Guideline for the management of hip fractures 2020: Guideline by the Association of Anaesthetists.

We convened a multidisciplinary Working Party on behalf of the Association of Anaesthetists to update the 2011 guidance on the peri-operative management of people with hip fracture. Importantly, these guidelines describe the core aims and principles of peri-operative management, recommending greater standardisation of anaesthetic practice as a component of multidisciplinary care. Although much of the 2011 guidance remains applicable to contemporary practice, new evidence and consensus inform the additional recommendations made in this document. Specific changes to the 2011 guidance relate to analgesia, medicolegal practice, risk assessment, bone cement implantation syndrome and regional review networks. Areas of controversy remain, and we discuss these in further detail, relating to the mode of anaesthesia, surgical delay, blood management and transfusion thresholds, echocardiography, anticoagulant and antiplatelet management and postoperative discharge destination. Finally, these guidelines provide links to supplemental online material that can be used at readers' institutions, key references and UK national guidance about the peri-operative care of people with hip and periprosthetic fractures during the COVID-19 pandemic.

Improving systems of care during and after a pregnancy complicated by hyperglycaemia: A protocol for a complex health systems intervention.

BACKGROUND: Many women with hyperglycaemia in pregnancy do not receive care during and after pregnancy according to standards recommended in international guidelines. The burden of hyperglycaemia in pregnancy falls disproportionately upon Indigenous peoples worldwide, including Aboriginal and Torres Strait Islander women in Australia. The remote and regional Australian context poses additional barriers to delivering healthcare, including high staff turnover and a socially disadvantaged population with a high prevalence of diabetes. METHODS: A complex health systems intervention to improve care for women during and after a pregnancy complicated by hyperglycaemia will be implemented in remote and regional Australia (the Northern Territory and Far North Queensland). The Theoretical Domains Framework was used during formative work with stakeholders to identify intervention components: (1) increasing workforce capacity, skills and knowledge and improving health literacy of health professionals and women; (2) improving access to healthcare through culturally and clinically appropriate pathways; (3) improving information management and communication; (4) enhancing policies and guidelines; (5) embedding use of a clinical register as a quality improvement tool. The intervention will be evaluated utilising the RE-AIM framework at two timepoints: firstly, a qualitative interim evaluation involving interviews with stakeholders (health professionals, champions and project implementers); and subsequently a mixed-methods final evaluation of outcomes and processes: interviews with stakeholders; survey of health professionals; an audit of electronic health records and clinical register; and a review of operational documents. Outcome measures include changes between pre- and post-intervention in: proportion of high risk women receiving recommended glucose screening in early pregnancy; diabetes-related birth outcomes; proportion of women receiving recommended postpartum care including glucose testing; health practitioner confidence in providing care, knowledge and use of relevant guidelines and referral pathways, and perception of care coordination and communication systems; changes to health systems including referral pathways and clinical guidelines. DISCUSSION: This study will provide insights into the impact of health systems changes in improving care for women with hyperglycaemia during and after pregnancy in a challenging setting. It will also provide detailed information on process measures in the implementation of such health system changes.

Incorporating indigenous knowledge in health services: a consumer partnership framework.

OBJECTIVES: Healthcare policy and planning should be informed by a partnership between healthcare services and healthcare users. This is critical for people who access care frequently such as indigenous Australians who have a high burden of chronic kidney disease. This study aimed to explore the most appropriate ways of enhancing services by incorporating renal patients' expectations and satisfaction of care in Australia's Northern Territory. STUDY DESIGN: This is a participatory action research. METHODS: Six aboriginal health users with end-stage kidney disease were recruited to form an Indigenous Reference Group. This group met bimonthly between April and November 2017 and meetings took the same structure as a focus group. Findings from these meetings were presented to health policy and planners in a feedback loop implemented by the study. RESULTS: This framework enabled indigenous knowledge to guide the project, indigenous priorities to be identified in this context and timely feedback of information to inform the strengths and priorities of the health service. Changes were recognised and addressed immediately. CONCLUSIONS: This qualitative research framework is a useful mechanism for providing local data to inform patient-centred health system change as expressed by health users. We recommend this consumer partnership framework be embedded into existing operational structures to support the ongoing sustainability of this group.

Genome-wide association studies of placebo and duloxetine response in major depressive disorder.

