Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo.

Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro. In this study we first show that modified-ACA measures of cisplatin and mitomycin-C-induced damage also correlate bladder cancer cell chemosensitivity in vitro, with essentially the same rank order for chemosensitivity as for radiosensitivity. Furthermore, ACA studies of radiation-induced damage in different cell-DNA substrates (nuclei, nucleoids and intact parent cells) suggest that it is a feature retained in the prepared nucleoids that is responsible for the relative damage sensitivity of bladder cancer cells, suggestive of differences in the organisation of DNA within resistant vs. sensitive cells. Second, we show that ACA analysis of biopsies from bladder tumours reveal that reduced DNA damage sensitivity associates with poorer treatment outcomes, notably that tumours with a reduced damage response show a significant association with local recurrence of non-invasive disease and that reduced damage response was a better predictor of recurrence than the presence of high-risk histology in this cohort. In conclusion, this study demonstrates that mechanisms governing treatment-induced DNA damage are both central to and predictive of bladder cancer cell treatment sensitivity and exemplifies a link between DNA damage resistance and both treatment response and tumour aggression.

Titanium Dioxide (E171 Grade) and the Search For Replacement Opacifiers and Colorants: Supplier Readiness Survey, Case Studies and Regulatory Perspective.

Titanium dioxide (TiO2) is used primarily as an opacifier in solid dosage forms and is present in the majority of tablet and capsule dosage forms on the market. The IQ* TiO2 Working Group has previously shown that titanium dioxide has unique properties which are necessary for its function in these formulations and noted that, as the potential replacements lack the semi-conductor properties, high refractive index and whiteness of E171, it might be hard to replicate these properties with alternative materials. In this paper we detail the results of readiness surveys and practical assessments that have been conducted with alternative materials by IQ member companies. A range of technical challenges and regulatory hurdles were identified which mean that, in the short term, it may be difficult to replace titanium dioxide with the currently available alternative materials while readily achieving the same drug product quality attributes, especially for some of the marketed formulations that titanium dioxide is currently used for. We note the higher technical complexity, due to the variability, color fading and identified scale up risk, of E171 free film coatings and the likely impact on development costs and timelines. We also highlight several regulatory hurdles that would have to be overcome if a titanium dioxide replacement was required for some markets but was not mandated by others.

Scarf versus chevron osteotomy for the correction of 1-2 intermetatarsal angle in hallux valgus: a systematic review and meta-analysis.

The chevron and scarf osteotomies are commonly used for the surgical management of hallux valgus (HV). However, there is debate as to whether one osteotomy provides more 1-2 intermetatarsal (1-2 IMA) correction than the other. The objective of this systematic review and meta-analysis was to compare the effectiveness of 3 types of first metatarsal osteotomy for reducing the 1-2 IMA in HV correction: the chevron osteotomy, the long plantar arm (modified) chevron osteotomy, and the scarf osteotomy. A systematic search for eligible studies was performed of the following databases: Medline, Embase (Ovid), CINAHL (EBSCO Host), and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials. Only English-language studies previous to May 2010 were included in the review. Additional hand and electronic content searches of relevant foot and orthopaedic journals were performed. Criteria for inclusion in this analysis included systematic reviews of randomized controlled trials, prospective and retrospective cohort studies, and case-control studies, as well as case-series studies involving the chevron, scarf, or long plantar arm chevron osteotomy of >20 participants with a minimum of 80% follow-up. Quality of evidence of the included studies was assessed with the Grading of Recommendations Assessment, Development and Evaluation system. All pooled analyses were based on a fixed effects model. There was a total of 1351 participants who underwent either a chevron (n = 1028), scarf (n = 300), or long plantar arm chevron osteotomy (n = 23). Only one study for the long plantar arm chevron group fitted the eligibility criteria for this review; however, it was not amenable to meta-analysis. The chevron osteotomy was associated with a mean reduction of 1-2 IMA from preoperative to postoperative of 5.33° (95% confidence interval, 5.12 to 5.54, p < .001), and the scarf osteotomy was associated with a mean reduction of 6.21° (95% confidence interval, 5.70 to 6.72, p < .001). There was a statistically significant 0.88° increase in the correction of the 1-2 IMA in favor of the scarf osteotomy compared with the chevron osteotomy. The studies included in this review were of very low- to low-quality evidence. Our findings indicate that the scarf osteotomy provides greater correction of the 1-2 IMA when used for HV correction. However, only a weak recommendation in favor of the scarf osteotomy can be made based on the low quality of evidence of the studies included in this analysis.

