How reconfiguration of a minor injuries unit has affected service delivery during the COVID-19 pandemic: a retrospective analysis.

INTRODUCTION: Redeployment of orthopaedic consultants to a minor injuries unit (MIU) during the COVID-19 pandemic provided a unique opportunity to assess the impact of early senior specialist input on patient management. METHODS: Patient demographics, diagnosis, location of injury and disposal method were compared between three 7-day periods: during the April 2020 COVID-19 lockdown (period A), one month prior to period A (period B) and one year prior to period A (period C). Orthopaedic consultants staffed the MIU during period A, and emergency nurse practitioners staffed the MIU during periods B and C. RESULTS: Period A witnessed higher injury severity either due to modified activities or altered healthcare-seeking behaviour during lockdown. For fractures, compared with periods B and C, period A saw a lower rate of referral to fracture clinic (41% vs 100% vs 86%, p<0.001) and higher rate of discharge (38% vs 0% vs 9%, p<0.001). The median time to fracture clinic was also longer (15 days vs 6 days vs 10 days, p<0.001), indicating earlier institution of definitive care. There were no other significant differences between periods with radiology alerts and complaints received remaining largely unchanged. CONCLUSION: Early senior orthopaedic input in the patient journey from MIU had clear benefits, this being most true for fracture diagnoses. Earlier definitive management planning was observed as lower rates of fracture clinic referral, higher rates of discharge and deferred first fracture clinic reviews. This study highlights the benefits of greater partnership between MIU and orthopaedics. As the pandemic subsides and redeployed staff return to normal duties, a modification of this model could be utilised to ensure this partnership is sustainable.

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures.

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.

Preliminary evaluation of a novel polymer nanocomposite as a root-end filling material.

AIM: To evaluate two nanoparticle-enhanced polymer root-end filling materials (NERP1 and NERP2) on the initial apical seal as compared to a polymer-based commercial compomer. METHODOLOGY: One hundred and forty extracted roots with completely formed apices were resected 3 mm from the apex. Cavities were then prepared in the apical openings of the resected root ends using an ultrasonic handpiece to a depth of 3 mm. The roots were then randomly divided into five groups to receive one of five root-end filling materials. Roots in groups 1 and 2 received NERP1 and NERP2, whilst those in groups 3 and 4 received identical polymers as groups 1 and 2 but without nanoparticle addition (RP1 and RP2, respectively). The root-end cavities for the fifth group were filled with commercially available root-end filling compomer. Roots were mounted in a dual-chamber leakage apparatus and inoculated coronally with Enterococcus faecalis. Turbidity of the apical broth was assessed daily for 4 weeks as a sign of initial leakage. The results were statistically analysed using odds ratio and Fisher's chi-square analysis. RESULTS: Nanoparticle-enhanced root-end filling polymer 1 displayed significantly fewer leaked samples compared to all other tested groups as early as 5 days, whilst NERP2 was not significantly different compared to other groups. Odds ratio analysis revealed leakage of the commercial compomer was 12 times more likely than NERP1. CONCLUSION: Nanoparticle-enhanced root-end filling polymer 1 can reduce apical microleakage significantly under laboratory conditions.

Residual postoperative tumour volume predicts outcome after high-dose radiotherapy for chordoma and chondrosarcoma of the skull base and spine.

AIMS: High-dose radiotherapy after surgical debulking is the treatment of choice for chordomas and chondrosarcomas. This study reviewed our outcomes, in relation to residual tumour volume and radiation dose, in order to inform our future practice. PATIENTS AND METHODS: Nineteen patients referred to the Neuro-Oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2009 and treated with photon radiotherapy were reviewed. Seventeen of the 19 were treated with curative intent. The median follow-up was 53 months. The tumours in the study had a mean gross tumour volume (GTV) of 17.2 cm(3) (median 10.5 cm(3)) and a range of 0-76.3 cm(3). The median dose was 65Gy in 39 fractions. RESULTS: The 5 year cause-specific survival for radically treated patients with chordomas was 92% and the 5 year local control rate was 83%. The 5 year cause-specific survival and local control rates with chondrosarcomas were both 100%. A planning target volume (PTV) below 90 cm(3) is predictive of local control, but volumes above this are not. The GTV seems to be a better predictor of outcome: among the 17 of 19 patients treated curatively, a GTV threshold of 30 cm(3) distinguished local failures from the 15 patients with local control, with sensitivity to detect local control of 100% (95% confidence interval 78-100%), specificity 100% (95% confidence interval 16-100%) and positive predictive value 100% (95% confidence interval 78-100%). CONCLUSIONS: Our results show a high level of efficacy for fractionated photon radiotherapy after surgery, in keeping with other series. In addition, we found that although surgical debulking is essential, a small residual tumour volume may still be controlled with high-dose photon radiotherapy. This information may be relevant during neurosurgical planning, possibly allowing a reduction in risk of serious neurological deficits. This should encourage the further development of sophisticated photon radiotherapy, for patients unsuitable for proton therapy.

