Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes.

BACKGROUND: 90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown. METHODS: All radiotherapy treatments delivered in a curative setting over seven years were extracted from the local electronic health record and linked to cancer registry data. 90DM rates were assessed and factors associated with this outcome were investigated using logistic regression. Cause of death was identified retrospectively further characterising the cause of 90DM. RESULTS: Overall 90DM was 1.25%. Levels varied widely with diagnosis (0.20-5.45%). Age (OR 1.066, 1.043-1.073), year of treatment (OR 0.900, 0.841-0.969) and diagnosis were significantly associated with 90DM on multi-variable logistic regression. Cause of death varied with diagnosis; 50.0% post-operative in rectal cancer, 40.4% treatment-related in head and neck cancer, 59.4% disease progression in lung cancer. CONCLUSION: Despite the drive to report centre level comparative outcomes, this study demonstrates that 90DM cannot be adopted routinely asa clinical indicator due to significant population heterogeneity and low event rates. Further national investigation is needed to develop a meaningful robust indicator to deliver appropriate comparisons and drive improvements in care.

Mechanical performance in axial compression of a titanium polyaxial locking plate system in a fracture gap model.

OBJECTIVE: To evaluate the bending strength of the VetLOX® polyaxial locking plate system. MATERIALS AND METHODS: Thirty-five 3.5 mm 12-hole titanium VetLOX® plates were used to stabilize seven different construct designs in a 1 cm fracture gap simulation model. Each construct was subjected to axial compression. Mean bending stiffness (BS) and yield load (YL) of each construct design were analysed using a one-way ANOVA and Tukey post-hoc analysis. Screw angulation was measured on reconstructed computed tomography (CT) images. RESULTS: Reducing plate working length for fixed-angle constructs significantly increased BS (p <0.01) and YL (p <0.01). For a constant plate working length, increasing screw number did not significantly affect BS (p = 1.0) or YL (p = 0.86). Screw angulation measurement technique was validated by intra-class correlation coefficients (ICC) (ICC >0.9 for inter- and intra-observer measurements). An average screw angle of 13.2° did not significantly affect mechanical performance although incomplete screw head-plate engagement was noted on some reconstructed CT images when angulation exceeded 10°. Prefabricated screw-head inserts did not significantly increase mechanical performance. A 4 mm bone-plate stand-off distance significantly reduced BS and YL by 63% and 69% respectively. CLINICAL RELEVANCE: The VetLOX® system allows the benefits of polyaxial screw insertion whilst maintaining comparable bending properties to fixed angle insertion. The authors recommend accurate plate contouring to reduce the risk of plate bending.

Preliminary evidence of an effect of cerebellar volume on postural sway in FMR1 premutation males.

Recent evidence suggests that early changes in postural control may be discernible among females with premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene at risk of developing fragile X-associated tremor ataxia syndrome (FXTAS). Cerebellar dysfunction is well described in males and females with FXTAS, yet the interrelationships between cerebellar volume, CGG repeat length, FMR1 messenger RNA (mRNA) levels and changes in postural control remain unknown. This study examined postural sway during standing in a cohort of 22 males with the FMR1 premutation (ages 26-80) and 24 matched controls (ages 26-77). The influence of cerebellar volume, CGG repeat length and FMR1 mRNA levels on postural sway was explored using multiple linear regression. The results provide preliminary evidence that increasing CGG repeat length and decreasing cerebellar volume were associated with greater postural sway among premutation males. The relationship between CGG repeat length and postural sway was mediated by a negative association between CGG repeat size and cerebellar volume. While FMR1 mRNA levels were significantly elevated in the premutation group and correlated with CGG repeat length, FMR1 mRNA levels were not significantly associated with postural sway scores. These findings show for the first time that greater postural sway among males with the FMR1 premutation may reflect CGG repeat-mediated disruption in vulnerable cerebellar circuits implicated in postural control. However, longitudinal studies in larger samples are required to confirm whether the relationships between cerebellar volume, CGG repeat length and postural sway indicate greater risk for neurological decline.

The strategies to reduce iron deficiency in blood donors randomized trial: design, enrolment and early retention.

