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BackgroundDespite the availability of vaccines and therapies, patients are being hospitalised with coronavirus disease 2019 (COVID-19). Interferon (IFN)-β is a naturally occurring protein that stimulates host immune responses against most viruses, including severe acute respiratory syndrome coronavirus 2. SNG001 is a recombinant IFN-β1a formulation delivered to the lungsvianebuliser. SPRINTER assessed the efficacy and safety of SNG001 in adults hospitalised due to COVID-19 who required oxygenvianasal prongs or mask.MethodsPatients were randomised double-blind to SNG001 (n=309) or placebo (n=314) once daily for 14 days plus standard of care (SoC). The primary objective was to evaluate recovery after administration of SNG001versusplacebo, in terms of times to hospital discharge and recovery to no limitation of activity. Key secondary end-points were progression to severe disease or death, progression to intubation or death and death.ResultsMedian time to hospital discharge was 7.0 and 8.0 days with SNG001 and placebo, respectively (hazard ratio (HR) 1.06 (95% CI 0.89–1.27); p=0.51); time to recovery was 25.0 days in both groups (HR 1.02 (95% CI 0.81–1.28); p=0.89). There were no significant SNG001–placebo differences for the key secondary end-points, with a 25.7% relative risk reduction in progression to severe disease or death (10.7% and 14.4%, respectively; OR 0.71 (95% CI 0.44–1.15); p=0.161). Serious adverse events were reported by 12.6% and 18.2% patients with SNG001 and placebo, respectively.ConclusionsAlthough the primary objective of the study was not met, SNG001 had a favourable safety profile, and the key secondary end-points analysis suggested that SNG001 may have prevented progression to severe disease.

BACKGROUND: Pulmonary thromboendarterectomy (PTE) is the gold standard treatment for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, the results are poorly quantified outside a few registry reports and several individual centers. METHODS: A systematic review was performed searching five electronic databases assessing the outcomes for adult patients undergoing PTE for CTEPH. All articles that reported mortality data were included. Primary outcome measures were early/inpatient mortality; secondary outcomes were survival, pulmonary haemodynamics, morbidity and functional status following PTE for CTEPH. Results were pooled via a meta-analysis of proportions and meta-regression. RESULTS: A total of 5,717 studies were identified, yielding sixty-one relevant papers. Thirty-day mortality ranged from 0.8% to 24.4%, and on meta-analysis was 8.4% [95% confidence interval (CI): 7.2–9.6%]. Mortality was noted to decrease with increasing center volume of PTE cases (P

BACKGROUND: At present, the optimal management strategy for chronic type B aortic dissection (CTBAD) remains unknown, as equipoise remains regarding medical management versus endovascular treatment versus open surgery. However, the results over recent years of thoracic endovascular aortic repair (TEVAR) in CTBAD appear promising. The aim of this systematic review was to provide a comprehensive analysis of the available data reporting outcomes and survival rates for TEVAR in CTBAD. METHODS: Electronic searches of six databases were performed from inception to April 2021. All studies reporting outcomes, specifically 30-day mortality rates, for endovascular repair of CTBAD were identified. Relevant data were extracted, and a random-effects meta-analysis of proportions or means was performed to aggregate the data. Survival data were pooled using data derived from original Kaplan-Meier curves, which allows reconstruction of individual patient data. RESULTS: Forty-eight studies with 2,641 patients were identified. Early (

