SPiRIT study protocol (Shoulder Pain: Randomised trial of Injectable Treatments): a randomised feasibility and pilot study of autologous protein solution (APS) vs corticosteroids for treating subacromial shoulder pain.

BACKGROUND: The management of subacromial shoulder pain represents a significant challenge and is typically managed through either physiotherapy, joint injection or surgical intervention. Recent surgical trials have questioned the efficacy and there is a need to improve the evidence base for the non-surgical management of this condition. The study aims to provide evidence of the feasibility of conducting a randomised controlled trial to compare the efficacy of autologous protein solution (APS) against the current standard of care, corticosteroid injection (CSI) for subacromial shoulder pain. Autologous protein solution (APS) is a blood-derived biological injection which has been shown to have anti-inflammatory effects. METHODS: A parallel-group two-arm randomised control trial will be conducted, comparing APS and CSI for shoulder pain. Fifty patients will be recruited. Feasibility will be assessed by examination of the conversion rate of eligible participants to the total number of participants recruited, whether it is possible to collect the appropriate outcome measures and the levels of retention/data compliance at follow-up dates. DISCUSSION: CSI is the mainstay of conservative management of subacromial shoulder pain. Trials and systematic reviews have reported differing conclusions, but the consensus view is that any benefits seen from CSI use are most likely to be short-term and there remains a significant number of patients who go on to have surgical intervention despite CSI. Biological injections, such as APS are being increasingly used, in the anticipation they may offer improved longer lasting outcomes for shoulder pain. However, the evidence to demonstrate the comparative efficacy of CSI versus APS does not currently exist. If feasible, a fully powered study will offer clarity to the treatment pathway of thousands of patients each year with subacromial pain. TRIAL REGISTRATION: The study is funded by the National Institute for Health Research-Research for Patient Benefit, NIHR 201473, Trial Registration Number (ISRCTN12536844: SPiRIT. Shoulder pain: randomised trial of injectable treatments-date of Registration 15/9/2021). Protocol Version V1.0_30Jul2021. IRAS Project ID: 294,982.

A neotropical perspective on the uniqueness of the Holocene among interglacials.

Understanding how tropical systems have responded to large-scale climate change, such as glacial-interglacial oscillations, and how human impacts have altered those responses is key to current and future ecology. A sedimentary record recovered from Lake Junín, in the Peruvian Andes (4085 m elevation) spans the last 670,000 years and represents the longest continuous and empirically-dated record of tropical vegetation change to date. Spanning seven glacial-interglacial oscillations, fossil pollen and charcoal recovered from the core showed the general dominance of grasslands, although during the warmest times some Andean forest trees grew above their modern limits near the lake. Fire was very rare until the last 12,000 years, when humans were in the landscape. Here we show that, due to human activity, our present interglacial, the Holocene, has a distinctive vegetation composition and ecological trajectory compared with six previous interglacials. Our data reinforce the view that modern vegetation assemblages of high Andean grasslands and the presence of a defined tree line are aspects of a human-modified landscape.

Efficacy of green infrastructure in reducing exposure to local, traffic-related sources of airborne particulate matter (PM).

