Chronic pain is reported after 10-35 per cent of inguinal hernia operations. The aim was to compare quality of life (QoL) after total extraperitoneal (TEP) and Lichtenstein hernia repairs in the setting of an RCT with operations performed by department-certified hernia surgeons. METHODS: Men aged 30-75 years with an ASA grade I-II primary inguinal hernia were randomized to TEP or Lichtenstein repair. Primary endpoint was pain at 1 year assessed with the Inguinal Pain Questionnaire (IPQ). Clinical examination, IPQ, SF-36® and study-specific questions were recorded before surgery, and at 1 and 3 years. RESULTS: Some 416 patients (202 TEP and 214 Lichtenstein) had surgery; 95·2 per cent completed 1-year and 89·9 per cent 3-year follow-up. At 1 year 'pain during last week' was reported by 6·9 per cent after TEP and by 9·8 per cent after Lichtenstein repair (P = 0·303), and 'pain right now' by 3·7 and 5·9 per cent respectively (P = 0·315). Favourable outcomes for TEP were duration of operation, 30-day complications, time to full recovery, foreign body sensation and sick leave. Groin sensory changes diminished after TEP but increased after Lichtenstein repair. Preoperative QoL was affected, especially in the physical subscales, but was restored to normal after surgery. At 1 and 3 years, 98·3 and 97·4 per cent respectively of the patients were satisfied; 1·6 per cent (6 of 374) suffered a recurrence at 3 years, four after TEP and two after Lichtenstein repair. CONCLUSION: In the medium term, both TEP and Lichtenstein hernia repair had similar outcomes after 1 year, with high rates of patient satisfaction and low rates of chronic pain and recurrence. There were short-term advantages for pain and recovery rate after TEP repair. Registration number: NCT00803985 ( www.clinicaltrials.gov).

Aerosol Pirfenidone Pharmacokinetics after Inhaled Delivery in Sheep: a Viable Approach to Treating Idiopathic Pulmonary Fibrosis.

PURPOSE: Inhaled delivery of pirfenidone to the lungs of patients with idiopathic pulmonary fibrosis holds promise to eliminate oral-observed side effects while enhancing efficacy. This study aimed to comprehensively describe the pulmonary pharmacokinetics of inhaled aerosol pirfenidone in healthy adult sheep. METHODS: Pirfenidone concentrations were evaluated in plasma, lung-derived lymph and epithelial lining fluid (ELF) with data subjected to non-compartmental pharmacokinetic analysis. RESULTS: Compartmental pharmacokinetic evaluation indicated that a 49 mg lung-deposited dose delivered an ELF Cmax of 62 ± 23 mg/L, and plasma Cmax of 3.1 ± 1.7 mg/L. Further analysis revealed that plasma pirfenidone reached Tmax faster and at higher concentrations than in lymph. These results suggested inhaled pirfenidone was cleared from the alveolar interstitium via blood faster than the drug could equilibrate between the lung interstitial fluid and lung lymphatics. However, the data also suggested that a 'reservoir' of pirfenidone feeds into lung lymph at later time points (after it has largely been cleared from plasma), prolonging lung lymphatic exposure. CONCLUSIONS: This study indicates inhaled pirfenidone efficiently deposits in ELF and is cleared from the lungs by initial absorption into plasma, followed by later equilibrium with lung interstitial and lymph fluid.

Patient-reported rates of chronic pain and recurrence after groin hernia repair.

BACKGROUND: The effectiveness of different procedures in routine surgical practice for hernia repair with respect to chronic postoperative pain and reoperation rates is not clear. METHODS: This was prospective cohort study based on a unique combination of patient-reported outcomes and national registry data. Virtually all patients with a groin hernia repair in Sweden between September 2012 and April 2015 were sent a questionnaire 1 year after surgery. Persistent pain, defined as at least 'pain present, cannot be ignored, and interferes with concentration on everyday activities' in the past week was the primary outcome. Reoperation for recurrence recorded in the register was the secondary outcome. RESULTS: In total, 22 917 patients (response rate 75·5 per cent) who had an elective unilateral groin hernia repair were analysed. Persistent pain present 1 year after hernia repair was reported by 15·2 per cent of patients. The risk was least for endoscopic total extraperitoneal (TEP) repair (adjusted odds ratio (OR) 0·84, 95 per cent c.i. 0·74 to 0·96), compared with open anterior mesh repair. TEP repair had an increased risk of reoperation for recurrence (adjusted OR 2·14, 1·52 to 2·98), as did open preperitoneal mesh repair (adjusted OR 2·34, 1·42 to 3·71) at 2·5-year follow-up. No other methods of repair differed significantly from open anterior mesh repair. CONCLUSION: The risk of significant pain 1 year after groin hernia repair in routine surgical practice was 15·2 per cent. This figure was lower in patients who had surgery by an endoscopic technique, but at the price of a significantly higher risk of reoperation for recurrence.

NHS health checks: a cross- sectional observational study on equity of uptake and outcomes.