Background People with post-COVID conditions can have a wide range of symptoms lasting months and it can affect as many as one in five infected people. Interferon beta (IFN-β) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-β-1a nebuliser solution) aims to restore lung IFN-β levels. SPRINTER (NCT04732949) was a RCT of inhaled interferon beta in hospitalised COVID-19. There was no effect of SNG001 on the primary endpoints of time to discharge or recovery most likely due to improvements in the standard of care. However, there was an encouraging signal for the key secondary endpoint of prevention of progression to severe disease or death (ITT 26% relative risk reduction [RRR]; Odds Ratio [95% CI]: 0.71 [0.44, 1.15]; Per Protocol 36% RRR; OR 0.63 [0.35, 1.13]). Post hoc analyses showed enhanced effects favouring SNG001 in subgroups at higher risk of progression. We report on the impact of SNG001 on long COVID symptoms in SPRINTER. Methods Patients requiring low-flow oxygen were randomized to receive SNG001 (314) or placebo (309) once daily for 14 days, plus standard-of-care. Long COVID symptoms were assessed as a secondary endpoint at follow-up visits via telephone/video call on Day 60 and Day 90. The following patient reported outcome (PRO) measures were also assessed: General Anxiety Disorder 7 Questionnaire (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale and Brief Pain Inventory (Short Form). Results When compared to placebo, SNG001 reduced the relative risk of common symptoms of long COVID (fatigue/malaise [RRR=35.4%]; dyspnoea [RRR=28.3%]; loss of smell and/or taste [RRR=61.4%]). Analysis of the PROs is ongoing. Assessment of COVID symptoms at Day 60 and 90 follow up visits Effect of SNG001 treatment on long COVID symptoms Conclusion Long COVID can leave patients with lingering cognitive, respiratory, and functional symptoms months after a SARS-CoV-2 infection. Given the shift from pandemic to endemic status for COVID-19 and the need for new treatments then these findings, suggesting SNG001 may be impacting common long COVID symptoms, provide additional support for the further investigation of SNG001. Disclosures Phillip D. Monk, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Board Member|Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Victoria J. Tear, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Jody L. Brookes, BSc, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Marcin Mankowski, MD, MFPM (Dis), CytoDyn: Advisor/Consultant|Entasis: Advisor/Consultant|ImmuPharma: Advisor/Consultant|Menarini: Advisor/Consultant|Pfizer: Advisor/Consultant|Synairgen: Advisor/Consultant|Venatorx: Advisor/Consultant Ratko Djukanovic, MD, Synairgen: Advisor/Consultant|Synairgen: Honoraria|Synairgen: Stocks/Bonds Stephen T. Holgate, FMedSci, MD, Synairgen: Board Member|Synairgen: Non executive board director, patent on inhaled interferon beta|Synairgen: Stocks/Bonds chris brightling, FMedSci, Synairgen: Advisor/Consultant|Synairgen: Grant/Research Support Tom Wilkinson, PhD, PhD, AZ: Grant/Research Support|AZ: Honoraria|My mhealth: Board Member|My mhealth: Ownership Interest|My mhealth: Stocks/Bonds|Synairgen: Grant/Research Support|Synairgen: Honoraria.

Aortic valve infective endocarditis is a life-threatening condition. Patients frequently present profoundly unwell and extensive surgery may be required to correct the underlying anatomical deficits and control sepsis. Periannular involvement occurs in more than 10% of patients with aortic valve endocarditis. Complex aortic valve endocarditis has a mortality rate of 10 to 40%. Longstanding surgical dogma suggests homografts represent the optimal replacement option in complex aortic valve endocarditis; however, there is a paucity of evidence and lack of consensus on the optimal replacement choice. A systematic review and meta-analysis was performed utilizing EMBASE, PubMed, and the Cochrane databases to review articles describing homografts versus aortic valve replacement and/or valved conduit graft implantation for complex aortic valve endocarditis. The outcomes of interest were mortality, reinfection, and reoperation. Eleven studies were included in this meta-analysis, contributing 810 episodes of complex aortic valve endocarditis. All included reports were cohort studies. There was no statistically significant difference in overall mortality (risk ratio [RR] 0.99; 95% confidence interval [CI], 0.61–1.59; p = 0.95), reinfection (RR 0.89; 95% CI, 0.45–1.78; p = 0.74), or reoperation (RR 0.91; 95% CI, 0.38–2.14; p = 0.87) between the homograft and valve replacement/valved conduit graft groups. Overall, there was no difference in mortality, reinfection, or reoperation rates between homografts and other valve or valved conduits in management of complex aortic endocarditis. However, there is a paucity of high-quality evidence in the area, and comparison of valve types warrants further investigation.

Understanding spatiotemporally varying animal distributions can inform ecological understanding of species' behavior (e.g., foraging and predator/prey interactions) and support development of management and conservation measures. Data from an array of echolocation‐click detectors (C‐PODs) were analyzed using Bayesian spatiotemporal modeling to investigate spatial and temporal variation in occurrence and foraging activity of harbor porpoises (Phocoena phocoena) and how this variation was influenced by daylight and presence of bottlenose dolphins (Tursiops truncatus). The probability of occurrence of porpoises was highest on an offshore sandbank, where the proportion of detections with foraging clicks was relatively low. The porpoises' overall distribution shifted throughout the summer and autumn, likely influenced by seasonal prey availability. Probability of porpoise occurrence was lowest in areas close to the coast, where dolphin detections were highest and declined prior to dolphin detection, leading potentially to avoidance of spatiotemporal overlap between porpoises and dolphins. Increased understanding of porpoises' seasonal distribution, key foraging areas, and their relationship with competitors can shed light on management options and potential interactions with offshore industries.

