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Aims: Diabetic patients are at elevated risk of neuropathy; early detection is desirable to minimise the risk of complications. The Medipin pin-prick device was appraised as a screening tool for diabetic neuropathy., Methods: Prospective cross-sectional comparative screening study in primary care setting, involving 389 participants with type 2 diabetes mellitus. The Medipin pin-prick method, involving dorsal application on the hallux of both feet, was compared to 10 g monofilament testing., Results: The ternary and semi-quantitative approach for scoring Medipin pin-prick sensation give very similar results (Spearman rho 0.67, P < 0.001). A total of 59 % patients had no signs of neuropathy (sharp sensation), 38 % reported impaired sensation (dull sensation), and an absence of sensation occurred in 3 % of patients. For the monofilament dorsal method, the figures were 79 % no neuropathy, 14 % elevated risk, and 7 % neuropathy respectively, and with the monofilament plantar method 87 % of patients had no neuropathy and 13 % did. Correlation analyses showed that taller patients and those with existing neuropathic pain are at very modest increased risk of neuropathy., Conclusions: The Medipin pin-prick device can identify diabetic neuropathy and detects (first signs of) neuropathy in relatively more patients than 10 g monofilament testing. The differential targeting of nerve types, namely predominant small (Medipin) versus large (monofilament) fibre, likely underpins the difference in outcomes., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Investigate efficacy of reduced compression bandage for the control of pain after total knee arthroplasty., Patients & Methods: Prospective, single-centre, randomised controlled trial involving data for 56 out of 94 consented patients; 29 standard care versus 27 Andoflex TLC Calamine Lite. Comparison of standard care (non-compression bandage applied for up to one day) versus Andoflex TLC Calamine Lite (25-30 mmHg) two-layer compression bandage worn for five days. Outcomes measured with validated pain (McGill, 10-cm visual scale) and functionality (KOOS) tools., Results: At day 5 post-surgery, the median pain level was 3.0 cm vs 4.0 cm (p-value 0.47, Mann-Whitney U test) respectively. Generic pain levels, pain types, and knee functionality did not differ between the interventions at days 3/5/12 and week 6 post-surgery. An exception was the degree of 'tender' pain at day 12, which was significantly lower in the Andoflex TLC Calamine Lite arm (p-value 0.041, Mann-Whitney U test). Binary logistic regression analysis showed that application of Andoflex TLC Calamine Lite, administration of oxycodone, and male sex were all significantly associated with less 'tender' pain., Conclusion: Reduced compression bandaging does not affect overall pain levels post knee arthroplasty surgery, but may alleviate pain experienced as 'tender', highlighting the different types of pain that may be experienced. Patients' need for, and the use of, opioid medication (oxycodone) is a significant confounding variable when assessing adjuvant therapy to control pain. The applicability of reduced compression bandaging may therefore be limited and is less efficient than medical pain control., Competing Interests: Declaration of competing interest Leon Jonker has in past received a single honorarium for non-orthopaedic consultancy work for Milliken Healthcare. The other authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Assess the efficacy, and potential impact of patient positioning for 10 minutes immediately post-procedure, of greater occipital nerve (GON) block for treatment of migraine., Methods: Prospective multicentre non-blinded randomised controlled trial, randomisation and treatment of 60 neurology clinic patients with poorly controlled migraine. Outcomes measured with Headache Impact Test-6 (HIT-6), modified MIgraine Disability Assessment Scale (M-MIDAS), and RELIEF scores., Results: Patient positioning did not lead to significant difference in RELIEF score (34% vs 11%, p-value 0.10, Chi-squared test) at day 90. When considered in a multiple regression analysis, the sitting position outperformed supine position significantly (p-value 0.04). However, no significant difference in HIT-6 score between the supine (n = 27) and sitting position groups (n = 33) was detected at baseline (p-value 0.76), day 30 (p-value 0.69) or day 90 (p-value 0.54, Mann-Whitney U-test). The HIT-6 score significantly improved post-GON block, from median 67 (baseline pre-GON) to 59 (day 30) and 62 (day 90) for the supine group and a score of 66, 61-62 for the sitting group (all p-value ≤ 0.001, intra-group comparison using Wilcoxon test); M-MIDAS achieved similar outcomes. Overall, a significant minimal clinically important improvement was obtained with GON block, and the GON injections were deemed very tolerable by patients (median score of 2 on 10 cm pain scale)., Conclusion: Regardless of patient positioning, GON block is an effective and near-painless procedure for migraine symptom control. Unlike earlier published observational study data, this trial concludes that a sitting patient position immediately post-GON is preferred., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The etiology of cryptorchidism remains poorly understood. Endocrine disrupting chemicals can impact estrogen signaling by interacting with aryl hydrocarbon receptor (AhR) activity., Objective: