Search

Heterotopic ossification (HO), the pathological formation of ectopic bone, is a debilitating condition which can cause chronic pain, limit joint movement, and prevent prosthetic limb fitting. The prevalence of this condition has risen in the military population, due to increased survivorship following blast injuries. Current prophylaxes, which aim to target the complex upstream biological pathways, are inconsistently effective ​and have a range of side-effects that make them unsuitable for combat-injured personnel. As such, many patients must undergo further surgery to remove the formed ectopic bone. In this study, a non-toxic, U.S. Food and Drug Administration (FDA) -approved calcium chelator, hexametaphosphate (HMP), is explored as a novel treatment paradigm for this condition, which targets the chemical, rather that biological, ​bone formation pathways. This approach allows not only prevention of pathological bone formation ​but also uniquely facilitates reversal, which current drugs cannot achieve. Targeted, minimally invasive delivery is achieved by loading HMP into an injectable colloidal alginate. These formulations significantly reduce ​the length of the ectopic bone formed in a rodent model of HO, with no effect on the adjacent skeletal bone. This study demonstrates the potential of localized dissolution as a new treatment ​and an alternative to surgery ​for pathological ossification and calcification conditions., Competing Interests: The authors have no competing interests to declare., (© 2020 The Author(s).)

Background: Incidences of colorectal cancer (CRC) and inflammatory bowel disease (IBD) are increasing in those aged <50 years., Aim: To identify and quantify clinical features in primary care of CRC/IBD in those aged <50 years. This study considered the two conditions together and aimed to determine which younger patients, presenting in primary care with symptoms, would benefit from investigation for potentially serious colorectal disease., Design and Setting: Matched case-control study using primary care records from the Clinical Practice Research Datalink, UK., Method: Incident cases (aged <50 years) of CRC ( n = 1661) and IBD ( n = 9578) diagnosed between 2000 and 2013 were each matched with up to three controls ( n = 3979 CRC; n = 22 947 IBD). Odds ratios (OR) and positive predictive values (PPV) were estimated for features of CRC/IBD in the year before diagnosis., Results: Ten features were independently associated with CRC/IBD (all P <0.001): rectal bleeding, change in bowel habit, diarrhoea, raised inflammatory markers, thrombocytosis, abdominal pain, low mean cell volume (MCV), low haemoglobin, raised white cell count, and raised hepatic enzymes. PPVs were >3% for rectal bleeding with diarrhoea, thrombocytosis, low MCV, low haemoglobin or raised inflammatory markers; for change in bowel habit with low MCV, thrombocytosis or low haemoglobin; and for diarrhoea with thrombocytosis., Conclusion: This study quantified the risk of serious bowel disease in symptomatic patients aged <50 years in primary care. Rectal bleeding and change in bowel habit are strongly predictive of CRC/IBD when combined with abnormal haematology. The present findings help prioritise patients for colonoscopy where the diagnosis is not immediately apparent., (© British Journal of General Practice 2017.)

Objectives: To estimate data loss and bias in studies of Clinical Practice Research Datalink (CPRD) data that restrict analyses to Read codes, omitting anything recorded as text., Design: Matched case-control study., Setting: Patients contributing data to the CPRD., Participants: 4915 bladder and 3635 pancreatic, cancer cases diagnosed between 1 January 2000 and 31 December 2009, matched on age, sex and general practitioner practice to up to 5 controls (bladder: n=21 718; pancreas: n=16 459). The analysis period was the year before cancer diagnosis., Primary and Secondary Outcome Measures: Frequency of haematuria, jaundice and abdominal pain, grouped by recording style: Read code or text-only (ie, hidden text). The association between recording style and case-control status (χ(2) test). For each feature, the odds ratio (OR; conditional logistic regression) and positive predictive value (PPV; Bayes' theorem) for cancer, before and after addition of hidden text records., Results: Of the 20 958 total records of the features, 7951 (38%) were recorded in hidden text. Hidden text recording was more strongly associated with controls than with cases for haematuria (140/336=42% vs 556/3147=18%) in bladder cancer (χ(2) test, p<0.001), and for jaundice (21/31=67% vs 463/1565=30%, p<0.0001) and abdominal pain (323/1126=29% vs 397/1789=22%, p<0.001) in pancreatic cancer. Adding hidden text records corrected PPVs of haematuria for bladder cancer from 4.0% (95% CI 3.5% to 4.6%) to 2.9% (2.6% to 3.2%), and of jaundice for pancreatic cancer from 12.8% (7.3% to 21.6%) to 6.3% (4.5% to 8.7%). Adding hidden text records did not alter the PPV of abdominal pain for bladder (codes: 0.14%, 0.13% to 0.16% vs codes plus hidden text: 0.14%, 0.13% to 0.15%) or pancreatic (0.23%, 0.21% to 0.25% vs 0.21%, 0.20% to 0.22%) cancer., Conclusions: Omission of text records from CPRD studies introduces bias that inflates outcome measures for recognised alarm symptoms. This potentially reinforces clinicians' views of the known importance of these symptoms, marginalising the significance of 'low-risk but not no-risk' symptoms., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Non-union of fractured bone is a major cause of morbidity in the orthopaedic population. Despite this, optimal management of non-union is still unclear and remains a significant clinical challenge. Research continues in animal models in an attempt to identify an effective clinical treatment. The proposed systematic review will evaluate current therapies of bone non-union in animal models, in order to identify those that may translate successfully to clinical therapies., Methods/design: The methodology for the systematic review will be in accordance with standard guidelines. All potential sources for pre-clinical studies will be interrogated and the search strategy written in conjunction with a specialist in this field. Data extraction will be conducted by two reviewers to minimise bias. Analysis will be predominantly qualitative because of the heterogeneity that is likely to exist between the studies. However, quantitative synthesis will be performed where homogeneity in a sub-group of studies exists. Quality assessment will be undertaken utilising a risk of bias tool., Discussion: To date, there has not been a systematic review addressing bone non-union therapies in animal models despite the plethora of pre-clinical research currently being undertaken. This protocol details and outlines the methodology and justification for such a review.