We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18-75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery-Åsberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points. In the placebo-treated subsample (N=205), we observed a genome-wide association with rs76767803 (ß=0.69, P=1.25 × 10-8) upstream of STAC1. STAC1 rs76767803 was also associated with response using mixed model analysis (χ2=3.95; P=0.001). In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; ß=-0.46, P=1.55 × 10-5), NCAM1 (rs2303377; ß=0.45, P=1.76 × 10-5) and MLL5 (rs117986340; ß=0.91, P=3.04 × 10-5). Our findings suggest that a variant upstream of STAC1 is associated with placebo response, which might have implications for treatment optimization, clinical trial design and drug development.

Deletion variant in the ADRA2B gene increases coupling between emotional responses at encoding and later retrieval of emotional memories.

A deletion variant of the ADRA2B gene that codes for the α2b adrenoceptor has been linked to greater susceptibility to traumatic memory as well as attentional biases in perceptual encoding of negatively valenced stimuli. The goal of the present study was to examine whether emotional enhancements of memory associated with the ADRA2B deletion variant were predicted by encoding, as indexed by the subjectively perceived emotional salience (i.e., arousal) of events at the time of encoding. Genotyping was performed on 186 healthy young adults who rated positive, negative, and neutral scenes for level of emotional arousal and subsequently performed a surprise recognition memory task 1 week later. Experience of childhood trauma was also measured, as well as additional genetic variations associated with emotional biases and episodic memory. Results showed that subjective arousal was linked to memory accuracy and confidence for ADRA2B deletion carriers but not for non-carriers. Our results suggest that carrying the ADRA2B deletion variant enhances the relationship between arousal at encoding and subsequent memory for moderately arousing events.

The prevalence of Dupuytren contractures in patients with psoriasis.

BACKGROUND: Dupuytren contracture (DC) is a fibrocontractile disease of the palms, affecting approximately 4% of the population, while psoriasis is an immune-mediated disease, affecting 2% of the population. Through clinical observation in our psoriasis clinic, we found an apparent increased prevalence of DC in patients with psoriasis compared with the general population. This has not previously been statistically verified in a clinical study. AIM: To evaluate the prevalence of DC in the full range of clinical psoriasis phenotypes. METHODS: In total, 98 patients with psoriasis attending our psoriasis clinic were examined for DC, based on predetermined criteria. In addition, 84 patients with DC, obtained from a specialist hand clinic, were assessed using a validated psoriasis questionnaire. We utilized Bayes theorem and bootstrap simulation to calculate the conditional prevalence of DC, then we used the results to compare the prevalence of DC between patients with psoriasis and a nonpsoriasis population. RESULTS: The percentage of patients with DC was 19.6% in the psoriasis population and 3.6% in the nonpsoriasis population. Development of DC showed a phenotypic predilection, with 39.1% of patients with predominantly palmoplantar involvement and 38.9% of patients with intertriginous psoriasis developing DC compared with 12.7% of patients with psoriasis who did not have these two phenotypical presentations. CONCLUSIONS: Our data show a positive correlation between psoriasis and DC. Patients with the palmoplantar phenotype of psoriasis were more likely to develop DC. By understanding this relationship, dermatologists may diagnose DC early in its onset in patients with psoriasis, prompting referral to hand surgeons when appropriate.

Oral Cavity Cancers: Ethnic Differences in Radiotherapy Outcomes in a Majority South Asian Leicester Community.

AIMS: Squamous cell carcinoma oral cavity cancers (SCCOCCs) have a higher reported incidence in South Asian countries. We sought to compare presenting stage and outcome by ethnicity in patients with SCCOCC treated with radical radiotherapy in a single centre in the UK. MATERIALS AND METHODS: All patients with SCCOCC treated with radical radiotherapy at an oncology department in Leicester (UK) between 2011 and 2017 were identified. Baseline demographic, clinical data and 2-year treatment outcomes were reported. RESULTS: Of the 109 patients included, 40 were South Asian and 59 were non-South Asian. South Asians had significantly poorer 2-year disease-free survival compared with non-South Asians (54.6% versus 73%, P = 0.01). CONCLUSION: Our analysis suggests that South Asians with SCCOCC have poorer outcomes despite a younger age and similar disease characteristics. Environmental, social factors and differing biology of disease may be responsible and further research is required to inform targeted interventions.

Riding out the storm: depleted fat stores and elevated hematocrit in a small bodied endotherm exposed to severe weather.