To evaluate whether AhR activity in breast milk samples is associated with cryptorchidism., Method: We conducted a case-control study based on 199 mother-child pairs (n = 91 cases/108 controls) selected from the Norwegian Human Milk Study (2002-2009). We defined cases for cryptorchidism based on maternal reports at 1-, 6-, 12-, and 24- months after birth. Chemically- and biologically stable AhR activity (pg 2,3,7,8-TCDD equivalent (TEQ)/g lipid) was determined by DR- CALUX® assay in the mothers' milk collected at a median of 33 (10th-90th percentile: 18-57) days after delivery. We used multivariate logistic regression to compare AhR activity levels between cases and controls, and linear regression separately, to establish the relationship with the presence of 27 potential EDCs measured in breast milk and AhR activity., Results: The average estimated daily intake (EDI) of dioxin and (dioxin-like (dl)-compounds via breast milk is 33.7 ± 17.9 pg TEQ/kg bodyweight per day among Norwegian children. There were no significant differences in AhR activation in breast milk samples between cases with cryptorchidism and controls. Among the 27 chemicals measured in breast milk, AhR activity was (borderline) significantly associated with all dl-PCBs, three non-dioxin-like (ndl)-PCBs (PCB-74, PCB-180, PCB-194) and two organochlorine pesticides (OCPs; HCB, β-HCH). No associations between AhR activity and brominated flame retardants (PBDEs) or poly- and perfluoroalkyl substances (PFASs)., Conclusion: No association between AhR activity and cryptorchidism was found among Norwegian boys. The average EDI of dioxin and dl-compounds in exclusively breastfed Norwegian infants remains above the safety threshold and, therefore requires further reduction measures. Consistent with a possible role in the observed AhR activity, all dl-PCBs were associated with AhR activity whereas the association was null for either PBDEs or PFASs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Headache diaries are recommended for migraine management in primary care., Objective: Determine the acceptability and use of a digital headache diary App for migraine METHODS: Evaluative prospective primary care cohort study in North of England. Part 1 was a postal survey; if responders were interested, in Part 2 participants trialled the digital N1-Headache App headache diary for 90 days, followed by survey feedback on the App's usability., Results: A total of 637 out of 2189 invited patients (29%) completed the initial survey, and 32% of respondents had previously used a headache diary; 437 out of 637 patients (69%) were interested in using the App. Regression analysis showed that interested patients were those with more severe migraines that limit physical/intellectual activities, and who indicate to not know enough about their migraine. Actual registration numbers and compliance with the App was very modest; 53 out of 173 participants (23%), who ultimately activated their personal N1-Headache App account, were able to generate a personalised trigger and protector map & report. Furthermore, at the end of the 90 day App trial period there was a non-significant trend towards improvements in participants' health confidence levels., Conclusion: Migraine patients - particularly those with more severe and frequent migraines - show an interest in using a digital headache diary App, Ultimately, consistent daily use is very modest. The challenge is to improve App usage and compliance rates to allow interpretation of more patients' migraine trigger and/or protector patterns, and wider use amongst patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To assess if application of dual-layer compression bandage to osteotomy patients post-surgery can positively influence levels of post-operative pain and swelling., Patients & Methods: Prospective, single-centre, randomised controlled trial comparing standard care, non-compression bandaging, versus Coban™ 2 (3M). Seven day application of the latter to index leg of osteotomy patients., Results: Primary outcome data was available for 36 out of 49 study subjects (18 standard care versus 18 Coban™ 2 subjects). Median 10-cm scale pain levels showed a statistically non-significant difference at day 5 and day 12 post-surgery between standard care and Coban™ 2 respectively: 5.5 cm vs 2.5 cm (p-value 0.068) and 4.0 cm vs 2.3 cm (p-value 0.39). However, on day 12 (p-value 0.029) and week 6 (p-value 0.027), 'throbbing pain' was significantly higher for Coban™ 2 patients. Changes in limb swelling measures, comparing before and after the surgical procedure, did not differ between treatment arms. Compression led to more patients reporting bandage-related discomfort (6% standard care versus 63% Coban™ 2 patients)., Conclusion: Compression bandaging changes the post-surgery pain profile in osteotomy patients, but does not reduce leg swelling. Any subsequent leg compression trials must take into account patient comfort and titrate intervention length and compression rates., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Greater occipital nerve (GON) block is a treatment option applied for a variety of primary headache disorders. Although a patient's body position is known to have an impact on the effect of local anaesthetics, this has not before been investigated for patients undergoing GON block. Therefore, the clinical effectiveness of either a sitting or supine position was assessed., Patients and Methods: This evaluative