Mortality in hip fractures: Stratifying the risk of operative delay and quantifying the benefit of early mobilisation.

INTRODUCTION: Early mortality following hip fracture surgery remains a significant issue with a much studied, multifactorial aetiology. This study designed to test the variables affecting 30 day mortality in a socially deprived cohort against national models, and secondarily aimed to uncover and quantify new risk factors. METHODS: This was a single centre retrospective study based on National Hip Fracture Database (NHFD) data for 3176 hip fracture patients from 1st May 2008 to December 31st 2017. Data was condensed into a single anonymised workbook and logistic regression used to analyse associations with 30 day mortality. Firstly, the 6 casemix variables used by the NHFD were modelled. Secondarily, a new optimised model based on our data was created. RESULTS: Gross mortality was 11.1% since May 2008 (344/3074). There were 1978 patients in our cohort with sufficient data to run the NHFD casemix model. Overall, this proved fair with a similar area under ROC curve to nationally (0.75 vs. 0.76), although the Odds Ratios (OR) of individual variables differed. The optimised casemix model suggested two powerful prognostic indicators for 30 day mortality, namely delay to theatre for clinical reasons (OR =3.98, p-value=0.02) and whether the patient was mobilised day one post op (OR=0.21, p-value=0.00). Delay to theatre for non clinical reasons conveyed only a marginal and statistically insignificant increase in risk (OR=1.15, p-value=0.77). CONCLUSION: This study has confirmed the NHFD casemix adjusted model is a fair barometer for units treating a socially deprived cohort. It also has shown a clear differentiation between risk conveyed by delay to theatre for clinical reasons and suggests delay for non-clinical reasons, although clearly not desired, may not have a significant effect on death rate. Finally, it both amplifies and prompts further investigation into the potential benefit of early mobilisation.

Cold spells in the Nordic Seas during the early Eocene Greenhouse.

The early Eocene (c. 56 - 48 million years ago) experienced some of the highest global temperatures in Earth's history since the Mesozoic, with no polar ice. Reports of contradictory ice-rafted erratics and cold water glendonites in the higher latitudes have been largely dismissed due to ambiguity of the significance of these purported cold-climate indicators. Here we apply clumped isotope paleothermometry to a traditionally qualitative abiotic proxy, glendonite calcite, to generate quantitative temperature estimates for northern mid-latitude bottom waters. Our data show that the glendonites of the Danish Basin formed in waters below 5 °C, at water depths of <300 m. Such near-freezing temperatures have not previously been reconstructed from proxy data for anywhere on the early Eocene Earth, and these data therefore suggest that regionalised cool episodes punctuated the background warmth of the early Eocene, likely linked to eruptive phases of the North Atlantic Igneous Province.

Establishing a link between composition and toxicity of offshore produced waters using comprehensive analysis techniques - A way forward for discharge monitoring?

Extracts of produced waters from five mature Norwegian Sea oil fields were examined as total organic extracts (TOEs) and after fractionation into operationally-defined 'polar' and 'apolar' fractions. The TOEs and fractions were examined by gas chromatography (GC), GC-mass spectrometry (GC-MS), two dimensional GC-MS (GC × GC-MS) and liquid chromatography with high-resolution spectrometry (LC-HRMS) techniques. Low molecular weight aromatics, phenols and other common petroleum-derived hydrocarbons were characterized and quantified in the TOEs and fractions. In addition, a range of more uncommon polar and apolar constituents, including those likely derived from production chemicals, such as trithiolane, imidazolines and quaternary amine compounds (so-called 'quats'), were tentatively identified, using GC × GC-MS and LC-HRMS. The acute toxicity of the TOEs and subfractions was investigated using early life stages of the marine copepod Acartia tonsa. Toxicity varied significantly for different PW TOEs and subfractions. For some PWs, the toxicity was attributed mainly to the 'polar' components, while that of other PWs was associated mainly with the 'apolar' components. Importantly, the observed toxicity could not be explained by the presence of the commonly reported compounds only. Although, due to the vast chemical complexity even of the sub-fractions of the PW extracts, specific compounds driving the observed toxicity could be not be elucidated in this study, the proposed approach may suggest a way forward for future revisions of monitoring regimes for PW discharges.

From 'Parent' to 'Expert': How Parents of Children with Autism Spectrum Disorder Make Decisions About Which Intervention Approaches to Access.