BACKGROUND AND OBJECTIVES: Repeated blood donation produces iron deficiency. Changes in dietary iron intake do not prevent donation-induced iron deficiency. Prolonging the interdonation interval or using oral iron supplements can mitigate donation-induced iron deficiency. The most effective operational methods for reducing iron deficiency in donors are unknown. MATERIALS AND METHODS: 'Strategies To Reduce Iron Deficiency' (STRIDE) was a two-year, randomized, placebo-controlled study in blood donors. 692 donors were randomized into one of two educational groups or one of three interventional groups. Donors randomized to educational groups either received letters thanking them for donating, or, suggesting iron supplements or delayed donation if they had low ferritin. Donors randomized to interventional groups either received placebo, 19-mg or 38-mg iron pills. RESULTS: Iron deficient erythropoiesis was present in 52·7% of males and 74·6% of females at enrolment. Adverse events within 60 days of enrolment were primarily mild gastrointestinal symptoms (64%). The incidence of de-enrolment within 60 days was more common in the interventional groups than in the educational groups (P = 0·002), but not more common in those receiving iron than placebo (P = 0·68). CONCLUSION: The prevalence of iron deficient erythropoiesis in donors enrolled in the STRIDE study is comparable to previously described cohorts of regular blood donors. De-enrolment within 60 days was higher for donors receiving tablets, although no more common in donors receiving iron than placebo.

Timing of surgical reconstruction for closed traumatic injury to the supraclavicular brachial plexus.

While it is widely accepted that cases of traumatic injury to the brachial plexus benefit from early surgical exploration and repair, with results deteriorating with long delays, policies vary regarding the exact timing of intervention. This is one of a pair of review articles considering the clinical issues, investigations, and surgical factors relating to management of injuries to the supraclavicular brachial plexus, as well evidence from experimental work and clinical outcomes.In this article Professor Birch argues for early exploration of the brachial plexus as the optimum both to delineate the pathology and undertake reconstructive surgery.

Understanding the neuropsychiatric phenotype of fragile X-associated tremor ataxia syndrome: a systematic review.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a recently identified X-linked neurodegenerative disorder affecting a proportion of premutation carriers of the Fragile X Mental Retardation 1 (FMR1) gene. Previous research suggests that cognitive and psychiatric features of FXTAS may include primary impairments in executive function and increased vulnerability to mood and anxiety disorders. A number of these reports, however, are based on overlapping cohorts or have produced inconsistent findings. A systematic review was therefore conducted to further elucidate the neuropsychiatric features characteristic of FXTAS. Fourteen papers met inclusion criteria for the review and were considered to represent nine independent FXTAS cohorts. Findings from the review suggest that the neuropsychiatric phenotype of FXTAS is characterised primarily by poorer performance on measures of executive function, working memory, information processing speed, and fine motor control when compared to matched comparison groups. Two studies were identified in which psychiatric symptoms in FXTAS were compared with controls, and these yielded mixed results. Overall the results of this review support previous reports that the neuropsychiatric profile of FXTAS is consistent with a dysexecutive fronto-subcortical syndrome. However, additional controlled studies are required to progress our understanding of FXTAS and how the neuropsychiatric profile relates to underlying pathological mechanisms.

Emerging key roles for P2X receptors in the kidney.

P2X ionotropic non-selective cation channels are expressed throughout the kidney and are activated in a paracrine or autocrine manner following the binding of extracellular ATP and related extracellular nucleotides. Whilst there is a wealth of literature describing a regulatory role of P2 receptors (P2R) in the kidney, there are significantly less data on the regulatory role of P2X receptors (P2XR) compared with that described for metabotropic P2Y. Much of the historical literature describing a role for P2XR in the kidney has focused heavily on the role of P2X1R in the autoregulation of renal blood flow. More recently, however, there has been a plethora of manuscripts providing compelling evidence for additional roles for P2XR in both kidney health and disease. This review summarizes the current evidence for the involvement of P2XR in the regulation of renal tubular and vascular function, and highlights the novel data describing their putative roles in regulating physiological and pathophysiological processes in the kidney.

Risk factors for human immunodeficiency virus infection among Brazilian blood donors: a multicentre case-control study using audio computer-assisted structured interviews.