One aim of roadside green infrastructure (GI) is to mitigate exposure to local, traffic-generated pollutants. Here, we determine the efficacy of roadside GI in improving local air quality through the deposition and/or dispersion of airborne particulate matter (PM). PM was collected on both pumped air filters and on the leaves of a recently installed 'tredge' (trees managed as a head-high hedge) at an open road environment next to a primary school in Manchester, U.K. The magnetic properties of PM deposited on leaves and filters (size fractions PM10 and PM2.5) were deduced from hysteresis loops, first-order reversal curves (FORCs), and low-temperature remanence measurements. These were complemented with electron microscopy to identify changes in magnetic PM concentration downwind of the tredge/GI. We show that the tredge is permeable to airflow using a simple CO2 tracer experiment; hence, it allows interception and subsequent deposition of PM on its leaves. Magnetic loadings per m3 of air from filters (PM10 saturation magnetisation, Ms, at 5 K) were reduced by 40 % behind the tredge and a further 63 % in the playground; a total reduction of 78 % compared to roadside air. For the PM2.5 fraction, the reduction in magnetic loading behind the tredge was remarkable (82 %), reflecting efficient diffusional capture of sub-5 nm Fe-oxide particles by the tredge. Some direct mixing of roadside and playground air occurs at the back of the playground, caused by air flow over, and/or through gaps in, the slowly-permeable tredge. The magnetic loading on tredge leaves increased over successive days, capturing ~23 % of local, traffic-derived PM10. Using a heuristic two-dimensional turbulent mixing model, we assess the limited dispersion of PM < 22.5 µm induced by eddies in the tredge wake. This study demonstrates that PM deposition on leaves reduces exposure significantly in this school playground setting; hence, providing a cost-effective mitigation strategy.

Transcriptomic analyses of joint tissues during osteoarthritis development in a rat model reveal dysregulated mechanotransduction and extracellular matrix pathways.

OBJECTIVE: Transcriptomic changes in joint tissues during the development of osteoarthritis (OA) are of interest for the discovery of biomarkers and mechanisms of disease. The objective of this study was to use the rat medial meniscus transection (MMT) model to discover stage and tissue-specific transcriptomic changes. DESIGN: Sham or MMT surgeries were performed in mature rats. Cartilage, menisci and synovium were scored for histopathological changes at 2, 4 and 6 weeks post-surgery and processed for RNA-sequencing. Differentially expressed genes (DEG) were used to identify pathways and mechanisms. Published transcriptomic datasets from animal models and human OA were used to confirm and extend present findings. RESULTS: The total number of DEGs was already high at 2 weeks (723 in meniscus), followed by cartilage (259) and synovium (42) and declined to varying degrees in meniscus and synovium but increased in cartilage at 6 weeks. The most upregulated genes included tenascins. The 'response to mechanical stimulus' and extracellular matrix-related pathways were enriched in both cartilage and meniscus. Pathways that were enriched in synovium at 4 weeks indicate processes related to synovial hyperplasia and fibrosis. Synovium also showed upregulation of IL-11 and several MMPs. The mechanical stimulus pathway included upregulation of the mechanoreceptors PIEZO1, PIEZO2 and TRPV4 and nerve growth factor. Analysis of data from prior RNA-sequencing studies of animal models and human OA support these findings. CONCLUSION: These results indicate several shared pathways that are affected during OA in cartilage and meniscus and support the role of mechanotransduction and other pathways in OA pathogenesis.

700,000 years of tropical Andean glaciation.

Our understanding of the climatic teleconnections that drove ice-age cycles has been limited by a paucity of well-dated tropical records of glaciation that span several glacial-interglacial intervals. Glacial deposits offer discrete snapshots of glacier extent but cannot provide the continuous records required for detailed interhemispheric comparisons. By contrast, lakes located within glaciated catchments can provide continuous archives of upstream glacial activity, but few such records extend beyond the last glacial cycle. Here a piston core from Lake Junín in the uppermost Amazon basin provides the first, to our knowledge, continuous, independently dated archive of tropical glaciation spanning 700,000 years. We find that tropical glaciers tracked changes in global ice volume and followed a clear approximately 100,000-year periodicity. An enhancement in the extent of tropical Andean glaciers relative to global ice volume occurred between 200,000 and 400,000 years ago, during sustained intervals of regionally elevated hydrologic balance that modified the regular approximately 23,000-year pacing of monsoon-driven precipitation. Millennial-scale variations in the extent of tropical Andean glaciers during the last glacial cycle were driven by variations in regional monsoon strength that were linked to temperature perturbations in Greenland ice cores1; these interhemispheric connections may have existed during previous glacial cycles.

Resistant fabric warming is a viable alternative to forced-air warming to prevent inadvertent perioperative hypothermia during hemiarthroplasty in the elderly.