BACKGROUND: The National Health Checks programme aims to reduce the incidence of cardiovascular diseases and health inequalities in England. We assessed equity of uptake and outcomes from NHS Health Checks in general practices in Bristol, UK. METHODS: A cross-sectional study using patient-level data, from 38 general practices. We descriptively analysed the socioeconomic status (SES) of patients invited and the SES and ethnicity of those attending. Logistic regression was used to test associations between invitation and attendance, with population characteristics. RESULTS: Between June 2010 to October 2014, 31,881 patients were invited, and 13,733 NHS Health Checks completed. 47% of patients invited from the three least and 39% from the two most-deprived index of multiple deprivation quintiles, completed a Check. Proportions of invited patients, by ethnicity were 64% non-black and Asian and 31% black and Asian. Men were less likely to attend than women (OR 0.73, 95% confidence interval 0.67 to 0.80), as were patients ≤ 49 compared to ≥ 70 years (OR 0.40, 95% confidence interval 0.65 to 0.83). After controlling for SES and population characteristics, compared to patients with low CVD risk, high risk patients were more likely to be prescribed cardiovascular drugs (OR 6.2, 95% confidence interval 4.51 to 8.40). Compared to men, women (OR 01.18, 95% confidence interval 1.03 to 1.35) were more likely to be prescribed cardiovascular drugs, as were those ≤ 49 years (50-59 years, OR 1.42, 95% confidence intervals 1.13-1.79, 60-69 years, OR 1.60, 95% confidence intervals, 1.22-2.10, ≥ 70 years, OR 1.64, 95% confidence intervals, 1.14 to 2.35). Controlling for population characteristics, the following groups were most likely to be referred to lifestyle services: younger women (OR 2.22, 95% CI 1.69 to 2.94), those in the most deprived IMD quintile (OR 3.22, 95% CI 1.63 to 6.36) and those at highest risk of CVD (OR, 2.77, 95% CI 1.91 to 4.02). CONCLUSIONS: We found no statistically significant evidence of inequity in attendance for an NHS Health Check by SES. Being older or a woman were associated with better attendance. Targeting men, younger patients and ethnic minority groups may improve equity in uptake for NHS Health Checks.

Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy.

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 108 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 108 to 109 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.

Validation of the Vitiligo Noticeability Scale: a patient-reported outcome measure of vitiligo treatment success.

BACKGROUND: Patient-reported outcome measures are rarely used in vitiligo trials. The Vitiligo Noticeability Scale (VNS) is a new patient-reported outcome measure assessing how 'noticeable' vitiligo patches are after treatment. The noticeability of vitiligo after treatment is an important indicator of treatment success from the patient's perspective. OBJECTIVES: To evaluate the construct validity, acceptability and interpretability of the VNS. METHODS: Clinicians (n = 33) and patients with vitiligo (n = 101) examined 39 image pairs, each depicting a vitiligo lesion pre- and post-treatment. Using an online questionnaire, respondents gave a global assessment of treatment success and a VNS score for treatment response. Clinicians also estimated percentage repigmentation of lesions (< 25%; 25-50%; 51-75%; > 75%). Treatment success was defined as 'yes' on global assessment, a VNS score of 4 or 5, and > 75% repigmentation. Agreement between respondents and the different scales was assessed using kappa (κ) statistics. RESULTS: Vitiligo Noticeability Scale scores were associated with both patient- and clinician-reported global treatment success (κ = 0·54 and κ = 0·47, respectively). Percentage repigmentation showed a weaker association with patient- and clinician-reported global treatment success (κ = 0·39 and κ = 0·29, respectively). VNS scores of 4 or 5 can be interpreted as representing treatment success. Images depicting post-treatment hyperpigmentation were less likely to be rated as successful. CONCLUSIONS: The VNS is a valid patient-reported measure of vitiligo treatment success. Further validation of the VNS is required, using larger sets of clinical pre- and post-treatment images, affecting a wider range of anatomical sites.

Experiences of patients and healthcare professionals of NHS cardiovascular health checks: a qualitative study.

BACKGROUND: NHS Health Checks are a national cardiovascular risk assessment and management programme in England and Wales. We examined the experiences of patients attending and healthcare professionals (HCPs) conducting NHS Health Checks. METHODS: Interviews were conducted with a purposive sample of 28 patients and 16 HCPs recruited from eight general practices across a range of socio-economic localities. Interviews were audio recorded, transcribed, anonymized and analysed thematically. RESULTS: Patients were motivated to attend an NHS Health Check because of health beliefs, the perceived value of the programme, a family history of cardiovascular and other diseases and expectations of receiving a general health assessment. Some patients reported benefits including reassurance and reinforcement of healthy lifestyles. Others experienced confusion and frustration about how results and advice were communicated, some having a poor understanding of the implications of their results. HCPs raised concerns about the skill set of some staff to competently communicate risk and lifestyle information. CONCLUSIONS: To improve the satisfaction of patients attending and improve facilitation of lifestyle change, HCPs conducting the NHS Health Checks require sufficient training to equip them with appropriate skills and knowledge to deliver the service effectively.