Parents of children with Autism Spectrum Disorder are responsible for deciding which interventions to implement with their child. There is limited research examining parental decision-making with regards to intervention approaches. A constructivist grounded theory methodology was implemented in this study. Semi-structured interviews were undertaken with 14 participants from 12 family units. Data collection and analysis occurred concurrently, allowing a grounded theory to be constructed. Parental decision-making was influenced by many factors, arranged into seven core categories (values, experience, information, motivation, understanding, needs and logistics). Decision-making evolved over time, as parents transformed from 'parent' to 'expert'. The results of this study provide an insight into parental decision-making, which has implications for the support provided to parents by health professionals.

When is it safe to exercise mechanically ventilated patients in the intensive care unit? An evaluation of consensus recommendations in a cardiothoracic setting.

RATIONALE: Consensus recommendations have been developed to guide exercise rehabilitation of mechanically ventilated patients in the intensive care unit. OBJECTIVE: This study aimed to investigate the safety of exercise rehabilitation of mechanically ventilated patients and evaluate the consensus recommendations. METHODS: This was a prospective, single-centre, cohort study conducted in a specialist cardiothoracic intensive care unit of a tertiary, university affiliated hospital in Australia. RESULTS: 91 mechanically ventilated participants; 54 (59.3%) male; mean age of 56.52 (16.3) years; were studied with 809 occasions of service recorded. Ten (0.0182%) minor adverse events were recorded, with only one adverse event occurring when a patient was receiving moderate level of vasoactive support. CONCLUSIONS: The consensus recommendations are a useful tool in guiding safe exercise rehabilitation of mechanically ventilated patients. Our findings suggest that there is further scope to safely commence exercise rehabilitation in patients receiving vasoactive support.

A substantial fraction of phytoplankton-derived DON is resistant to degradation by a metabolically versatile, widely distributed marine bacterium.

The capacity of bacteria for degrading dissolved organic nitrogen (DON) and remineralising ammonium is of importance for marine ecosystems, as nitrogen availability frequently limits productivity. Here, we assess the capacity of a widely distributed and metabolically versatile marine bacterium to degrade phytoplankton-derived dissolved organic carbon (DOC) and nitrogen. To achieve this, we lysed exponentially growing diatoms and used the derived dissolved organic matter (DOM) to support an axenic culture of Alteromonas sp.. Bacterial biomass (as particulate carbon and nitrogen) was monitored for 70 days while growth dynamics (cell count), DOM (DOC, DON) and dissolved nutrient concentrations were monitored for up to 208 days. Bacterial biomass increased rapidly within the first 7 days prior to a period of growth/death cycles potentially linked to rapid nutrient recycling. We found that ≈75% of the initial DOC and ≈35% of the initial DON were consumed by bacteria within 40 and 4 days respectively, leaving a significant fraction of DOM resilient to degradation by this bacterial species. The different rates and extents to which DOC and DON were accessed resulted in changes in DOM stoichiometry and the iterative relationship between DOM quality and bacterial growth over time influenced bacterial cell C:N molar ratio. C:N values increased to 10 during the growth phase before decreasing to values of ≈5, indicating a change from relative N-limitation/C-sufficiency to relative C-limitation/N-sufficiency. Consequently, despite its reported metabolic versatility, we demonstrate that Alteromonas sp. was unable to access all phytoplankton derived DOM and that a bacterial community is likely to be required. By making the relatively simple assumption that an experimentally derived fraction of DOM remains resilient to bacterial degradation, these experimental results were corroborated by numerical simulations using a previously published model describing the interaction between DOM and bacteria in marine systems, thus supporting our hypothesis.

Class Type Separation of the Polar and Apolar Components of Petroleum.

Identification of the heteroatom (nitrogen, sulfur, and oxygen)-containing compounds of petroleum is of key importance when considering industrial and environmental issues associated with crude oil production. The more commonly performed methods of crude oil fractionation are often insufficient in the extent to which they separate oils, not allowing defined "molecular" fractions to be obtained. Methods capable of performing a class type separation are uncommon and are often extensive and resource and time intensive. Here we report a method for the separation of crude oils into discrete compound classes. The method utilizes both ion exchange and normal phase chromatography to generate fractions of saturated hydrocarbons, aromatic hydrocarbons, basic compounds, naphthenic acids, and other oxygen-containing species, carbazoles, sulfones, and thiophenes from small crude oil samples (∼0.5 g). Assessment of method selectivity with a suite of model compounds has shown the fractions to be well-defined, with classes of model compounds isolated within discrete fractions. Application of the method to five crude oils of varying API gravity (12.1-38.3°) demonstrates a potential for wide-ranging use. Sample recoveries were high (77-98%) with simple evaporative losses correlating closely with total sample loss. Repeatability was also high, demonstrated by triplicate analyses of model compound mixtures, oils spiked with model compounds and oils alone. Separation selectivity was further demonstrated by application of the scheme to the Alaska North Slope (ANS) crude oil and analysis of fractions by comprehensive two-dimensional gas-chromatography mass-spectrometry (GC × GC/MS) and/or liquid-chromatography high-resolution accurate-mass mass-spectrometry methods (LC-HRAM-MS). Isolation of discrete fractions then allowed excellent separation (by LC and GC methods) of carbazole, dibenzothiophene, fluorenones, xanthones, and quinoline fractions. Individual parent and C1-5 alkyl homologues were easily separated (GC × GC/MS), allowing high-quality mass spectra (EI) to be obtained for the individual compounds in many cases. Analysis of fractions by GC × GC/MS also allowed a series of thioxanones to be identified.