Footwear and insole design parameters to prevent occurrence and recurrence of neuropathic plantar forefoot ulcers in patients with diabetes: a series of N-of-1 trial study protocol.

BACKGROUND: Foot complications occur in conjunction with poorly controlled diabetes. Plantar forefoot ulceration contributes to partial amputation in unstable diabetics, and the risk increases with concomitant neuropathy. Reducing peak plantar forefoot pressure reduces ulcer occurrence and recurrence. Footwear and insoles are used to offload the neuropathic foot, but the success of offloading is dependent on patient adherence. This study aims to determine which design and modification features of footwear and insoles improve forefoot plantar pressure offloading and adherence in people with diabetes and neuropathy. METHODS: This study, involving a series of N-of-1 trials, included 21 participants who had a history of neuropathic plantar forefoot ulcers. Participants were recruited from two public hospitals and one private podiatry clinic in Sydney, New South Wales, Australia. This trial is non-randomised and unblinded. Participants will be recruited from three sites, including two high-risk foot services and a private podiatry clinic in Sydney, Australia. Mobilemat™ and F-Scan® plantar pressure mapping systems by TekScan® (Boston, USA) will be used to measure barefoot and in-shoe plantar pressures. Participants' self-reports will be used to quantify the wearing period over a certain period of between 2 and 4 weeks during the trial. Participant preference toward footwear, insole design and quality-of-life-related information will be collected and analysed. The descriptive and inferential statistical analyses will be performed using IBM SPSS Statistics (version 27). And the software NVivo (version 12) will be utilised for the qualitative data analysis. DISCUSSION: This is the first trial assessing footwear and insole interventions in people with diabetes by using a series of N-of-1 trials. Reporting self-declared wearing periods and participants' preferences on footwear style and aesthetics are the important approaches for this trial. Patient-centric device designs are the key to therapeutic outcomes, and this study is designed with that strategy in mind. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000699965p. Registered on June 23, 2020.

The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.

Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.

Postoperative infection rates in foot and ankle surgery: a clinical audit of Australian podiatric surgeons, January to December 2007.

BACKGROUND: Surgical site infections are one of the most common post-operative complications encountered by foot and ankle surgeons. The incidence reported in the literature varies between 0.5 and 6.5%. The results of a 12-month Australia-wide clinical audit analysing the rates of postoperative infections in association with podiatric surgery are presented. METHODS: De-identified patient data was collected from nine podiatric surgeons Australia-wide. Infections were identified according to Australian Council on Health Care Standards (ACHS) definitions and data was entered no earlier than thirty days post procedure. RESULTS: A total of 1339 patient admissions and 2387 surgical procedures were reported using the International Classification of Diseases (ICD-10) and Medicare Benefit Schedule (MBS) coding systems. The overall infection rate was 3.1% and the rate of infection resulting in hospital re-admission was 0.25%. CONCLUSIONS: The benchmark results presented in this paper suggest that infection rates associated with podiatric surgery are well within accepted industry standards as stated in recent literature.

Footwear and insole design features that reduce neuropathic plantar forefoot ulcer risk in people with diabetes: a systematic literature review.