BACKGROUND: Surgical site infection (SSI) is associated with inadvertent perioperative hypothermia (IPH). This can be prevented by active patient warming. However, results from comparisons of warming techniques are conflicting. They are based mostly on elective surgery, are from small numbers of patients, and are dominated by the market leader, forced-air warming (FAW). Furthermore, the definition of hypothermia is debatable and systematic reviews of warming systems conclude that a stricter control of temperature is required to study the benefits of warming. AIM: To analyse core temperatures in detail in a large subset of elderly patients who took part in a randomized trial of patient warming following hemiarthroplasty who had received constant zero-flux thermometry to record their temperature. METHODS: Regression models with a fixed effect for warming group and covariates related to temperature were compared for 257 participants randomized to FAW or resistant fabric warming (RFW) from a prior clinical trial. FINDINGS: Those in the RFW group were -0.08°C cooler and had a cumulative hypothermia score -1.87 lower than those in the FAW group. There was no difference in the proportion of hypothermic patients at either <36.5°C or <36.0°C. CONCLUSIONS: This is the first study to provide accurate temperature measurements in patients undergoing a procedure predominantly under regional rather than general anaesthetic. It shows that RFW is a viable alternative to FAW for preventing IPH during hemiarthroplasty. Further studies are needed to measure the benefits of patient warming in terms of clinically important outcomes.

PM-Scl and Th/To in systemic sclerosis: a comparison of different autoantibody assays.

OBJECTIVE: To compare test characteristics of the Euroimmun line blot assay with other assays for two uncommon autoantibody specificities in systemic sclerosis (SSc). METHODS: Patients from the Johns Hopkins Scleroderma Center were assayed routinely using the Euroimmun platform. Patients positive for anti-Th/To (N = 73) and anti-PM-Scl (PM75 and/or PM100; N = 290) by Euroimmun were compared with SSc patients negative for these autoantibodies. For Th/To antibodies, the comparison assay was immunoprecipitation (IP), performed using 4 Th/To complex components: POP1, RPP40, RPP30, and RPP25. For anti-PM-Scl, IPs were performed with PM100 and PM75. Different Euroimmun cut-offs for assigning antibody positive status (≥ 15/+, ≥ 36/++, ≥ 71/+++) were examined. Kappa statistics were calculated to determine agreement between assays. RESULTS: The best performing thresholds for defining anti-PM-Scl positivity were both PM75 and PM100 ≥ 15/+ on Euroimmun, corresponding to a kappa statistic of 0.79, sensitivity 72% and specificity 100%. For anti-Th/To, kappa values were lower for all comparisons (κ < 0.5). Given the high sensitivity of defining anti-Th/To by ≥ 15/+ (91-95%), a potential approach is to use Euroimmun screening (15/+ cut-off), followed by confirmatory IP. CONCLUSION: Given the increasing utilization of Euroimmun and the importance of comparing data across cohorts, continued use of this platform is warranted, acknowledging discordance with IP for some specificities. For these, using a two-step approach (Euroimmun to maximize sensitivity, confirmatory assay to increase specificity) is suggested. KEY POINTS: • For less common SSc autoantibody specificities, some discordances exist between IP and Euroimmun LIA. • The best performing thresholds for defining anti-PM-Scl positivity were both PM75 and PM100 ≥ 15/+ on Euroimmun. • For Th/To, a two-step approach (Euroimmun to maximize sensitivity, confirmatory assay to increase specificity) is suggested.

Fundamental dissipation due to bound fermions in the zero-temperature limit.

The ground state of a fermionic condensate is well protected against perturbations in the presence of an isotropic gap. Regions of gap suppression, surfaces and vortex cores which host Andreev-bound states, seemingly lift that strict protection. Here we show that in superfluid 3He the role of bound states is more subtle: when a macroscopic object moves in the superfluid at velocities exceeding the Landau critical velocity, little to no bulk pair breaking takes place, while the damping observed originates from the bound states covering the moving object. We identify two separate timescales that govern the bound state dynamics, one of them much longer than theoretically anticipated, and show that the bound states do not interact with bulk excitations.