"More than blowing bubbles": What parents want from therapists working with children with autism spectrum disorder.

PURPOSE: Providing therapy to children with autism spectrum disorder (ASD) often requires therapists to work closely with both the child with ASD and their family. Although there is evidence outlining best practice for therapists when working with families of children with disabilities, few studies have examined the parental perspective. This study investigated the qualities parents seek in therapists who work with their children with ASD. METHOD: Semi-structured interviews were conducted with 14 parents of children with ASD. Thematic analysis was undertaken to analyse the data, with emergence of two core themes; Partnership and Effective Therapy. RESULT: The parents of children with ASD interviewed for this study valued both working in partnership with therapists and therapists delivering effective therapy. Parents ultimately wanted therapists to produce positive outcomes for their children and were willing to sacrifice other desired qualities, as long as the therapy program was effective. CONCLUSION: While parents of children with ASD identified a range of qualities that they want in therapists, a therapist being able to produce positive outcomes for their child was considered most important. The implications of these findings are discussed both in terms of clinical implications for therapists and directions for future research.

Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction.

Sacubitril/valsartan (Entresto™; LCZ696) is an orally administered supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved in the US and the EU for the treatment of chronic heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). In the large, randomized, double-blind, PARADIGM-HF trial, sacubitril/valsartan reduced the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure (composite primary endpoint) significantly more than the angiotensin converting enzyme (ACE) inhibitor enalapril. Sacubitril/valsartan was also superior to enalapril in reducing death from any cause and in limiting the progression of heart failure. Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events. Symptomatic hypotension was significantly more common with sacubitril/valsartan than with enalapril; the incidence of angio-oedema was low. Therefore, sacubitril/valsartan is a more effective replacement for an ACE inhibitor or an ARB in the treatment of HFrEF, and is likely to influence the basic approach to treatment.

Capsaicin 8 % Patch: A Review in Peripheral Neuropathic Pain.

The capsaicin 8 % patch (QUTENZA®) is an adhesive patch containing a high concentration (8 % w/w) of synthetic capsaicin, a selective agonist of transient receptor potential vanilloid 1 channel. It is approved for treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for pain in the EU; it is only approved to treat postherpetic neuralgia (PHN) in the USA. In patients with painful diabetic peripheral neuropathy (PDPN), a single 30-min application of the capsaicin 8 % patch significantly improved pain relief and sleep quality compared with placebo in a 12-week double-blind trial. In a 52-week, randomized trial, up to seven consecutive 30-min treatments with the capsaicin 8 % patch (≤7 treatments each at least 8 weeks apart) plus standard of care therapy was associated with sustained pain relief and no negative neurological safety consequences compared with standard of care. In two randomized trials, a single 60-min application of the capsaicin 8 % patch reduced pain scores significantly more than a low-concentration (0.04 %) capsaicin control patch in patients with PHN. Capsaicin 8 % patch treatment was noninferior to pregabalin (optimized dosage) in a randomized trial in patients with nondiabetic peripheral neuropathic pain. Results in two trials in patients with HIV-AN were equivocal, with a significant improvement in pain intensity observed in one trial, but not in the other. The capsaicin 8 % patch was associated with expected, transient, capsaicin-related application-site adverse events such as erythema and pain.

Marking of verb tense in the English of preschool English-Mandarin bilingual children: evidence from language development profiles within subgroups on the Singapore English Action Picture Test.