prospective study took place in a single neurology department in the UK. Baseline and follow-up data were collated during standard clinic consultations for 95 consecutive patients who underwent GON block and follow-up consultations for treatment-refractory headache disorder. The GON block procedure was identical for all patients in terms of constitution of the applied medication and volume injected (lidocaine hydrochloride 20 mg and methylprednisolone acetate 80 mg in 2 ml vial). Directly afterwards, patients opted to either sit up (n = 34) or lie down (n = 61) for ten minutes., Results: Twenty-seven patients (44%) reported substantial benefit and 17 (28%) complete benefit (pain freedom) for a median duration of 70 days and 84 days in the 'supine' group, compared with 10 (29%) substantial and 6 (18%) complete benefit (pain freedom) for a median duration of 25 days (substantial) and 119 days (complete) in the 'sitting' group. Overall, a supine position results in a longer overall post-GON block headache-free period (p-value 0.007) and median relief score (p-value 0.017) compared to a sitting up position, as determined by Mann-Whitney U-test. Backward multiple linear regression analysis showed that the chronicity of the patient's condition is negatively associated (beta -0.24, p-value 0.024) and the post-GON block patient position is positively associated (beta 0.25, p-value 0.018) with the achieved headache-free period. Apart from variation in baseline headache characteristics, the 'sitting' and 'supine' cohorts did not significantly differ in terms of other clinical parameters and patient demographics., Conclusions: Placing a patient in a supine position following a GON block procedure for headache may significantly improve the resulting clinical effectiveness of this treatment. Further research, through a prospective, multi-centre, randomised, controlled trial, is indicated to determine if the initial positive observations in this present pragmatic evaluation can be confirmed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Evidence supporting the notion that clinical research activity in itself is of benefit to organisations as a whole is inconclusive. In the recent past, a positive association between research activity and reduced mortality has been shown. This study aimed to ascertain if clinical research activity is associated with established organisational outcome measures., Study Design: Retrospective cross-sectional study., Methods: For 129 English National Health Service hospital Trusts, National Institute for Health Research study activity data, Summary Hospital-level Mortality Indicator (SHMI) scores and Care Quality Commission (CQC) ratings were collected. Research activity was controlled for Trust size by dividing it by clinical staffing levels. Multiple linear regression and Spearman correlation analyses were performed., Results: Although there is a significant association between the number of studies and participants with both SHMI score and CQC rating, one particular variable is correlated more significantly than others: the number of participants recruited into interventional studies. It shows a significant correlation with better CQC ratings (standardised coefficient beta 0.26, P-value 0.003) and lower SHMI scores (standardised coefficient beta -0.50, P-value 0.001)., Conclusions: The mortality-related results corroborate with other published data showing a correlation between increased research and reduced deaths. Furthermore, there is also a statistically significant association between clinical trials activity and improved CQC ratings. However, these tie-ins are predominantly driven by the number of participants in interventional research rather than observational research activity., (Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Objective: Since the late 2000's, the creation of the National Institute for Health Research (NIHR) has transformed clinical research activity in the United Kingdom. This study sought to establish if there is a link between clinical research activity and overall NHS Trust performance., Study Design: Retrospective cohort study., Methods: Data for NHS Trust performance were obtained from public databases, namely the Care Quality Commission (CQC) 2013 risk rating for overall performance, and 2012-13 NIHR records for clinical research activity., Results: Applying Spearman's rank analysis, none of the Trust categories showed a correlation with CQC risk rating: small hospitals, r = -0.062 (P = 0.76; n = 27); medium, r = -0.224 (P = 0.13; n = 47); large, r = -0.008 (P = 0.96; n = 57); academic, r = -0.18 (P = 0.41; n = 24). Similar results were observed when CQC risk rating was compared with the number of different clinical research studies conducted per Trust., Conclusion: The degree of NIHR National Portfolio clinical research activity is not significantly related to CQC risk rating, used as an indicator of overall NHS Trust performance. Other studies have previously shown that increased research activity correlates with improved mortality rates, one component of CQC risk rating scores. Alternative tools may have to be explored to evaluate the impact of clinical research on NHS Trusts and its patients., (Copyright © 2015 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism., Methods: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured., Results: Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters., Conclusions: Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566)., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: We investigated whether the POSSUM physiology score, originally designed as an indicator for 30-day mortality for comparative audit, could be used as an indicator of long-term survival in vascular surgery practice., Methods: Data from 184 different vascular procedures conducted between 1989 and 2000, containing survival data for each patient of 10 years or longer, were analysed retrospectively. Parameters collected were the pre-operative physiological and the operative severity POSSUM score, gender, and type of procedure. Multivariate analyses were performed using Cox regression method and, on the basis of their physiological POSSUM score grouping, Kaplan-Meier analysis was performed for estimation of overall survival., Results: Both an increase in physiological POSSUM score (hazard ratio [HR] 1.050, 95% confidence interval [CI] 1.031 to 1.070) and one of its components, age (HR 1.025, 95% CI 1.006 to 1.045; p = 0.009), were shown to be indicators of long-term all-cause mortality. The sample's mean physiological POSSUM score of 21 was then used as a cut-off point to categorise low and high-risk vascular surgery patients. Median survival in the low-risk group was 70 months (95% CI 56-86 months), whereas in the high-risk group this was 17 months (95% CI 3-31 months)., Conclusion: The physiological POSSUM score, including patient age, is an indicator of long-term survival of patients with vascular disease. This may help in choosing the appropriate vascular intervention., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Objectives: We aimed to survey the current management of venous thromboprophylaxis in patients undergoing elective surgery for abdominal aortic aneurysm (AAA) by vascular surgeons in the United Kingdom., Design: A questionnaire was designed to investigate anticoagulation strategies in the perioperative period of elective AAA repair, both open and endovascular. This included both chemical and mechanical prophylaxis. A total of 395 questionnaires was posted to the members of the Vascular Society of Great Britain and Ireland., Results: One hundred and seventy-two (44%) valid responses were received. Half of the respondents administered pre-operative chemical prophylaxis at a mean of 13 h prior to AAA surgery. There was a high level of concordance in administration of heparin during surgery and in thromboprophylaxis post-operatively, with 97% giving some form of thromboprophylaxis. However there was a variation in the dose and timing, if administered, of chemical and mechanical prophylaxis., Conclusion: The survey revealed diversity in perioperative thromboprophylaxis strategies among vascular surgeons. This suggests that standardisation of pre-operative and post-operative mechanical and chemical thromboprophylaxis may be required which could potentially improve the outcomes in elective management of AAA in the UK., (Copyright © 2011 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

The practise of Immediate Breast Reconstruction (IBR) following mastectomy for primary breast cancer is being increasingly adopted. Here the impact of IBR on disease progression and survival was assessed following treatment for invasive breast cancer. 1697 consecutive patients received surgical treatment for operable primary breast cancer between January 1996 and December 2007. Overall, 691 (41%) received mastectomy of whom 136 (20%) underwent IBR (82 Latissimus Dorsi, 54 Subpectoral). The effect of IBR on overall survival, local and distant recurrence was analysed in all patients studied and also separately within subgroups defined by Nottingham Prognostic Index (NPI) scores. The median follow up of patients studied was 55 months (range 16-148). There was no difference between IBR and mastectomy alone in survival (p=0.176), time to distant metastasis (p=0.783) or local recurrence (p=0.505), either overall or within Nottingham Prognostic groups., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

This study was designed to increase the diagnostic detection rate for subtelomeric unbalanced chromosomal rearrangements (UCRs) that are believed to cause 3-5% of all cases of mental retardation (MR), but often remain undetected by routine karyotyping because of limited resolution in light microscopy. Increased detection of such cryptic UCRs may be achieved by CGH- or SNP-array technology adapted for genome wide screening but these techniques are labor-intensive and expensive. We have implemented subtelomeric Multiplex Ligation-dependant Probe Amplification (MLPA), a relatively low cost and technically uncomplicated molecular approach, as a high throughput prospective screening tool for UCRs in MR patients. We prospectively studied a cohort of 466 MR patients and detected 53 aberrant MLPA signals. After exclusion of false-positives, potential familial polymorphisms and of non-cryptic UCRs also found in routine chromosome analysis, 18 cases or 3.9% of total could be confirmed as true cryptic subtelomeric UCRs. These were 6 terminal deletions, 8 unbalanced translocations, 3 Prader-Willi deletions and 1 subtelomeric interstitial deletion. This result increases our laboratory's detection rate in this patient cohort from 8.3% (without MLPA) to 12.2% (with MLPA), representing a 47% improvement. This study demonstrates that when applying MLPA in a routine cytogenetic diagnostic setting, a major increase of the diagnostic yield can be achieved.