The epidemiology and trends in the surgical management of calcaneal fractures in England between 2000 and 2017.

AIMS: This paper documents the epidemiology of adults (aged more than 18 years) with a calcaneal fracture who have been admitted to hospital in England since 2000. Secondary aims were to document whether publication of the United Kingdom Heel Fracture Trial (UK HeFT) influenced the proportion of patients admitted to hospital with a calcaneal fracture who underwent surgical treatment, and to determine whether there has been any recent change in the surgical technique used for these injuries. PATIENTS AND METHODS: In England, the Hospital Episode Statistics (HES) data are recorded annually. Between 2000/01 and 2016/17, the number of adults admitted to an English NHS hospital with a calcaneal fracture and whether they underwent surgical treatment was determined. RESULTS: During this 17-year period, 62 858 patients were admitted to hospital with a calcaneal fracture. The male-to-female ratio was 2.66:1. The mean annual incidence was 10.5/100 000 for men and 3.8/100 000 for women. The results of the UK HeFT were published in July 2014. The percentage of patients admitted with a calcaneal fracture undergoing internal fixation was 7.31% (3792/51 859) before and 7.38% (534/7229) after its publication. This difference was not statistically significant (p = 0.94). Since 2015, there has been a significant increase in the percentage of calcaneal fractures treated by closed reduction and internal fixation, as opposed to open reduction and internal fixation, from 7.7% (292/3792) to 13.29% (71/534) (p < 0.001). CONCLUSION: This study documents the epidemiology and trends in surgical treatment of calcaneal fractures in England. We established that surgeons did not change their practice in terms of offering surgery to these patients in response to the results of the UK HeFT. There has been a significant (p < 0.001) increase in the number of calcaneal fractures being treated surgically using less invasive procedures.

An intravenous insulin protocol designed for pregnancy reduces neonatal hypoglycaemia following betamethasone administration in women with gestational diabetes.

AIMS: Marked hyperglycaemia is common following betamethasone administration in women with gestational diabetes (GDM), and may contribute to neonatal hypoglycaemia. Validated protocols to deliver glycaemic stability following betamethasone are lacking. We hypothesized that an intravenous insulin (IVI) protocol for pregnancy-specific glycaemic targets (Pregnancy-IVI) would achieve greater at-target glycaemic control than a generic adult intravenous insulin protocol (Adult-IVI), and may reduce neonatal hypoglycaemia. METHODS: A retrospective cohort study of the performance Adult-IVI and Pregnancy-IVI following betamethasone in GDM, sequentially implemented at a tertiary hospital, without change in indication for IVI. Cases were identified by electronic record search. Primary outcome was percentage of on-IVI time with at-target glycaemia [blood glucose level (BGL) 3.8-7 mmol/l]. Secondary outcomes were time with critical hyperglycaemia (BGL > 10 mmol/l), occurrence of maternal hypoglycaemia (BGL < 3.8 mmol/l), and incidence of neonatal hypoglycaemia (BGL ≤ 2.5 mmol/l) if betamethasone was administered within 48 h of birth. RESULTS: The cohorts comprised 151 women (Adult-IVI n = 86; Pregnancy-IVI n = 65). The primary outcome was 68% time-at-target [95% confidence interval (CI) 64-71%) for Pregnancy-IVI compared with 55% (95% CI 50-60%) for Adult-IVI (P = 0.0002). Critical maternal hyperglycaemia (0% vs. 2%, P = 0.02) and hypoglycaemia (2% vs. 12%, P = 0.02) were both lower with Pregnancy-IVI than Adult-IVI. Neonatal hypoglycaemia was less common after Pregnancy-IVI (29%) than after Adult-IVI (54%, P = 0.03). A multiple logistic regression model adjusting for potential confounders gave an odds ratio for neonatal hypoglycaemia with Pregnancy-IVI of 0.27 (95% CI 0.10-0.76, P = 0.01). CONCLUSIONS: An IVI protocol designed for pregnancy effectively controlled maternal hyperglycaemia following betamethasone administration in GDM. This is the first intervention to show a reduction in betamethasone-associated neonatal hypoglycaemia, linked with optimum maternal glycaemic control.