BACKGROUND: The phonological and morphosyntactic structures of English and Mandarin contrast maximally and an increasing number of bilinguals speak these two languages. Speech and language therapists need to understand bilingual development for children speaking these languages in order reliably to assess and provide intervention for this population. AIMS: To examine the marking of verb tense in the English of two groups of bilingual pre-schoolers learning these languages in a multilingual setting where the main educational language is English. The main research question addressed was: are there differences in the rate and pattern of acquisition of verb-tense marking for English-language 1 children compared with Mandarin-language 1 children? METHODS & PROCEDURES: Spoken language samples in English from 481 English-Mandarin bilingual children were elicited using a 10-item action picture test and analysed for each child's use of verb tense markers: present progressive '-ing', regular past tense '-ed', third-person singular '-s', and irregular past tense and irregular past-participle forms. For 4-6 year olds the use of inflectional markers by the different language dominance groups was compared statistically using non-parametric tests. OUTCOMES & RESULTS: This study provides further evidence that bilingual language development is not the same as monolingual language development. The results show that there are very different rates and patterns of verb-tense marking in English for English-language 1 and Mandarin-language 1 children. Furthermore, they show that bilingual language development in English in Singapore is not the same as monolingual language development in English, and that there are differences in development depending on language dominance. CONCLUSIONS: Valid and reliable assessment of bilingual children's language skills needs to consider the characteristics of all languages spoken, obtaining accurate information on language use over time and accurately establishing language dominance is essential in order to make a differential diagnosis between language difference and impairment.

Evogliptin: First Global Approval.

Evogliptin (Suganon) is an orally bioavailable, selective dipeptidyl peptidase-4 (DPP-4; CD26 antigen) inhibitor being developed by Dong-A ST for the treatment of type 2 diabetes mellitus. DPP-4 inhibitors control glucose levels by preventing the breakdown of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which stimulate insulin secretion in response to the increased levels of glucose in the period following meals. In October 2015, evogliptin received its first global approval in South Korea for blood glucose control in patients with type 2 diabetes mellitus. This article summarizes the milestones in the development of evogliptin leading to this first approval for type 2 diabetes mellitus.

Cariprazine: First Global Approval.

Cariprazine (Vraylar) is an oral atypical antipsychotic originated by Gedeon Richter. It is a potent dopamine D3 and D2 receptor partial agonist, which preferentially binds to the D3 receptor. Cariprazine also has partial agonist activity at serotonin 5-HT1A receptors. In September 2015, cariprazine received its first global approval in the USA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is also in development in a variety of countries for the treatment of schizophrenia with predominant negative symptoms (phase III), as adjunctive therapy for major depressive disorder (phase II/III) and for the treatment of bipolar depression (phase II). This article summarizes the milestones in the development of cariprazine leading to this first approval for schizophrenia and manic or mixed episodes associated with bipolar I disorder.

Vilazodone: a review in major depressive disorder in adults.

Vilazodone (Viibryd(®)) exhibits the combined properties of a selective serotonin reuptake inhibitor (SSRI) and a serotonin 5-HT1A receptor partial agonist, and is approved in the US for the treatment of major depressive disorder (MDD) in adults. In four randomized, double-blind, clinical trials, oral vilazodone 20 or 40 mg once daily for 8 or 10 weeks reduced from baseline (improved) the Montgomery-Åsberg Depression Rating Scale (MADRS) total score significantly more than placebo in adult patients with MDD. In these trials, significantly greater reductions in MADRS total score with vilazodone compared with placebo were seen from either week 1, week 2 (two trials) or week 6. In a noncomparative study, MADRS total scores continued to improve throughout therapy for up to 1 year. Vilazodone was generally well tolerated, with the most common treatment-emergent adverse events being mild or moderate diarrhoea, nausea and headache. Vilazodone had only limited adverse effects on sexual function or bodyweight. Therefore, vilazodone is an effective agent for treating MDD in adults.

Perindopril/amlodipine (Prestalia(®)): a review in hypertension.

Perindopril, an ACE inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, are established antihypertensive agents with complementary mechanisms of action. Recently, a once-daily, orally-administered, fixed-dose combination (FDC) of perindopril arginine plus amlodipine besylate (Prestalia(®); hereafter referred to as perindopril/amlodipine FDC) was approved in the USA for the treatment of hypertension. This article reviews the efficacy and tolerability of perindopril/amlodipine FDC and briefly summarizes the agent's pharmacologic properties. As demonstrated in short-term randomized controlled trials, perindopril/amlodipine FDC was significantly more effective in reducing blood pressure (BP) than monotherapy with either of the component drugs, and it appeared to be more effective than an up-titration scheme using valsartan and valsartan/amlodipine. The FDC agent was generally well tolerated, with the most common adverse events (peripheral edema, cough, headache, and dizziness) being consistent with the well-defined tolerability profiles of the individual component drugs. Furthermore, perindopril/amlodipine FDC was associated with a numerically lower incidence of peripheral edema compared with amlodipine monotherapy. Thus, perindopril/amlodipine FDC represents a useful option for the treatment of hypertension, including as initial therapy for patients likely to require multiple drugs to achieve their BP targets.

