Epidemiology & management of complex ankle fractures in the United Kingdom: A multicentre cohort study.

BACKGROUND: Patient factors are known to contribute to decision making and treatment of ankle fractures. The presence of poor baseline mobility, diabetes, neuropathy, alcoholism, cognitive impairment, inflammatory arthritis or polytrauma can result in a higher risk of failure or complications. Limited evidence is available on the optimum management for this challenging cohort of patients herein described as complex ankle fractures. This UK multicentre study assessed and evaluated the epidemiology of ankle fractures complicated by significant comorbidity and patient factors and use of specialist surgical techniques such as hindfoot nails (HFN) / tibiotalarcalcaneal (TCC) nails and enhanced open reduction and internal fixation (ORIF). PATIENTS AND METHODS: A UK-wide collaborative study was performed of adult distal AO43/AO44 fractures, associated with 1 or more of the patient factors listed above. Primary outcomes included patient demographics, comorbidities, surgical technique and implants. Secondary outcomes included surgical complications and early post-operative weight bearing instructions. Statistical analysis was performed to assess patient and fracture characteristics on outcome, including propensity matching. RESULTS: One-thousand three hundred and sixty patients, with at least one of the above complex factors, from 56 centres were included with a mean age of 53.1 years. 90.2% (1227) patients underwent primary fixation which included 78.9% (1073) standard open reduction internal fixations (ORIF), 3.25% (43) extended ORIF and 8.1% (111) primary HFN / TCC. Overall wound complications and thromboembolic events were similar in the hindfoot nail group and the ORIF group (11.7% vs 10.7%). Wound complications were greater in diabetic patients versus non-diabetic patients independent of fixation method (15.8% vs 9.0%). After propensity matching for comorbidities and fracture type, overall complications were lower in the hindfoot nail (11.8%) and extended ORIF groups (16.7%), than the standard ORIF group (18.6%). CONCLUSION: Only a minority of complex ankle fractures are treated with specialised techniques (HFN/TCC or extended ORIF). Though more commonly used in older and frail patients their perceived advantages are often negated by a reluctance to bear weight early. These techniques demonstrated a better complication profile to standard ORIF but hindfoot nail with joint preparation for fusion was associated with more complications than hindfoot nail for fixation. LEVEL OF EVIDENCE: III.

Follow-up arrangements in head and neck cancer clinics during the COVID-19 pandemic: results from two tertiary UK head and neck cancer centres.

INTRODUCTION: The aim of this paper is to report the pattern of follow-up that occurred for a cohort of head and neck cancer (HNC) patients across two large centres in the UK (Aintree and Leeds), as a consequence of the COVID-19 pandemic. METHODS: Patients had been treated for HNC with curative intent between April 2017 and October 2019 by 14 oral and maxillofacial (OMFS) and ear nose and throat (ENT) oncology surgeons in the Patient Concerns Inventory intervention trial. In October 2020, hospital records were reviewed, and information collected on the timing and mode (face-to-face/telephone/video) of follow-up consultations. In addition, recurrence, second primary tumours and deaths were recorded. RESULTS: At the start of 'lockdown', 212 members of the cohort were known to be alive. During the post-lockdown period (follow-up appointment data comprised 5 months in Aintree and 7 months in Leeds) 7 died and 13 were identified as palliative/recurrence/new primary/metastases ('new event'). In Aintree, the first ENT/OMFS consultations after lockdown were 51 (67%) telephone and 25 (33%) face-to-face appointments. In Leeds, 46 (78%) consultations were by telephone and 13 (22%) were face-to-face. The second ENT/OMFS consultations post lockdown included 11 (44%) telephone and 14 (56%) face-to-face in Aintree, and 21 (75%) telephone and 7 (25%) face-to-face in Leeds. CONCLUSIONS: These data suggest that clinicians favoured remote consultations. Variations in practice were observed but reached a point of a 'hybrid follow-up approach' that included both face-to-face and remote consultations. With the emergence of telemedicine, clinicians may consider a follow-up model tailored to risk stratification. The development of the mode of such a consultation model needs further evaluation.

A general swimming response in exhausted obligate swimming fish.

Marine organisms normally swim at elevated speeds relative to cruising speeds only during strenuous activity, such as predation or escape. We measured swimming speeds of 29 ram ventilating sharks from 10 species and of three Atlantic bluefin tunas immediately after exhaustive exercise (fighting a capture by hook-and-line) and unexpectedly found all individuals exhibited a uniform mechanical response, with swimming speed initially two times higher than the cruising speeds reached approximately 6 h later. We hypothesized that elevated swimming behaviour is a means to increase energetic demand and drive the removal of lactate accumulated during capture via oxidation. To explore this hypothesis, we estimated the mechanical work that must have been spent by an animal to elevate its swim speed and then showed that the amount of lactate that could have been oxidized to fuel it comprises a significant portion of the amount of lactate normally observed in fishes after exhaustive exercise. An estimate for the full energetic cost of the catch-and-release event ensued.