Dynamic shear analysis: a novel method to determine mechanical integrity of normal and torn human acetabular labra: Implications for prediction of outcome of repair.

OBJECTIVES: The aim of this study was to investigate the structural integrity of torn and non-torn human acetabular labral tissue. METHODS: A total of 47 human labral specimens were obtained from a biobank. These included 22 torn specimens and 25 control specimens from patients undergoing total hip arthroplasty with macroscopically normal labra. The specimens underwent dynamic shear analysis using a rheometer to measure storage modulus, as an indicator of structural integrity. RESULTS: There was a significant difference in the storage modulus between torn (mean modulus = 2144.08 Pa) and non-torn (3178.1 Pa) labra (p = 0.0001). CONCLUSION: The acetabular labrum of young patients with a tear has significantly reduced structural integrity compared with a non-torn labrum in older patients with end-stage osteoarthritis. This study contributes to the understanding of the biomechanics of labral tears, and the observation of reduced structural integrity in torn labra may explain why some repairs fail. Our data demonstrate that labral tears probably have a relatively narrow phenotype, presenting a basis for further investigations that will provide quantifiable data to support their classification and a means to develop a standardized surgical technique for their repair. This study also demonstrates the value of novel biomechanical testing methods in investigating pathological tissues of orthopaedic interest.Cite this article: A. K. Woods, J. Broomfield, P. Monk, F. Vollrath, S. Glyn-Jones. Dynamic shear analysis: a novel method to determine mechanical integrity of normal and torn human acetabular labra: Implications for prediction of outcome of repair. Bone Joint Res 2018;7:440-446. DOI: 10.1302/2046-3758.77.BJR-2017-0282.R2.

Effects of Fermented Papaya Preparation (FPP) on Safety Outcomes in Older Adults - A Short Report of a Placebo-Controlled Clinical Trial.

Fermented Papaya Preparation (FPP®) has shown antioxidative and anti-inflammatory effects in preclinical and clinical aging studies. However, clinical trials are needed to fully evaluate the safety of FPP® in moderate-functioning, generally healthy older adults. In this randomized (9g/day of FPP® or placebo), crossover design study, we enrolled 30 older moderate-functioning older adults (70-100 years old). The participants completed both a treatment and a placebo condition. After eight (8) weeks on each of these regimens (with a 4-week wash-out period in between), participants had their venous blood drawn for assessment of blood chemistries, metabolic outcomes and inflammatory biomarkers. Participants were asked to report any adverse events during the course of the study and complete post-treatment outcome assessments for anthropometric and metabolic outcomes. The major finding related to safety was that there were no adverse changes in blood chemistries and few adverse events in the FPP® condition, which did not differ from placebo (p>0.05). There were no serious adverse effects in either condition. Twenty-nine (29) participants (mean age 78.2±5.3 yrs) completed the study with 94% adherence to the dosing regimen. There were no significant effects of FPP® on anthropometric and metabolic outcomes. In addition, no effects on markers of inflammation were observed. Our trial demonstrates FPP® supplementation is safe and feasible in adults ages 70 years and older. Based on these findings and the positive effects FPP has demonstrated in previous trials, future trials should examine the effects of FPP® in older adults with impaired health status and/or older adults who may have insufficient anti-oxidant protection due to their genetic background.

A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box.

Cryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies, in vitro toxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound against Cryptosporidium parvum Iowa and field isolates was comparable to that against Cryptosporidium hominis Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic for C. parvum, we developed a novel in vitro parasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stage Cryptosporidium drug leads and may aid in planning in vivo efficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

A pilot investigation on the effects of combination transcranial direct current stimulation and speed of processing cognitive remediation therapy on simulated driving behavior in older adults with HIV.