Edoxaban: a review in nonvalvular atrial fibrillation.

The factor Xa inhibitor edoxaban (Lixiana(®)) is a new direct oral anticoagulant recently approved in the EU for the prevention of stroke and systemic embolic events (SEE) in patients with nonvalvular atrial fibrillation and one or more risk factors. In the large, randomized, double-blind, double-dummy, ENGAGE AF-TIMI 48 trial, oral edoxaban dosages of 30 and 60 mg once daily for a median treatment duration of 907 days in patients with moderate-to-high-risk nonvalvular atrial fibrillation were noninferior to warfarin for the incidence of first stroke or SEE. Both high-dose and low-dose edoxaban were associated with significantly lower rates than warfarin of major bleeding, including intracranial haemorrhage, and death from cardiovascular causes. Edoxaban has a rapid onset of action, a short half-life, few drug interactions and offers the convenience of oral, once-daily, fixed-dose administration, without the need for coagulation monitoring and without regard to food. Therefore, edoxaban is an effective and well tolerated therapeutic option in patients with nonvalvular atrial fibrillation.

Word production inconsistency of Singaporean-English-speaking adolescents with Down Syndrome.

BACKGROUND: The nature of speech disorders in individuals with Down Syndrome (DS) remains controversial despite various explanations put forth in the literature to account for the observed speech profiles. A high level of word production inconsistency in children with DS has led researchers to query whether the inconsistency continues into adolescence, and if the inconsistency stems from inconsistent phonological disorder (IPD) or childhood apraxia of speech (CAS). Of the studies that have been published, most suggest that the speech profile of individuals with DS is delayed, while a few recent studies suggest a combination of delayed and disordered patterns. However, no studies have explored the nature of word production inconsistency in this population, and the relationship between word production inconsistency, receptive vocabulary and severity of speech disorder. AIMS: To investigate in a pilot study the extent of word production inconsistency in adolescents with DS and to examine the correlations between word production inconsistency, measures of receptive vocabulary, severity of speech disorder and oromotor skills in adolescents with DS. METHODS & PROCEDURES: The participants were 32 native speakers of Singaporean-English adolescents, comprising 16 participants with DS and 16 typically developing (TD) participants. The participants completed a battery of standardized speech and language assessments, including The Diagnostic Evaluation of Articulation and Phonology (DEAP) assessment. Results from each test were correlated to determine relationships. Qualitative analyses were also carried out on all the data collected. OUTCOMES & RESULTS: In this study, seven out of 16 participants with DS scored above 40% on word production inconsistency, a diagnostic criterion for IPD. In addition, all participants with DS performed poorly on the oromotor assessment of DEAP. The overall speech profile observed did not exactly correspond with the cluster symptoms observed in children with IPD or CAS. CONCLUSIONS & IMPLICATIONS: Word production inconsistency is a noticeable feature in the speech of individuals with DS. In addition, the speech profiles of individuals with DS consist of atypical and unusual errors alongside developmental errors. Significant correlations were found between the measures investigated, suggesting that speech disorder in DS is multifactorial. The results from this study will help to improve differential diagnosis of speech disorders and individualized treatment plans in the population with DS.

Bortezomib: A Review in Mantle Cell Lymphoma in Previously Untreated Patients Unsuitable for Stem-Cell Transplantation.

Bortezomib (Velcade(®)) is a proteasome inhibitor that is approved for the treatment of multiple myeloma and mantle cell lymphoma (MCL). This article reviews the efficacy and tolerability of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in the treatment of previously untreated MCL unsuitable for stem-cell transplantation, and overviews the pharmacology of bortezomib. In the large, randomized, assessor-blinded, multinational LYM-3002 trial, induction therapy with VR-CAP improved progression-free survival significantly more than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) after a median follow-up of 40 months in patients with newly diagnosed MCL ineligible or not considered for stem-cell transplantation. Complete response and certain other secondary endpoints were improved significantly more with VR-CAP than R-CHOP. Overall survival data were not mature at the time of assessment. The improved efficacy with VR-CAP was accompanied by an increased incidence of grade 3 or higher adverse events, particularly haematological adverse events.