BACKGROUND: Although risk factors for HIV infection are known, it is important for blood centres to understand local epidemiology and disease transmission patterns. Current risk factors for HIV infection in blood donors in Brazil were assessed. METHODS: A case-control study was conducted at large public blood centres located in four major cities between April 2009 and March 2011. Cases were persons whose donations were confirmed positive by enzyme immunoassays followed by Western blot confirmation. Audio computer-assisted structured interviews (ACASI) were completed by all cases and controls. Multivariable logistic regression was used to estimate adjusted odds ratios (AORs) and associated 95% confidence intervals (CIs). RESULTS: There were 341 cases, including 47 with recently acquired infection, and 791 controls. Disclosed risk factors for both females and males were sex with an HIV-positive person AOR 11.3, 95% CI (4.1, 31.7) and being an IVDU or sexual partner of an IVDU [AOR 4.65 (1.8, 11.7)]. For female blood donors, additional risk factors were having male sex partners who also are MSM [AOR 13.5 (3.1, 59.8)] and having unprotected sex with multiple sexual partners [AOR 5.19 (2.1, 12.9)]. The primary risk factor for male blood donors was MSM activity [AOR 21.6 (8.8, 52.9)]. Behaviours associated with recently acquired HIV were being a MSM or sex partner of MSM [13.82, (4.7, 40.3)] and IVDU [11.47, (3.0, 43.2)]. CONCLUSION: Risk factors in blood donors parallel those in the general population in Brazil. Identified risk factors suggest that donor compliance with selection procedures at the participating blood centres is inadequate.

Nerve injuries sustained during warfare: part I--Epidemiology.

We describe 261 peripheral nerve injuries sustained in war by 100 consecutive service men and women injured in Iraq and Afghanistan. Their mean age was 26.5 years (18.1 to 42.6), the median interval between injury and first review was 4.2 months (mean 8.4 months (0.36 to 48.49)) and median follow-up was 28.4 months (mean 20.5 months (1.3 to 64.2)). The nerve lesions were predominantly focal prolonged conduction block/neurapraxia in 116 (45%), axonotmesis in 92 (35%) and neurotmesis in 53 (20%) and were evenly distributed between the upper and the lower limbs. Explosions accounted for 164 (63%): 213 (82%) nerve injuries were associated with open wounds. Two or more main nerves were injured in 70 patients. The ulnar, common peroneal and tibial nerves were most commonly injured. In 69 patients there was a vascular injury, fracture, or both at the level of the nerve lesion. Major tissue loss was present in 50 patients: amputation of at least one limb was needed in 18. A total of 36 patients continued in severe neuropathic pain. This paper outlines the methods used in the assessment of these injuries and provides information about the depth and distribution of the nerve lesions, their associated injuries and neuropathic pain syndromes.

Nerve injuries sustained during warfare: part II: Outcomes.

The outcomes of 261 nerve injuries in 100 patients were graded good in 173 cases (66%), fair in 70 (26.8%) and poor in 18 (6.9%) at the final review (median 28.4 months (1.3 to 64.2)). The initial grades for the 42 sutures and graft were 11 good, 14 fair and 17 poor. After subsequent revision repairs in seven, neurolyses in 11 and free vascularised fasciocutaneous flaps in 11, the final grades were 15 good, 18 fair and nine poor. Pain was relieved in 30 of 36 patients by nerve repair, revision of repair or neurolysis, and flaps when indicated. The difference in outcome between penetrating missile wounds and those caused by explosions was not statistically significant; in the latter group the onset of recovery from focal conduction block was delayed (mean 4.7 months (2.5 to 10.2) vs 3.8 months (0.6 to 6); p = 0.0001). A total of 42 patients (47 lower limbs) presented with an insensate foot. By final review (mean 27.4 months (20 to 36)) plantar sensation was good in 26 limbs (55%), fair in 16 (34%) and poor in five (11%). Nine patients returned to full military duties, 18 to restricted duties, 30 to sedentary work, and 43 were discharged from military service. Effective rehabilitation must be early, integrated and vigorous. The responsible surgeons must be firmly embedded in the process, at times exerting leadership.

Genotype-phenotype associations in SCN1A-related epilepsies.

OBJECTIVE: Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+, or develop a severe epilepsy such as Dravet syndrome. Our objective was to examine whether the nature of a SCN1A mutation affects the epilepsy phenotype. METHODS: We retrospectively evaluated clinical and genetic data from 273 individuals with SCN1A mutations identified in our laboratory and reviewed data from 546 published cases. We examined whether the mutation class or distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids. RESULTS: Compared to missense mutations, truncating mutations were associated with earlier mean onset of prolonged seizures (7.4 vs 8.8 months; p = 0.040), myoclonic seizures (16.4 vs 19.4 months; p = 0.041), and atypical absence seizures (19.1 vs 30.6 months; p = 0.001). The median GS was higher in patients with Dravet syndrome compared to polymorphisms (94 vs 58; p = 0.029) and orthologs (94 vs 45; p < 0.001). A high GS was correlated with early onset of seizures (r(s) = -0.235; p = 0.008). Missense mutations occurred most frequently in the voltage and ion-pore regions where changes in amino acid polarity were greater in the Dravet group compared to the genetic epilepsy with febrile seizures plus group (3.6 vs 2.7; p = 0.031). CONCLUSIONS: These findings help define the clinical significance of specific SCN1A mutations based on mutation class and amino acid property and location.