Cognitive impairments seen in people living with HIV (PLWH) are associated with difficulties in everyday functioning, specifically driving. This study utilized speed of processing cognitive remediation therapy (SOP-CRT) with transcranial direct current stimulation (tDCS) to gauge the feasibility and impact on simulated driving. Thirty PLWH (M age = 54.53, SD = 3.33) were randomly assigned to either: sham tDCS SOP-CRT or active tDCS SOP-CRT. Seven indicators of simulated driving performance and safety were obtained. Repeated measures ANOVAs controlling for driver's license status (valid and current license or expired/no license) revealed a large training effect on average driving speed. Participants who received active tDCS SOP-CRT showed a slower average driving speed (p = 0.020, d = 0.972) than those who received sham tDCS SOP-CRT. Non-significant small-to-medium effects were seen for driving violations, collisions, variability in lane positioning, and lane deviations. Combination tDCS SOP-CRT was found to increase indices of cautionary simulated driving behavior. Findings reveal a potential avenue of intervention and rehabilitation for improving driving safety among vulnerable at-risk populations, such as those aging with chronic disease.

Neural response to working memory demand predicts neurocognitive deficits in HIV.

Human immunodeficiency virus (HIV) continues to have adverse effects on cognition and the brain in many infected people, despite a reduced incidence of HIV-associated dementia with combined antiretroviral therapy (cART). Working memory is often affected, along with attention, executive control, and cognitive processing speed. Verbal working memory (VWM) requires the interaction of each of the cognitive component processes along with a phonological loop for verbal repetition and rehearsal. HIV-related functional brain response abnormalities during VWM are evident in functional MRI (fMRI), though the neural substrate underlying these neurocognitive deficits is not well understood. The current study addressed this by comparing 24 HIV+ to 27 demographically matched HIV-seronegative (HIV-) adults with respect to fMRI activation on a VWM paradigm (n-back) relative to performance on two standardized tests of executive control, attention and processing speed (Stroop and Trail Making A-B). As expected, the HIV+ group had deficits on these neurocognitive tests compared to HIV- controls, and also differed in neural response on fMRI relative to neuropsychological performance. Reduced activation in VWM task-related brain regions on the 2-back was associated with Stroop interference deficits in HIV+ but not with either Trail Making A or B performance. Activation of the posterior cingulate cortex (PCC) of the default mode network during rest was associated with Hopkins Verbal Learning Test-2 (HVLT-2) learning in HIV+. These effects were not observed in the HIV- controls. Reduced dynamic range of neural response was also evident in HIV+ adults when activation on the 2-back condition was compared to the extent of activation of the default mode network during periods of rest. Neural dynamic range was associated with both Stroop and HVLT-2 performance. These findings provide evidence that HIV-associated alterations in neural activation induced by VWM demands and during rest differentially predict executive-attention and verbal learning deficits. That the Stroop, but not Trail Making was associated with VWM activation suggests that attentional regulation difficulties in suppressing interference and/or conflict regulation are a component of working memory deficits in HIV+ adults. Alterations in neural dynamic range may be a useful index of the impact of HIV on functional brain response and as a fMRI metric in predicting cognitive outcomes.

Obesity, heuristic reasoning and the organisation of communicative embarrassment in diagnostic radiography.

This paper, the second of three arising from a broader qualitative study, explores difficulties emerging around radiographer-patient communication regarding obesity in hospital-based encounters, and the situated strategies found by experienced radiographers for handling such situations. Semi-structured interviews with eight clinicians working in plain radiography (mean experience = 21.56 years) were analysed using Interpretative Phenomenological Analysis (IPA), so as to highlight the practical, nuanced and real-world experiences of these individuals regarding obesity communication. Participants generally viewed communicating with obese patients as a potential interpersonal 'minefield'. Most reported having had negative experiences in which patients had acted with denial or outright aggression during examinations but, conversely, all reported cases in which patients had been frank and open about their obesity, and even been happy to joke about it. Equally, all participants were able to document a range of communicative strategies for effectively handling potentially difficult situations. Results further indicate that the documented communicative problems and embarrassment for the patient only generally arose within specific material contexts; i.e. when equipment is inadequate or multiple exposures are necessary. It is concluded that, while participants largely expected any interaction about obesity with a patient to be embarrassing for both parties, their actual experience was much more varied. This indicates a more complex communicative environment than may be expected, and also a potential metacognitive availability heuristic in play - something that might be clarified with future quantitative investigation.