The epidermis is a derivative of the surface ectoderm. It forms a protective barrier and specific appendages including hair, nails, and different eccrine glands. The surface ectoderm also forms the epithelium of the oral cavity and tongue, which develop a slightly different barrier and form different appendages such as teeth, filiform papillae, taste papillae, and salivary glands. How this region-specific differentiation is genetically controlled is largely unknown. We show here that Pax9, which is expressed in the epithelium of the tongue but not in skin, regulates several aspects of tongue-specific epithelial differentiation. In Pax9-deficient mice filiform papillae lack the anterior-posterior polarity, a defect that is associated with temporal-spatial changes in Hoxc13 expression. Barrier formation is disturbed in the mutant tongue and genome-wide expression profiling revealed that the expression of specific keratins (Krt), keratin-associated proteins, and members of the epidermal differentiation complex is significantly down-regulated. In situ hybridization demonstrated that several 'hard' keratins, Krt1-5, Krt1-24, and Krt2-16, are not expressed in the absence of Pax9. Notably, specific 'soft' keratins, Krt2-1 and Krt2-17, normally weakly expressed in the tongue but present at high levels in skin and in orthokeratinized oral dysplasia are up-regulated in the mutant tongue epithelium. This result indicates a partial trans-differentiation to an epithelium with skin-specific characteristics. Together, our findings show that Pax9 regulates appendage formation in the mammalian tongue and identify Pax9 as an important factor for the region-specific differentiation of the surface ectoderm.

The metabolic pathway of the PAH fluorene and the cometabolic pathway of the PAHs phenanthrene, fluoranthene, anthracene and dibenzothiophene in Sphingomonas sp. LB126 were examined. To our knowledge this is the first study on the cometabolic degradation of the three-ring PAHs phenanthrene, anthracene and the four-ring PAH fluoranthene by a fluorene-utilizing species. Metabolism of fluorene was shown to proceed via the 9-fluorenone pathway to form o-phthalic acid and protocatechuic acid. The cometabolic mono-hydroxylation found for phenanthrene, fluoranthene and anthracene shows similarity with the hydroxylation of fluorene. Several mono- and dihydroxy products and ring-cleavage products were identified for phenanthrene, fluoranthene and anthracene. It appeared that the cometabolism of those three compounds is a non-specific process, in contrast to the metabolism of fluorene. For dibenzothiophene the metabolites dibenzothiophene-5-oxide and dibenzothiophene-5,5-dioxide were identified; these compounds appeared to be the products of a dead-end pathway. Since apart from dibenzothiophene no metabolites were found in very high concentrations for any of the other substrates, complete degradation is suggested, even for the cometabolic degradation of phenanthrene, fluoranthene and anthracene.

Endoglin is an auxiliary receptor for the transforming growth factor-beta family of cytokines and is required for angiogenesis and heart development. Endoglin expression during mouse embryogenesis was analysed by monitoring beta-galactosidase expression from a lacZ reporter cassette inserted downstream of the endoglin promoter. Expression was first detected at 6.5 days post-coitum (dpc) in the amniotic fold and developing allantois. Between 7.5 and 8.5 dpc, endoglin was expressed in endothelial cells of the yolk sac, dorsal aorta and primitive heart tube, and from 9.5 to 13.5 dpc in endothelial cells throughout the developing vasculature. Interestingly, this pattern of endoglin expression is almost identical to that reported for Alk1.