In the mid-continental grasslands of North America, climate change is increasing the intensity and frequency of extreme weather events. Increasingly severe storms and prolonged periods of elevated temperatures can impose challenges that adversely affect an individual's condition and, ultimately, survival. However, despite mounting evidence that extreme weather events, such as heavy rain storms, can impose short-term physiological challenges, we know little regarding the putative costs of such weather events. To determine the consequences of extreme weather for small endotherms, we tested predictions of the relationships between both severe precipitation events and wet bulb temperatures (an index that combines temperature and humidity) prior to capture with body composition and hematocrit of grasshopper sparrows (Ammodramus savannarum) caught during the breeding season at the Konza Prairie Biological Station, Kansas, USA, between 2014 and 2016. We measured each individual's fat mass, lean mass and total body water using quantitative magnetic resonance in addition to their hematocrit. Individuals exposed to storms in the 24 hours prior to capture had less fat reserves, more lean mass, more water and higher hematocrit than those exposed to moderate weather conditions. Furthermore, individuals stored more fat if they experienced high wet bulb temperatures in the week prior to capture. Overall, the analysis of these data indicate that extreme weather events take a physiological toll on small endotherms, and individuals may be forced to deplete fat stores and increase erythropoiesis to meet the physiological demands associated with surviving a storm. Elucidating the potential strategies used to cope with severe weather may enable us to understand the energetic consequences of increasingly severe weather in a changing world.

Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain.

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients.

2,4-Dinitrophenol: 'diet' drug death following major trauma.

There has been a resurgence in the illicit use of 2,4-dinitrophenol by people wishing to achieve rapid weight loss. Despite its availability, the drug is banned for human consumption as it is toxic and can have fatal consequences. We present the case of a 23-year-old man who regularly consumed 2,4-dinitrophenol to generate fat loss without apparent ill effect. He was involved in a high-speed road traffic collision and sustained limb-threatening injuries. The combination of emergency surgery, trauma and 2,4-dinitrophenol consumption culminated in deterioration under anaesthesia, with subsequent death from multiorgan failure in the intensive care unit 48 h later. Previous cases have reported death from 2,4-dinitrophenol toxicity alone. We believe this is the first reported case of 2,4-dinitrophenol toxicity triggered by the additional physiological stress of polytrauma and emergency surgery.

Higher sociability leads to lower reproductive success in female kangaroos.

In social mammals, social integration is generally assumed to improve females' reproductive success. Most species demonstrating this relationship exhibit complex forms of social bonds and interactions. However, female eastern grey kangaroos (Macropus giganteus) exhibit differentiated social relationships, yet do not appear to cooperate directly. It is unclear what the fitness consequences of such sociability could be in species that do not exhibit obvious forms of cooperation. Using 4 years of life history, spatial and social data from a wild population of approximately 200 individually recognizable female eastern grey kangaroos, we tested whether higher levels of sociability are associated with greater reproductive success. Contrary to expectations, we found that the size of a female's social network, her numbers of preferential associations with other females and her group sizes all negatively influenced her reproductive success. These factors influenced the survival of dependent young that had left the pouch rather than those that were still in the pouch. We also show that primiparous females (first-time breeders) were less likely to have surviving young. Our findings suggest that social bonds are not always beneficial for reproductive success in group-living species, and that female kangaroos may experience trade-offs between successfully rearing young and maintaining affiliative relationships.

Corrigendum to "Osmotherapy: science and evidence-based practice" [BJA Education 18 (2018) 284-290].

[This corrects the article DOI: 10.1016/j.bjae.2018.05.005.].

Quantifying the effects of melittin on liposomes.

Melittin, the soluble peptide of bee venom, has been demonstrated to induce lysis of phospholipid liposomes. We have investigated the dependence of the lytic activity of melittin on lipid composition. The lysis of liposomes, measured by following their mass and dimensions when immobilised on a solid substrate, was close to zero when the negatively charged lipids phosphatidyl glycerol or phosphatidyl serine were used as the phospholipid component of the liposome. Whilst there was significant binding of melittin to the liposomes, there was little net change in their diameter with melittin binding reversed upon salt injection. For the zwitterionic phosphatidyl choline the lytic ability of melittin is dependent on the degree of acyl chain unsaturation, with melittin able to induce lysis of liposomes in the liquid crystalline state, whilst those in the gel state showed strong resistance to lysis. By directly measuring the dimensions and mass changes of liposomes on exposure to melittin using Dual Polarisation Interferometry, rather than following the florescence of entrapped dyes we attained further information about the initial stages of melittin binding to liposomes.

Early major complications after bariatric surgery in the USA, 2003-2014: a systematic review and meta-analysis.