Injuries to the spinal accessory nerve: a lesson to surgeons.

The integrity of the spinal accessory nerve is fundamental to thoracoscapular function and essential for scapulohumeral rhythm. This nerve is vulnerable along its superficial course. This study assessed the delay in diagnosis and referral for management of damage to this nerve, clarified its anatomical course and function, and documented the results of repair. From examination of our records, 111 patients with lesions of the spinal accessory nerve were treated between 1984 and 2007. In 89 patients (80.2%) the damage was iatropathic. Recognition and referral were seldom made by the surgeon responsible for the injury, leading to a marked delay in instituting treatment. Most referrals were made for painful loss of shoulder function. The clinical diagnosis is straightforward. There is a characteristic downward and lateral displacement of the scapula, with narrowing of the inferior scapulohumeral angle and loss of function, with pain commonly present. In all, 80 nerves were explored and 65 were repaired. The course of the spinal accessory nerve in relation to the sternocleidomastoid muscle was constant, with branches from the cervical plexus rarely conveying motor fibres. Damage to the nerve was predominantly posterior to this muscle. Despite the delay, the results of repair were surprising, with early relief of pain, implying a neuropathic source, which preceded generally good recovery of muscle function.

Low abdominoperineal excision rates are associated with high-workload surgeons and lower tumour height. Is further specialization needed?

AIM: Wide variation, independent of disease extent and case mix, has been observed in the rate of use of abdominoperineal excision (APE) for rectal cancer. Previous analyses have, however, been confounded by failure to adjust for the location of the tumour within the rectum. This population-based study sought to examine whether variations in tumour height explained differences in APE use. METHOD: Information was obtained on all individuals who underwent a major resection for a rectal tumour diagnosed between 1998 and 2005 across the Northern and Yorkshire regions of the UK. Median distances from the dentate line were calculated for all tumours excised by APE and compared with rates of use of APE between specialists and nonspecialist surgeons and across hospital trusts. RESULTS: The completeness of pathological reporting of height of tumour within the rectum was variable. A low rate of APE use was associated with a lower median distance of tumours from the dentate line. Specialist colorectal cancer surgeons performed fewer APEs on patients with a tumour located lower in the rectum than nonspecialist surgeons. CONCLUSION: Variations in the height of tumour did not explain the variation in APE use. Specialist high-volume surgeons undertook fewer APEs and those they performed were closer to the dentate line than low-volume nonspecialist surgeons.

Ischaemia and the pink, pulseless hand complicating supracondylar fractures of the humerus in childhood: long-term follow-up.

A series of 26 children was referred to our specialist unit with a 'pink pulseless hand' following a supracondylar fracture of the distal humerus after a mean period of three months (4 days to 12 months) except for one referred after almost three years. They were followed up for a mean of 15.5 years (4 to 26). The neurovascular injuries and resulting impairment in function and salvage procedures were recorded. The mean age at presentation was 8.6 years (2 to 12). There were eight girls and 18 boys. Only four of the 26 patients had undergone immediate surgical exploration before referral and three of these four had a satisfactory outcome. In one child the brachial artery had been explored unsuccessfully at 48 hours. As a result 23 of the 26 children presented with established ischaemic contracture of the forearm and hand. Two responded to conservative stretching. In the remaining 21 the antecubital fossa was explored. The aim of surgery was to try to improve the function of the hand and forearm, to assess nerve, vessel and muscle damage, to relieve entrapment and to minimise future disturbance of growth. Based on our results we recommend urgent exploration of the vessels and nerves in a child with a 'pink pulseless hand', not relieved by reduction of a supracondylar fracture of the distal humerus and presenting with persistent and increasing pain suggestive of a deepening nerve lesion and critical ischaemia.

Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours.