BACKGROUND: In people with diabetes, offloading high-risk foot regions by optimising footwear, or insoles, may prevent ulceration. This systematic review aimed to summarise and evaluate the evidence for footwear and insole features that reduce pathological plantar pressures and the occurrence of diabetic neuropathy ulceration at the plantar forefoot in people with diabetic neuropathy. METHODS: Six electronic databases (Medline, Cinahl, Amed, Proquest, Scopus, Academic Search Premier) were searched in July 2019. The search period was from 1987 to July 2019. Articles, in English, using footwear or insoles as interventions in patients with diabetic neuropathy were reviewed. Any study design was eligible for inclusion except systematic literature reviews and case reports. Search terms were diabetic foot, physiopathology, foot deformities, neuropath*, footwear, orthoses, shoe, footwear prescription, insole, sock*, ulcer prevention, offloading, foot ulcer, plantar pressure. RESULTS: Twenty-five studies were reviewed. The included articles used repeated measure (n = 12), case-control (n = 3), prospective cohort (n = 2), randomised crossover (n = 1), and randomised controlled trial (RCT) (n = 7) designs. This involved a total of 2063 participants. Eleven studies investigated footwear, and 14 studies investigated insoles as an intervention. Six studies investigated ulcer recurrence; no study investigated the first occurrence of ulceration. The most commonly examined outcome measures were peak plantar pressure, pressure-time integral and total contact area. Methodological quality varied. Strong evidence existed for rocker soles to reduce peak plantar pressure. Moderate evidence existed for custom insoles to offload forefoot plantar pressure. There was weak evidence that insole contact area influenced plantar pressure. CONCLUSION: Rocker soles, custom-made insoles with metatarsal additions and a high degree of contact between the insole and foot reduce plantar pressures in a manner that may reduce ulcer occurrence. Most studies rely on reduction in plantar pressure measures as an outcome, rather than the occurrence of ulceration. There is limited evidence to inform footwear and insole interventions and prescription in this population. Further high-quality studies in this field are required.

Risk factors for infection following ingrowing toenail surgery: a retrospective cohort study.

BACKGROUND: Ingrowing toenails are a common and painful condition often requiring surgical management. Practitioners who perform surgery on ingrowing toenails include orthopaedic surgeons, general practitioners, podiatrists and podiatric surgeons. There has been limited investigation into the specific surgical approaches used by Australian podiatric surgeons for ingrowing toenails, or the associated infection rates for these procedures. The aim of this study was to assess the frequency and type of ingrowing toenail surgery performed by podiatric surgeons, and identify risk factors for post-operative infection. METHODS: Data was entered into the Australian College Podiatric Surgeons (ACPS) National Audit Tool for all patients who underwent foot and ankle surgery performed by podiatric surgeons in Australia between January 2014 and December 2017. Infection within the first 30 days following surgery was recorded according to the ACPS national audit descriptors. Infection rates, risk ratios (RR) and 95% Confidence Intervals (CI) were calculated to determine postoperative infection risk. RESULTS: Of 7682 records, 1831 reported 2712 diagnoses of ingrowing nails. Patients with a diagnosis of ingrowing toenails were younger, less likely to have systemic disease, and a lower proportion were female compared to those without ingrowing toenails. Furthermore, they were more likely to be diagnosed with a post-operative infection than those without ingrowing toenails (RR = 2.72; CI = 2.00-3.69; P < 0.01). Univariate risk factors for post-operative infection following ingrowing toenail surgery include age greater than 60 years (RR = 3.16; CI = 1.53-6.51; P < 0.01), surgery performed in an office setting (RR = 1.77; CI = 1.05-2.98; P = 0.04), and radical excision of toenail bed procedure (RR = 2.35; CI = 1.08-5.01; P = 0.04). Patients that underwent radical excision or office based procedures were on average older, and more likely to have systemic disease. Further, radical excision procedures were more likely to be performed in office base settings. CONCLUSIONS: Ingrowing toenail surgery carries a greater risk of postoperative infection than other procedures performed by podiatric surgeons. Radical excision of toenail bed was associated with higher postoperative infection rates compared to other ingrowing toenail procedures. Procedures performed in an office setting carry a higher risk of infection. Further research into these associations is recommended.