Publisher Correction: Measuring the ionisation fraction in a jet from a massive protostar.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Measuring the ionisation fraction in a jet from a massive protostar.

It is important to determine if massive stars form via disc accretion, like their low-mass counterparts. Theory and observation indicate that protostellar jets are a natural consequence of accretion discs and are likely to be crucial for removing angular momentum during the collapse. However, massive protostars are typically rarer, more distant and more dust enshrouded, making observational studies of their jets more challenging. A fundamental question is whether the degree of ionisation in jets is similar across the mass spectrum. Here we determine an ionisation fraction of ~5-12% in the jet from the massive protostar G35.20-0.74N, based on spatially coincident infrared and radio emission. This is similar to the values found in jets from lower-mass young stars, implying a unified mechanism of shock ionisation applies in jets across most of the protostellar mass spectrum, up to at least ~10 solar masses.

A re-audit of the technical quality of undergraduate root canal treatment after the introduction of new technology and teaching practices.

AIM: To revaluate through re-audit the technical quality of undergraduate nonsurgical root canal treatment (RCTx) in a dental teaching hospital as a result of recommended changes to teaching practices. METHODOLOGY: The technical quality of undergraduate RCTx was evaluated radiographically after educational changes and the mandatory introduction of new technologies (nickel-titanium files, apex locators, greater taper gutta-percha points) in 182 root canals. Evaluation was based on four criteria: presence of voids, root canal filling termination (0-2 mm of radiographic apex), all roots filled and the prepared canal contained the original anatomy. Chi-squared analysis was used to determine statistically significant improvements in quality between the respective audits (P < 0.05). RESULTS: Twenty-three of the 40 canals in single-rooted teeth (57.5%) and 68 of the 129 (52.7%) canals in multirooted teeth analysed had an acceptable root filling. This compared with 48% of canals in single-rooted teeth and 38% of canals in multirooted teeth in the original audit. Specifically, the frequency of root canal voids and unsatisfactory apical root filling termination were reduced in multirooted teeth by 23% and 14% and in single-rooted teeth by 11% and 12%, respectively, compared with the original audit. When multirooted teeth were taken as one unit, 45.2% were considered to be acceptable, significantly better than the 18.8% multirooted teeth in the original audit (P = 0.042). Deviations from the canal anatomy on radiographic examination were rare findings in both audits. CONCLUSIONS: Changes to endodontic teaching practices significantly improved the technical standards of undergraduate root filling in multirooted teeth. The regular auditing of undergraduate teaching practice is necessary to inform current teaching, instigate change and improve standards.

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470).

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet ß-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm.

Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.

Adjusting DLCO for Hb and its effects on the Hematopoietic Cell Transplantation-specific Comorbidity Index.

The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is used to counsel patients regarding the risk of transplantation and selection of conditioning regimens. Pulmonary disease, most frequently demonstrated by a decreased diffusion capacity of carbon monoxide (DLCO), is the most prevalent comorbidity captured by the HCT-CI. The HCT-CI was validated using the Dinakara method for adjusting DLCO for Hb, but our institution and others utilize the Cotes method. The purpose of this study was to determine the impact of using the Cotes method rather than the Dinakara method on the HCT-CI score. We reviewed pre-transplant pulmonary function tests in 73 patients who underwent allogeneic hematopoietic SCT. Patients were stratified into low, intermediate or high-risk groups based on HCT-CI scores of 0, 1-2 or 3, respectively. We found that compared with the Dinakara method, the Cotes method increased the HCT-CI score in 45% of patients and resulted in total HCT-CI scores predictive of higher non-relapse mortality in 33% of patients. These results indicate that if an institution uses the Cotes method to adjust DLCO for Hb, their patients may be counseled to expect a higher risk of mortality than is actually predicted by the HCT-CI, and may be excluded from transplantation. Therefore, unless the HCT-CI is validated using other methods for correcting DLCO for Hb, the Dinakara method should be used.

Use of a single question to screen trauma patients for alcohol dependence.