Background: Diagnosis of bladder cancer relies on investigation of symptoms presented to primary care, notably visible haematuria. The importance of non-visible haematuria has never been estimated., Aim: To estimate the risk of bladder cancer with non-visible haematuria., Design and Setting: A case-control study using UK electronic primary care medical records, including uncoded data to supplement coded records., Method: A total of 4915 patients (aged ≥40 years) diagnosed with bladder cancer between January 2000 and December 2009 were selected from the Clinical Practice Research Datalink and matched to 21 718 controls for age, sex, and practice. Variables for visible and non-visible haematuria were derived from coded and uncoded data. Analyses used multivariable conditional logistic regression, followed by estimation of positive predictive values (PPVs) for bladder cancer using Bayes' theorem., Results: Non-visible haematuria (coded/uncoded data) was independently associated with bladder cancer: odds ratio (OR) 20 (95% confidence interval [CI] =12 to 33). The PPV of non-visible haematuria was 1.6% (95% CI = 1.2 to 2.1) in those aged ≥60 years and 0.8% (95% CI = 0.1 to 5.6) in 40-59-year-olds. The PPV of visible haematuria was 2.8% (95% CI = 2.5 to 3.1) and 1.2% (95% CI = 0.6 to 2.3) for the same age groups respectively, lower than those calculated using coded data alone. The proportion of records of visible haematuria in coded, rather than uncoded, format was higher in cases than in controls (P<0.002, χ(2) test). There was no evidence for such differential recording of non-visible haematuria by case/control status (P = 0.78), although, overall, the uncoded format was preferred (P<0.001)., Conclusion: Both non-visible and visible haematuria are associated with bladder cancer, although the visible form confers nearly twice the risk of cancer compared with the non-visible form. GPs' style of record keeping varies by symptom and possible diagnosis., (© British Journal of General Practice 2014.)

The use of hypertonic saline Dextran (HSD) for resuscitation following trauma has many potential benefits, especially for the treatment of military casualties, but there is very limited data on the responses following multiple dosing with this fluid. The effects of a second dose of hypertonic saline dextran for resuscitation of uncontrolled intra-abdominal haemorrhage were studied in an experimental model. Under general anaesthesia, 17 large white pigs (weight range, 48-67 kg) were subjected to uncontrolled hemorrhage produced by a tear in the common iliac artery. This resulted in a significant (P < 0.01) reduction of both mean arterial pressure (MAP) and cardiac index. One hour after injury, animals were assigned to one of three groups, receiving either no resuscitation (Group A), or two doses of HSD (at a dose rate of 4 mL/kg), administered either 1 and 4 h after injury (Group B) or 1 and 7 h after injury (Group C). Animals were monitored for 12 h post-injury. A second infusion of HSD caused a significant hypernatremia and diuresis (P< 0.01) in both Groups B and C. There was a non-significant rise in MAP in both treatment groups, and in Group B only, there was a significant increase in cardiac index (P= 0.014). It is concluded that repeat administration of HSD for the resuscitation of uncontrolled hemorrhage results in limited cardiovascular improvements, but that the metabolic sequelae are potentially detrimental to survival.

Peroxidation of low density lipoproteins (LDL) may be involved in the development of atherosclerosis which is prevalent in patients with chronic renal failure and renal transplant recipients. We determined the copper ion catalyzed oxidation in vitro, vitamin E content, and chemical and fatty acid composition of LDL isolated from 38 patients with renal disease and 15 healthy subjects. Also the acute effect of hemodialysis treatment on LDL oxidation variables was tested. The lag time in conjugated diene formation during oxidation was significantly (P = 0.011) shorter in LDL from renal transplant recipients (66 min, N = 18) mainly due to significantly (P < 0.05) shorter times in women (47 min, N = 7), compared with healthy subjects (83 min, N = 15), patients on hemodialysis (91 min, N = 13) and patients treated by continuous ambulatory peritoneal dialysis (CAPD) (82 min, N = 7). The maximum rate and the extent of LDL oxidation were significantly (P < 0.01) lower in all patients with renal disease compared with healthy subjects. The triglyceride content of LDL was significantly (P < 0.001) higher in women with kidney grafts (7.3%) compared with levels in the corresponding men (5.3%) and healthy women (5.0%), and was correlated significantly with the lag time in LDL oxidation in renal transplant recipients (Spearmans r = -0.502, P = 0.034). The percentage oleic acid in LDL was significantly higher (P = 0.002) and the percentage linoleic acid was significantly lower (P = 0.046) in patients with renal disease, and may largely account for their lower rates and extent of LDL oxidation. Levels of the LDL oxidation variables and organic lipid peroxide content of LDL were not significantly different before and after hemodialysis and 24 hours later. These results suggest that LDL from women with renal transplants may be abnormally susceptible to oxidation possibly due to increased triglyceride content.