We studied 123 patients with malignant peripheral nerve sheath tumours (MPNSTs) between 1979 and 2002. However, 90 occurred sporadically whereas 33 were associated with neurofibromatosis type 1 (NF1). Survival was calculated using Kaplan-Meier survival curves and we used Cox's proportional hazards model to identify independent prognostic factors. A 5-year survival for 110 nonmetastatic patients was 54%; (33% NF1 and 63% sporadic P = .015). Tumour stage and site were significant prognostic indicators after univariate analysis. After multivariate analysis, however, only NF1 (P = .007) and tumour volume more than 200 m (P = .015) remained independent predictors of poor outcome. We recommend that NF1 be taken into account during MPNST staging. As the survival rate in the NF group was dependant on tumour volume, routine screening of these patients with FDG PET and/or MRI may be warranted, thereby staging and controlling them at the earliest possible opportunity.

A history of limb amputation.

John Kirkup, the distinguished orthopaedic surgeon and archivist recently published a book describing the history of amputation. This annotation highlights the importance of this work and the particular relevance of many of its themes to current orthopaedic and trauma practice.

TRPA1 receptor localisation in the human peripheral nervous system and functional studies in cultured human and rat sensory neurons.

TRPA1 is a receptor expressed by sensory neurons, that is activated by low temperature (<17 degrees C) and plant derivatives such as cinnamaldehyde and isoeugenol, to elicit sensations including pain. Using immunohistochemistry, we have, for the first time, localised TRPA1 in human DRG neurons, spinal cord motoneurones and nerve roots, peripheral nerves, intestinal myenteric plexus neurones, and skin basal keratinocytes. TRPA1 co-localised with a subset of hDRG neurons positive for TRPV1, the heat and capsaicin receptor. The number of small/medium TRPA1 positive neurons (< or =50 microm) was increased after hDRG avulsion injury [percentage of cells, median (range): controls 16.5 (7-23); injured 46 (34-55); P<0.005], but the number of large TRPA1 neurons was unchanged [control 19.5 (13-31); injured 21 (11-35)]. Similar TRPA1 changes were observed in cultured hDRG neurons, after exposure to a combination of key neurotrophic factors NGF, GDNF and NT-3 (NTFs) in vitro. We used calcium imaging to examine responses of HEK cells transfected with hTRPA1 cDNA, and of human and rat DRG neurons cultured with or without added NTFs, to cinnamaldehyde (CA) and isoeugenol (IE). Exposure to NTFs in vitro sensitized cultured human sensory neuronal responses to CA; repeated CA exposure produced desensitisation. In rDRG neurons, low (225 microM) CA preincubation enhanced capsaicin responses, while high (450 microM and 2mM) CA caused inhibition which was partially reversed in the presence of 8 bromo cAMP, indicating receptor dephosphorylation. While TRPA1 localisation is more widespread than TRPV1, it represents a promising novel drug target for the treatment of chronic pain and hypersensitivity.

Benign solitary schwannomas: a review of 234 cases.

We reviewed 234 benign solitary schwannomas treated between 1984 and 2004. The mean age of the patients was 45.2 years (11 to 82). There were 170 tumours (73%) in the upper limb, of which 94 (40%) arose from the brachial plexus or other nerves within the posterior triangle of the neck. Six (2.6%) were located within muscle or bone. Four patients (1.7%) presented with tetraparesis due to an intraspinal extension. There were 198 primary referrals (19 of whom had a needle biopsy in the referring unit) and in these patients the tumour was excised. After having surgery or an open biopsy at another hospital, a further 36 patients were seen because of increased neurological deficit, pain or incomplete excision. In these, a nerve repair was performed in 18 and treatment for pain or paralysis was offered to another 14. A tender mass was found in 194 (98%) of the primary referrals. A Tinel-like sign was recorded in 155 (81%). Persistent spontaneous pain occurred in 60 (31%) of the 194 with tender mass, impairment of cutaneous sensibility in 39 (20%), and muscle weakness in 24 (12%). After apparently adequate excision, two tumours recurred. No case of malignant transformation was seen.

Sciatic nerve injury caused by pre-operative intraneural injection of local anaesthetic during total hip replacement.

We report a case of iatrogenic sciatic nerve injury caused by pre-operative intraneural injection of local anaesthetic at total hip replacement. To our knowledge, this is unreported in the orthopaedic literature. We consider sacral nerve blockade in patients undergoing total hip replacement to be undesirable and present guidelines for the management of peri-operative sciatic nerve injury.