Reactions of phosphate and phosphorothiolate diesters with nucleophiles: comparison of transition state structures.

A series of methyl aryl phosphorothiolate esters (SP) were synthesized and their reactions with pyridine derivatives were compared to those for methyl aryl phosphate esters (OP). Results show that SP esters react with pyridine nucleophiles via a concerted S(N)2(P) mechanism. Brønsted analysis suggests that reactions of both SP and OP esters proceed via transition states with dissociative character. The overall similarity of the transition state structures supports the use of phosphorothiolates as substrate analogues to probe mechanisms of enzyme-catalyzed phosphoryl transfer reactions.

Morphometric analysis of neuromuscular topography in the serratus anterior muscle.

Groups of neurons form ordered topographic maps on their targets, and defining the mechanisms that develop such maps, and re-connect them after disruption, has biological as well as clinical importance. The neuromuscular system is an accessible and well-studied model for defining the principles that guide map formation, both during its development and its reformation after motor nerve damage. We present evidence for the expression of this map at the level of nerve terminal morphology and muscle fiber type in the serratus anterior muscle. Morphometric analyses indicate, first, a rostrocaudal difference in nerve terminal size depending on the ventral root of origin of the axons. Second, motor endplates are larger on type IIB than type IIA muscle fibers. Third, whereas IIB muscle fibers are distributed rather evenly along the rostrocaudal axis of the muscle, the more rostral type IIB fibers are preferentially innervated by anteriorly derived (C6) motor neurons, and more caudal IIB fibers are preferentially innervated by posteriorly derived (C7) motor neurons. This inference is supported by analysis of the size of nerve terminals formed in each muscle sector by rostral and caudal roots, and by evidence that the larger terminals are on IIB fibers. These results demonstrate a subcellular expression of neuromuscular topography in the serratus anterior muscle (SA) muscle in the form of differences in nerve terminal size. These results provide deeper insights into the organization of a neuromuscular system. They also offer a rationale for a topographic map, that is, to allow spinal motor centers to activate selectively different compartments within a muscle.

Ephrin-A5 overexpression degrades topographic specificity in the mouse gluteus maximus muscle.

Motor neurons project onto specific muscles with a distinct positional bias. We have previously shown using electrophysiological techniques that overexpression of ephrin-A5 degrades this topographic map. Here, we show that positional differences in axon terminal areas, an entirely different parameter of neuromuscular topography, are also eliminated with ephrin-A5 overexpression. Therefore, we now have both morphological and electrophysiological approaches to explore the mechanisms of neuromuscular topography.

A morphological technique for exploring neuromuscular topography expressed in the mouse gluteus maximus muscle.

Motor neuron pools innervate muscle fibers forming an ordered topographic map. In the gluteus maximus (GM) muscle, as well as additional muscles, we and others have demonstrated electrophysiologically that there exists a rostrocaudal distribution of axon terminals on the muscle surface. The role of muscle fiber type in determining this topography is unknown. A morphological approach was designed to investigate this question directly. We combined three different methods in the same muscle preparation: (1) the uptake of activity-dependent dyes into selected axon terminals to define the spinal segmental origin of a peripheral nerve terminal; (2) the fluorescent labeling of nicotinic acetylcholine receptors to determine motor endplate size; (3) the immunocytochemical staining of skeletal muscle to determine fiber subtype. We applied these methods to the mouse GM muscle to determine the relationship between muscle fiber type and the topographic map of the inferior gluteal nerve (IGN). Results from this unique combination of techniques in the same preparation showed that axon terminals from more rostral spinal nerve segments of origin are larger on rostral muscle fibers expressing myosin heavy chain (MyHC) IIB epitope than caudal type IIB fibers. Because type IIB fibers dominate the GM, this suggests that for these rostral axons terminal size is independent of fiber type. How this axon terminal size is related to the topographic map is the next question to be answered.

Geometric analysis of cross-linkability for protein fold discrimination.

Protein structure provides insight into the evolutionary origins, functions, and mechanisms of proteins. We are pursuing a minimalist approach to protein fold identification that characterizes possible folds in terms of consistency of their geometric features with restraints derived from relatively cheap, high-throughput experiments. One such experiment is residue-specific cross-linking analyzed by mass spectrometry. This paper presents a suite of novel lower- and upper-bounding algorithms for analyzing the distance between surface cross-link sites and thereby validating predicted models against experimental cross-linking results. Through analysis and computational experiments, using simulated and published experimental data, we demonstrate that our algorithms enable effective model discrimination.