Venous Thromboembolism in Podiatric Foot and Ankle Surgery.

BACKGROUND: The extent to which podiatric surgeons follow venous thromboembolism guidelines is unknown. The aim of this study therefore, was 2-fold: (a) to determine the rate of venous thromboembolism following podiatric surgery and (b) to investigate the factors that influence the use of thromboprophylaxis. METHODS: Data from 4238 patients who underwent foot and ankle surgery over 2 years were analyzed. Venous thromboembolism within the first 30 days following surgery was recorded using the Australasian College of Podiatric Surgeons surgical audit tool. Logistic regression analyses were undertaken to determine the factors that influenced thromboprophylaxis. RESULTS: Of the 4238 patient records, 3677 records (87%) provided complete data (age range 2-94 years; mean ± SD, 49.1 ± 19.7 years; 2693 females). A total of 7 venous thromboembolic events (0.2% rate) were reported. Operative duration and age (OR 12.63, 95% CI 9.47 to 16.84, P < 0.01), postoperative immobilization (OR 6.94, 95% CI 3.95 to 12.20, P < 0.01), and a prior history of VTE (OR 3.41, 95% CI 1.01 to 11.04, P = 0.04) were the strongest predictors of thromboprophylaxis. CONCLUSION: Podiatric foot and ankle surgery is associated with a low rate of venous thromboembolism. This may be due in part to the thromboprophylaxis regime implemented by podiatric surgeons, which closely aligns with current evidence-based guidelines. LEVELS OF EVIDENCE: Level II: Prospective cohort study.

Increase in body weight over a two-year period is associated with an increase in midfoot pressure and foot pain.

BACKGROUND: There is a well-recognised relationship between body weight, plantar pressures and foot pain, but the temporal association between these factors is unknown. The aim of this study was to investigate the relationships between increasing weight, plantar pressures and foot pain over a two-year period. METHODS: Fifty-one participants (33 women and 18 men) completed the two-year longitudinal cohort study. The sample had a mean (standard deviation (SD)) age of 52.6 (8.5) years. At baseline and follow-up, participants completed the Manchester Foot Pain and Disability Index questionnaire, and underwent anthropometric measures, including body weight, body mass index, and dynamic plantar pressures. Within-group analyses examined differences in body weight, foot pain and plantar pressures between baseline and follow up, and multivariate regression analysis examined associations between change in body weight, foot pain and plantar pressure. Path analysis assessed the total impact of both the direct and indirect effects of change in body weight on plantar pressure and pain variables. RESULTS: Mean (SD) body weight increased from 80.3 (19.3), to 82.3 (20.6) kg, p = 0.016 from baseline to follow up. The change in body weight ranged from -16.1 to 12.7 kg. The heel was the only site to exhibit increased peak plantar pressures between baseline and follow up. After adjustment for age, gender and change in contact time (where appropriate), there were significant associations between: (i) change in body weight and changes in midfoot plantar pressure (B = 4.648, p = 0.038) and functional limitation (B = 0.409, p = 0.010), (ii) plantar pressure change in the heel and both functional limitation (B = 4.054, p = 0.013) and pain intensity (B = 1.831, p = 0.006), (iii) plantar pressure change in the midfoot and both functional limitation (B = 4.505, p = 0.018) and pain intensity (B = 1.913, p = 0.015). Path analysis indicated that the effect of increasing body weight on foot-related functional limitation and foot pain intensity may be mediated by increased plantar pressure in the midfoot. CONCLUSIONS: These findings suggest that as body weight and plantar pressure increase, foot pain increases, and that the midfoot may be the most vulnerable site for pressure-related pain.

Fat Mass Is Associated with Foot Pain in Men: The Geelong Osteoporosis Study.