BACKGROUND: Alcohol-dependent trauma patients are known to be at future risk for both recidivism and mortality. Psychological tools exist to screen for alcohol-dependent disorders, and among patients with alcohol-dependent disorders, a brief intervention has been shown to modify behavior. However, the training involved and time required to administer these tools may decrease their utility. We explored the possibility that yet simpler screening tools could be used. METHODS: A prospective consecutive study was designed whereby all adult patients admitted to the trauma service were asked to participate in the study. If consent was obtained, one trained member of the research team would apply a standard alcohol-misuse screening tool (i.e., the Alcohol Use Disorders Identification Test [AUDIT]). One hundred forty-nine patients met criteria and agreed to participate. Fully completed questionnaires were then subjected to statistical analysis. RESULTS: Among the 149 participating patients, 36% were women and 64% were men, and 146 had blood alcohol levels (BALs) drawn. Those 146 patients form the basis of this report. Fifty-seven of the 146 (39%) patients had positive BALs and, among them, 74% of men and 54% of women recorded screening results consistent with harmful or dependent drinking. Among those with negative blood alcohol levels, 8% of women and 13% of men had scores consistent with harmful or dependent drinking by the AUDIT score. In both groups of patients, a cutoff of three or more drinks per day as a response to question 2 on the AUDIT (i.e., "On a typical day when you are drinking, how many drinks do you have?") correlated strongly with scores on the entire screening tool (AUDIT) in identifying those at risk for alcohol misuse. CONCLUSION: It may be reasonable to substitute a single question for the entire AUDIT screening instrument to screen for those at risk for alcohol misuse. If so, this single question could easily be incorporated into the history taken among patients admitted to a trauma service. Confirmation with a larger study is recommended.

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist.

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

CD20 expression in normal canine B cells and in canine non-Hodgkin lymphoma.

We examined the expression of CD20 in normal canine peripheral blood mononuclear cells, normal canine spleen, and canine non-Hodgkin lymphoma (NHL) to determine the feasibility of using this antigen as a diagnostic aid and as a possible target for therapy. An antibody generated against a C-terminal (intracytoplasmic) epitope of human CD20 recognized proteins of 32-36 kd in normal and malignant canine lymphocytes. This antibody showed restricted membrane binding in a subset of lymphocytes in peripheral blood, in the B-cell regions from a normal canine spleen and lymph node, and in malignant cells from 19 dogs with B-cell NHL, but not from 15 dogs with T-cell NHL. The patterns of CD20 reactivity in these samples overlapped those seen using an antibody that recognizes canine CD79a. This anti-CD20 antibody is therefore suitable as an aid to phenotype canine NHL. In contrast, normal canine B cells were not recognized by any of 28 antibodies directed against the extracellular domains of human CD20 (including the chimeric mouse-human antibody Rituximab) or by any of 12 antibodies directed against the extracellular domains of mouse CD20. Thus, the use of CD20 as a therapeutic target will require the generation of specific antibodies against the extracellular domains of canine CD20.

The stages of change questionnaire as a predictor of trauma patients most likely to decrease alcohol use.

BACKGROUND: Research has shown that negative trauma-related consequences of drinking can predict readiness to change drinking behavior. These findings are confined to patients with positive blood alcohol levels at admission. The current study extends such findings by examining whether stage of readiness to change among all adult trauma activations admitted to the emergency department for 24 hours or more can be used to predict a change in behavior at followup. STUDY DESIGN: Patients 18 years of age or older admitted to a Level II trauma center between December 1, 2001, and January 31, 2003, with a trauma activation were eligible to participate. Enrolled patients were screened for alcohol use and readiness to change with the Alcohol Use Disorders Identification Test (AUDIT) and Short Form Stages of Change (SFSC), respectively, within 2 days of discharge. Blood alcohol level (BAL) was obtained for all study patients. Six to 18 months after discharge, patients were followed up with the AUDIT. The ability of the SFSC to predict change in alcohol behavior at followup was analyzed by multiple regression. RESULTS: Of 253 eligible patients, 146 patients were enrolled and had BAL taken. Most were men (64%) and 36% were women. Mean positive BAL (n = 57) was 186 mg/dL (range 10 to 537 mg/dL). Of these, 23% (13 of 57) met AUDIT criteria for harmful drinking and 47% (27 of 57) met criteria for dependent drinking. Even among those with undetectable BAL (n = 89), harmful or dependent drinking was identified by the AUDIT for 11% (10 of 89). A readiness to change was common among those reporting harmful or dependent drinking (26%) at baseline. The SFSC independently and significantly predicted change in drinking behavior among the 72 patients with followup (p = 0.05). Patients indicating greater readiness to change at baseline were those more likely to decrease their consumption pattern at followup. CONCLUSIONS: Findings suggest that administering the brief SFSC questionnaire to all trauma patients and providing assistance to those demonstrating a willingness to change may prove to be an effective strategy for reducing problem alcohol use.