Difficult cases in heart failure: Expanding the therapeutic armamentarium in decompensated heart failure: using intravenous fenoldopam.

The authors report the clinical use of fenoldopam, a dopamine agonist, in a patient with decompensated heart failure and severe pulmonary hypertension. In addition, they explore the potential mechanisms by which fenoldopam exerts its beneficial effects and review the literature regarding the use of this agent in systolic heart failure. (c)2001 by CHF, Inc.

Adherence of Acanthamoeba to human corneal epithelial cells recovered from normal non-lens wearers and asymptomatic contact lens wearers.

To increase our knowledge of factors leading to Acanthamoeba keratitis in contact lens wearers, we determined the ability of this organism to adhere to corneal epithelial cells (EC) recovered from non-lens wearers (NL) and from subjects using hydrogel contact lenses on a daily (DW) and extended wear (EW) schedule. ECs were incubated with trophozoites of Acanthamoeba and, after 3 h, the median per cent of cells exhibiting adherence was 24, 23 and 23 for NL, DW and EW groups respectively (P=0.552, Kruskal-Wallis Test). There were no differences between the groups for the number of adherent amoebae and a significant majority had only one adherent trophozoite per EC. No difference in adherence was seen with increasing exposure time. Factors other than amoebic adherence to superficial corneal EC are responsible for the increased incidence of Acanthamoeba keratitis in lens wearers.

Laparoscopic assisted vaginal hysterectomy (LAVH): report of the first eleven cases done in the Caribbean, by a Trinidadian

The first report of laparoscopic hysterectomy (LH) was in 1989 by Reich et al and there have been more than 60 reports describing about 6 000 cases since then. This paper reports the first eleven LAVH procedures done in the English speaking Caribbean, and compares them with international experiences. The average age of the patients was 43 years, with the parity of nearly all of them ranging from 1+1 to 4+4 (5+0 for one patient). The indications for surgery were mainly uterine fibroids with abnormal uterine bleeding (8 of 11), which differs from most reported series. This resulted in a mean duration of surgery of 4 hours 12 minutes, compared with a mean of 2 hours 12 minutes (maximum of 3 hours published in 17 other reports). The complication rate in this series was 3 in 11 patients or 27 percent compared with 13.2 percent in 18 other reports, in which the rate rose maximally to 44 percent. Hospital charges in this series (mean US$1,047), the lowest reported internationally, may be compared with those in 8 reports in which costs are reported (mean US$7,386, range: US$3,926 to US$12, 814). The mean duration of hospital stay was 1.3 days which compared favourably with a mean of 2.28 days in 19 reported studies, in which the hospital stage ranged from 0.9 to 3.7 days(AU)

Secretion of an anti-inflammatory, immunomodulatory factor by Schistosomulae of Schistosoma mansoni.

Penetration and migration of schistosomulae of Schistosoma mansoni through the skin of mice is associated with reduced inflammatory responses especially after a moderate infection. Previous studies to identify the mechanisms by which schistosomulae of S. mansoni suppress inflammatory responses in human skin showed that the excretory/secretory (ES) products of schistosomulae of s. mansoni contain activities that induce production of the antiinflammatory cytokine IL-1ra from human keratinocytes. In the present study we have characterized the ES products of the schistosomulae of S. mansoni to identify the IL-1ra inducing activity. We demonstrate that this anti-inflammatory activity is associated with a protein of molecular mass 16.8 kDa (Sm 16.8). Depletion studies confirm that Sm 16.8 is the major IL-1ra inducing activity in the ES products. A comparison of the proteins in the ES products of schistosomulae of S. mansoni with those of Trichobilharzia ocellata, a bird schistosome that induces an acute inflammation in human skin, shows that Sm 16.8 is absent in the ES products of T. ocellata. Interestingly, ES products of the schistosomulae of T. ocellata were potent inducers of IL-1 alpha from human keratinocytes, whereas ES products from schistosomulae of s. mansoni induce little or no IL-1 alpha secretion from keratinocytes. Functional studies show that Sm 16.8 suppresses antigen induced lymphoproliferative responses in vitro. Addition of Sm 16.8 to spleen or axillary lymph node cell cultures resulted in a significant reduction in antigen induced IL-2 secretion. These studies show that schistosomulae of S. mansoni elaborate an anti-inflammatory, immunomodulatory factor that may help the parasite to evade host immune responses in the skin. Given the capabilities of Sm 16.8 to induce IL-ira and suppress lymphoproliferation, this protein may also have a potential use as a therapeutic agent for inflammatory skin disorders.