OBJECTIVE: Foot pain is a common complaint in adults. Evidence suggests that body composition is involved in the development of foot pain. However, whether this is the case in men remains unclear because previous studies mainly examined women. The aim of this cross-sectional study was to determine the relationship between body composition and foot pain in men while accounting for important risk factors. METHODS: Among 978 men (median age 60 yrs, range 24-98) from the Geelong Osteoporosis Study who participated in a followup study in 2006 to 2011, 796 provided responses to questions on health status and foot pain. Foot pain was determined using the Manchester Foot Pain and Disability Index, and body composition was measured using dual-energy x-ray absorptiometry. RESULTS: Of the 796 respondents, 177 (22%) had foot pain. Risk factors for foot pain were age (OR 1.03, 95% CI 1.02-1.04), self-reported depression (OR 2.05, 95% CI 1.30-3.20), decreased mobility (OR 1.54, 95% CI 1.05-2.24), and lower education (OR 1.47, 95% CI 1.03-2.09). Foot pain was associated with body mass index (OR 1.05, 95% CI 1.00-1.10), fat mass (OR 1.02, 95% CI 1.03-1.05), and fat mass index (OR 1.08, 95% CI 1.01-1.15), but not fat-free mass (OR 1.01, 95% CI 0.98-1.04) or fat-free mass index (OR 1.05, 95% CI 0.95-1.15) after appropriate adjustments were made. CONCLUSION: Fat mass is associated with foot pain in men. These findings complement those in studies that have mainly examined women, and provide further evidence for the relationship between obesity and foot pain.

A quality control method enhancement concept-Continual improvement of regulatory approved QC methods.

Quality Control methods (QC-methods) play an important role in the overall control strategy for drug manufacturing. However, efficient life-cycle management and continual improvement are hindered due to a variety of post-approval variation legislations across territories and a lack of harmonization of the requirements. As a result, many QC-methods fall behind the technical development. Developing the QC-method in accordance with the Quality by Design guidelines gives the possibility to do continual improvements inside the original Method Operable Design Region (MODR). However, often it is necessary to do changes outside the MODR, e.g. to incorporate new technology that was not available at the time the original method was development. Here, we present a method enhancement concept which allows minor adjustments, within the same measuring principle, outside the original MODR without interaction with regulatory agencies. The feasibility of the concept is illustrated by a case study of a QC-method based on HPLC, assumed to be developed before the introduction of UHPLC, where the switch from HPLC to UHPLC is necessary as a continual improvement strategy. The concept relies on the assumption that the System Suitability Test (SST) and failure modes are relevant for other conditions outside the MODR as well when the same measuring principle is used. It follows that it should be possible to move outside the MODR as long as the SST has passed. All minor modifications of the original, approved QC-method must be re-validated according to a template given in the original submission and a statistical equivalence should be shown between the original and modified QC-methods. To summarize, revalidation is handled within the pharmaceutical quality control system according to internal change control procedures, but without interaction with regulating agencies.

The effectiveness of extracorporeal shock wave therapy for the treatment of lower limb ulceration: a systematic review.

Extracorporeal shock wave therapy has been reported as an effective treatment for lower limb ulceration. The aim of this systematic review was to investigate the effectiveness of extracorporeal shock wave therapy for the treatment of lower limb ulceration. Five electronic databases (Ovid MEDLINE, CINAHL, Web of Knowledge, Scopus and Ovid AMED) and reference lists from relevant studies were searched in December 2013. All study designs, with the exception of case-reports, were eligible for inclusion in this review. Assessment of each study's methodological quality was performed using the Quality Index tool. The effectiveness of studies was measured by calculating effect sizes (Cohen's d) from means and standard deviations. Five studies, including; three randomised controlled trials, one quasi-experimental study and one case-series design met our inclusion criteria and were reviewed. Quality assessment scores ranged from 38 to 63% (mean 53%). Improvements in wound healing were identified in these studies following extracorporeal shock wave therapy. The majority of wounds assessed were associated with diabetes and the effectiveness of ESWT as an addition to standard care has only been assessed in one randomised controlled trial. Considering the limited evidence identified, further research is needed to support the use of extracorporeal shock wave therapy in the treatment of lower limb ulceration.