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration.

Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of (111)In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p<0.001). When normalised to the delivered lung dose, the clearance kinetics of (111)In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5±0.9h (R(2)=0.995) and 10.6±0.3h (R(2)=1.000) for healthy and inflamed lungs respectively (n=3). In contrast, (111)In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation.

Dimensions of depressive symptoms and cingulate volumes in older adults.

Clinical depression and subthreshold depressive symptoms in older adults have been linked to structural changes in the cingulate gyrus. The cingulate comprises functionally distinct subregions that may have distinct associations with different types, or symptom dimensions, of depression. This study examined the relationship between symptom dimensions of depression and gray matter volumes in the anterior cingulate, posterior cingulate and isthmus of the cingulate in a nonclinical sample. The study included 41 community-dwelling older adults between the ages of 55 and 81. Participants received a structural magnetic resonance imaging scan and completed the Center for Epidemiologic Studies Depression Scale. Subscale scores for depressed mood, somatic symptoms and lack of positive affect were calculated, and Freesurfer was used to extract cingulate gray matter volumes. Regression analyses were conducted to examine the relationship between depressive symptoms and volumes of cingulate subregions while controlling for sex, age and estimated total intracranial volume. Higher scores on the depressed mood subscale were associated with larger volumes in the left posterior cingulate and smaller volumes in the isthmus cingulate. Higher scores on the somatic symptoms subscale were significantly related to smaller volumes in the posterior cingulate. A trend was observed for a positive relationship between higher scores on the lack of positive affect subscale and larger volumes in the anterior cingulate cortex. These results are consistent with previous findings of altered cingulate volumes with increased depressive symptomatology and suggest specific symptom dimensions of depression may differ in their relationship with subregions of the cingulate.

Resident reflections on end-of-life education: a mixed-methods study of the 3 Wishes Project.

OBJECTIVE: The objectives of this study were to describe residents' experiences with end-of-life (EOL) education during a rotation in the intensive care unit (ICU), and to understand the possible influence of the 3 Wishes Project. DESIGN: We enrolled dying patients, their families and 1-3 of their clinicians in the 3 Wishes Project, eliciting and honouring a set of 3 wishes to bring peace to the final days of a critically ill patient's life, and ease the grieving process for families. We conducted semistructured interviews with 33 residents who had cared for 50 dying patients to understand their experiences with the project. Interviews were recorded, transcribed verbatim, then analysed using a qualitative descriptive approach. SETTING: 21-bed medical surgical ICU in a tertiary care, university-affiliated hospital. RESULTS: 33 residents participated from internal medicine (24, 72.7%), anaesthesia (8, 24.2%) and laboratory medicine (1, 3.0%) programmes in postgraduate years 1-3. 3 categories and associated themes emerged. (1) EOL care is a challenging component of training in that (a) death in the ICU can invoke helplessness, (b) EOL education is inadequate, (c) personal connections with dying patients is difficult in the ICU and (d) EOL skills are valued by residents. (2) The project reframes the dying process for residents by (a) humanising this aspect of practice, (b) identifying that family engagement is central to the dying process, (c) increasing emotional responsiveness and (d) showing that care shifts, not stops. (3) The project offers experiential education by (a) intentional role modelling, (b) facilitating EOL dialogue, (c) empowering residents to care in a tangible way and (d) encouraging reflection. CONCLUSIONS: For residents, the 3 Wishes Project integrated many forms of active learning for residents. Practice-based rather than classroom-based programmes may engage trainees to develop EOL skills transferable to other settings.