Synthetic approaches to indolo[6,7-a]pyrrolo[3,4-c]carbazoles: potent cyclin D1/CDK4 inhibitors.

Synthesis of indolo[6,7-a]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction of functionality (-OR, NR(2)) at C(12) and N(13) facilitating structure-activity relationship (SAR) evaluation of this indolocarbazole platform.

Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports.

BACKGROUND: Deep brain stimulation (DBS) offers a non-ablative alternative to thalamotomy for the surgical treatment of medically refractory tremor in multiple sclerosis. However, relatively few outcomes have been reported. OBJECTIVE: To provide a systematic review of the published cases of DBS use in multiple sclerosis and to present four additional patients. METHODS: Quantitative and qualitative review of the published reports and description of a case series from one centre. RESULTS: In the majority of reported cases (n=75), the surgical target for DBS implantation was the ventrointeromedial nucleus of the thalamus. Tremor reduction and improvement in daily functioning were achieved in most patients, with 87.7% experiencing at least some sustained improvement in tremor control postsurgery. Effects on daily functioning were less consistently assessed across studies; in papers reporting relevant data, 76.0% of patients experienced improvement in daily functioning. Adverse effects were similar to those reported for DBS in other patient populations. CONCLUSIONS: Few of the studies reviewed used highly standardised quantitative outcome measures, and follow up periods were generally one year or less. Nonetheless, the data suggest that chronic DBS often produces improved tremor control in multiple sclerosis. Complete cessation of tremor is not necessarily achieved, there are cases in which tremor control decreases over time, and frequent reprogramming appears to be necessary.

Prognostic significance of percentage of bronchioloalveolar pattern in adenocarcinomas of the lung.

Bronchioloalveolar (BA) carcinoma of the lung is considered to have a better prognosis than that of common adenocarcinomas of the lung. However, a minor component of the BA pattern is common in many lung adenocarcinomas and the criteria for designating an adenocarcinoma as BA are not well defined. We assessed the clinicopathologic features of 238 cases of lung adenocarcinoma with a partial or predominant BA pattern. Tumors were classified as BA if more than 75% of the tumor had a BA growth pattern. In other words, the tumor grew along pre-existing lung structures without invasion or destruction of parenchyma. Tumors with 50% to 75% BA pattern were considered mixed and tumors with less than 50% BA pattern were designated as solid/acinar (S/A). Fixed, paraffin-embedded tissue sections of each neoplasm were also assessed using immunohistochemical methods with a panel of antibodies specific for p53, retinoblastoma protein, p16, cyclin D1, and cyclin E, and the results were correlated with clinical and pathologic parameters. Our results show that the 5-year survival rate of patients with BA and mixed tumors, 63% and 60%, respectively, was significantly better than that of patients with S/A tumors (P =.026). Patients with BA tumors were more frequently women (55.9%) compared with patients with mixed (48.3%) and S/A (43.8%) tumors. Bronchioloalveolar and mixed tumors were similarly associated with tobacco use, 88.2% and 85%, respectively; slightly less than S/A tumors (93.8%). Clinical and pathologic parameters did not correlate with immunohistochemical results. In conclusion, patients with BA or mixed tumors have similar 5-year survival, better than that of patients with S/A tumors, suggesting that adenocarcinomas can be designated as BA when at least 50% of the tumor has a BA pattern.

The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid.

Histone deacetylase inhibitors (HDACIs) inhibit the growth of a variety of transformed cells in culture. We demonstrated previously that the hybrid-polar HDACI m-carboxycinnamic acid bis-hydroxamide (CBHA) induces apoptosis of human neuroblastoma in vitro and is effective in lower doses when combined with retinoids. The current study investigates the effect of CBHA on the growth of human neuroblastoma in vivo, both alone and in combination with all-trans retinoic acid (atRA), using a severe combined immunodeficiency-mouse xenograft model. CBHA (50, 100, and 200 mg/kg/day) inhibited growth of SMS-KCN-69n tumor xenografts in a dose-dependent fashion, with 200 mg/kg CBHA resulting in a complete suppression of tumor growth. The efficacy of 50 and 100 mg/kg CBHA was enhanced by the addition of 2.5 mg/kg atRA. This dose of atRA was ineffective when administered alone. Treatment was accompanied by mild weight loss in all groups except the lowest dose of CBHA. Our results suggest HDACIs alone or combined with retinoids may have therapeutic utility for neuroblastoma.