Foot posture, range of motion and plantar pressure characteristics in obese and non-obese individuals.

Obesity is a world-wide health problem and is strongly associated with musculoskeletal disorders of the lower limb. The aim of this study was to evaluate plantar loading patterns in obese and non-obese individuals, while accounting for the contribution of foot structure, range of motion and walking speed. Sixty-eight participants (mean±SD age, 52.6±8.0 years), including 47 females (69%), underwent assessments of body mass index, foot pain and foot structure. Plantar pressures were also obtained, using a floor-mounted resistive sensor mat system. Multiple regression analysis was used to determine which variables were most strongly associated with plantar loading patterns. Obese individuals exhibited flatter feet, reduced inversion-eversion range of motion, and higher peak plantar pressures when walking. After accounting for foot structure and walking speed, bodyweight was found to be significantly associated with elevated loading of the foot, particularly the forefoot and midfoot. These findings suggest that obesity increases the stresses applied to the foot directly, via increased bodyweight, and indirectly, via alterations to foot structure, which may partly explain the link between obesity and the development of foot pain. Clinicians dealing with foot problems should consider the effect of increased bodyweight on plantar loading in obese patients.

Relationship between mental health and foot pain.

OBJECTIVE: Although mental health is related to the persistence of musculoskeletal pain, our understanding of the relationship between mental health and foot pain is limited. Subsequently, we conducted a 3-year longitudinal study to examine the relationship between mental health and foot pain in a community-based population. METHODS: Eighty-three community-dwelling participants (mean ± SD body mass index [BMI] 35.3 ± 9.0 kg/m2) who had foot pain at study inception in 2008 and for whom measures of mental health (Short Form 36 [SF-36] health survey mental component summary [MCS]) were available, were invited to take part in this followup study in 2011. Change in foot pain was determined by the difference between the Manchester Foot Pain and Disability Index score at baseline and followup; therefore, a decrease in the score indicated improved foot pain and an increase indicated deterioration in foot pain. Linear regression was used to determine the factors affecting change in foot pain. RESULTS: Of the 62 respondents (75% response rate, 49 women and 13 men), there were 27 (44%) whose foot pain deteriorated. A higher MCS score of the SF-36 health survey at baseline was associated with a slower progression of foot pain (ß coefficient −0.29, 95% confidence interval −0.42, −0.01), adjusted for age, sex, BMI, and physical health. CONCLUSION: Mental health is associated with changes in foot pain. Clinicians dealing with this population should consider the contribution of mental health in their management and treatment of foot pain.

The relationship between foot posture and lower limb kinematics during walking: A systematic review.

Variations in foot posture, such as pes planus (low-arched foot) or pes cavus (high-arched foot), are thought to be an intrinsic risk factor for injury due to altered motion of the lower extremity. Hence, the aim of this systematic review was to investigate the relationship between foot posture and lower limb kinematics during walking. A systematic database search of MEDLINE, CINAHL, SPORTDiscus, Embase and Inspec was undertaken in March 2012. Two independent reviewers applied predetermined inclusion criteria to selected articles for review and selected articles were assessed for quality. Articles were then grouped into two broad categories: (i) those comparing mean kinematic parameters between different foot postures, and (ii) those examining associations between foot posture and kinematics using correlation analysis. A final selection of 12 articles was reviewed. Meta-analysis was not conducted due to heterogeneity between studies. Selected articles primarily focused on comparing planus and normal foot postures. Five articles compared kinematic parameters between different foot postures - there was some evidence for increased motion in planus feet, but this was limited by small effect sizes. Seven articles investigated associations between foot posture and kinematics - there was evidence that increasing planus foot posture was positively associated with increased frontal plane motion of the rearfoot. The body of literature provides some evidence of a relationship between pes planus and increased lower limb motion during gait, however this was not conclusive due to heterogeneity between studies and small effect sizes.