The effectiveness of bariatric surgery has been well-studied. However, complications after bariatric surgery have been understudied. This review assesses <30-d major complications associated with bariatric procedures, including anastomotic leak, myocardial infarction and pulmonary embolism. This review included 71 studies conducted in the USA between 2003 and 2014 and 107,874 patients undergoing either gastric bypass, adjustable gastric banding or sleeve gastrectomy, with mean age of 44 years and pre-surgery body mass index of 46.5 kg m-2 . Less than 30-d anastomotic leak rate was 1.15%; myocardial infarction rate was 0.37%; pulmonary embolism rate was 1.17%. Among all patients, mortality rate following anastomotic leak, myocardial infarction and pulmonary embolism was 0.12%, 0.37% and 0.18%, respectively. Among surgical procedures, <30-d after surgery, sleeve gastrectomy (1.21% [95% confidence interval, 0.23-2.19%]) had higher anastomotic leak rate than gastric bypass (1.14% [95% confidence interval, 0.84-1.43%]); gastric bypass had higher rates of myocardial infarction and pulmonary embolism than adjustable gastric banding or sleeve gastrectomy. During the review, we found that the quality of complication reporting is lower than the reporting of other outcomes. In summary, <30-d rates of the three major complications after either one of the procedures range from 0% to 1.55%. Mortality following these complications ranges from 0% to 0.64%. Future studies reporting complications after bariatric surgery should improve their reporting quality.

Structural and functional characterization of the promoter region of the mouse c-Ki-ras gene.

We isolated and characterized the 5' region of the mouse c-Ki-ras gene, including a 5' untranslated exon (exon 0). These studies used genetic material from Y1 mouse adrenocortical tumor cells in which the c-Ki-ras gene is amplified and overexpressed. Our data demonstrate that transcription initiates at multiple sites, predicting size heterogeneity at the 5' ends of the c-Ki-ras mRNAs. Using transient expression assays, we identified a genomic fragment within the 5' region which exhibits bidirectional promoter activity.

A conserved proline-rich region of the Saccharomyces cerevisiae cyclase-associated protein binds SH3 domains and modulates cytoskeletal localization.

Saccharomyces cerevisiae cyclase-associated protein (CAP or Srv2p) is multifunctional. The N-terminal third of CAP binds to adenylyl cyclase and has been implicated in adenylyl cyclase activation in vivo. The widely conserved C-terminal domain of CAP binds to monomeric actin and serves an important cytoskeletal regulatory function in vivo. In addition, all CAP homologs contain a centrally located proline-rich region which has no previously identified function. Recently, SH3 (Src homology 3) domains were shown to bind to proline-rich regions of proteins. Here we report that the proline-rich region of CAP is recognized by the SH3 domains of several proteins, including the yeast actin-associated protein Abp1p. Immunolocalization experiments demonstrate that CAP colocalizes with cortical actin-containing structures in vivo and that a region of CAP containing the SH3 domain binding site is required for this localization. We also demonstrate that the SH3 domain of yeast Abp1p and that of the yeast RAS protein guanine nucleotide exchange factor Cdc25p complex with adenylyl cyclase in vitro. Interestingly, the binding of the Cdc25p SH3 domain is not mediated by CAP and therefore may involve direct binding to adenylyl cyclase or to an unidentified protein which complexes with adenylyl cyclase. We also found that CAP homologous from Schizosaccharomyces pombe and humans bind SH3 domains. The human protein binds most strongly to the SH3 domain from the abl proto-oncogene. These observations identify CAP as an SH3 domain-binding protein and suggest that CAP mediates interactions between SH3 domain proteins and monomeric actin.

Selection of chymotrypsin inhibitors from a conformationally-constrained combinatorial peptide library.

A synthetic library of cyclic peptides was constructed utilizing the anti-tryptic loop region of the Bowman-Birk inhibitor, D4 from Macrotyloma axillare, as a template. The loop region of this proteinase inhibitor was reproduced by an 11 residue sequence, conformationally constrained by the presence of a disulfide bridge, to act as a mimetic of the functional reactive site region of this protein. This sequence, plus a pentaglycine spacer arm, was used to create a "one bead, one peptide" combinatorial library after on-resin deprotection and cyclization. Randomization at three positions considered to be important for proteinase specificity (P2, P1 and P'2) with the genetically coded amino acids (minus cysteine) plus norleucine generated 8000 permutations. Screening this library with biotinylated alpha-chymotrypsin under appropriate conditions revealed a small number (<0.05%) of beads that selectively bound the labeled proteinase. The sequences present on these active beads were determined, and found to have a well-defined consensus. Analysis of chymotrypsin inhibition in solution using re-synthesized peptides reveals that the sequences identified are potent inhibitors with Ki values in the nanomolar range. These results show that directed randomization of the canonical loop is a powerful way of generating proteinase inhibitors with targeted specificities. Incorporation of selective random changes within a defined structural framework is found to be an effective means of generating variation in large synthetic systems. The functional basis for inhibition by the identified sequences is discussed.