BACKGROUND: One of the most frequent complications of coronary artery bypass grafting (CABG) is pleural effusion. Limited previous studies have found post-CABG pleural effusion to be associated with increased length-of-stay and greater morbidity post-CABG. Despite this the associations of this common complication are poorly described. This study sought to identify modifiable risk factors for effusion post-CABG. METHODS: A retrospective cohort study of prospectively collected data assessed patients who underwent CABG over two-years. Data was collected for risk factors and sequelae related to pleural effusion requiring drainage. RESULTS: A total of 409 patients were included. Average age was 64.9±10.2 years, 330 (80.7%) were male. 59 (14.4%) patients underwent drainage of pleural effusion post-CABG. Effusions were drained on average 9.9±8.4 days post-CABG. Earlier removal of drain tubes and removal near time of extubation were associated with development of pleural effusion. Post-CABG pleural effusion was associated with post-operative renal impairment (P

Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory airway disease. The epithelial-derived IL-33 and its receptor ST2 have been implicated in airway inflammation and infection. We aimed to determine whether astegolimab, a selective ST2 IgG2 monoclonal antibody, reduces exacerbations in COPD.COPD-ST2OP was a single-centre, randomised, double-blinded, placebo-controlled phase 2a trial in moderate-to-very severe COPD. Participants were randomly assigned (1:1) with a web-based system to received 490 mg subcutaneous astegolimab or subcutaneous placebo, every 4 weeks for 44 weeks. The primary endpoint was exacerbation rate assessed for 48 weeks assessed with a negative binomial count model in the intention-to-treat population, with prespecified subgroup analysis by baseline blood eosinophil count. The model was the number of exacerbations over the 48-week treatment period, with treatment group as a covariate. Safety was assessed in the whole study population until week 60. Secondary endpoints included Saint George's Respiratory Questionnaire for COPD (SGRQ-C), FEVThe exacerbation rate at 48 weeks in the intention-to-treat analysis was not significantly different between the astegolimab group (2·18 [95% CI 1·59 to 2·78]) and the placebo group (2·81 [2·05 to 3·58]; rate ratio 0·78 [95% CI 0·53 to 1·14]; p=0·19]). In the prespecified analysis stratifying patients by blood eosinophil count, patients with 170 or fewer cells per μL had 0·69 exacerbations (0·39 to 1·21), whereas those with more than 170 cells per μL had 0·83 exacerbations (0·49 to 1·40). For the secondary outcomes, the mean difference between the SGRQ-C in the astegolimab group versus placebo group was -3·3 (95% CI -6·4 to -0·2; p=0·039), and mean difference in FEVIn patients with moderate-to-very severe COPD, astegolimab did not significantly reduce exacerbation rate, but did improve health status compared with placebo.Funded by Genentech and National Institute for Health Research Biomedical Research Centres.

Increasing levels of anthropogenic underwater noise have caused concern over their potential impacts on marine life. Offshore renewable energy developments and seismic exploration can produce impulsive noise which is especially hazardous for marine mammals because it can induce auditory damage at shorter distances and behavioral disturbance at longer distances. However, far-field effects of impulsive noise remain poorly understood, causing a high level of uncertainty when predicting the impacts of offshore energy developments on marine mammal populations. Here we used a 10-year dataset on the occurrence of coastal bottlenose dolphins over the period 2009–2019 to investigate far-field effects of impulsive noise from offshore activities undertaken in three different years. Activities included a 2D seismic survey and the pile installation at two offshore wind farms, 20–75 km from coastal waters known to be frequented by dolphins. We collected passive acoustic data in key coastal areas and used a Before-After Control-Impact design to investigate variation in dolphin detections in areas exposed to different levels of impulsive noise from these offshore activities. We compared dolphin detections at two temporal scales, comparing years and days with and without impulsive noise. Passive acoustic data confirmed that dolphins continued to use the impact area throughout each offshore activity period, but also provided evidence of short-term behavioral responses in this area. Unexpectedly, and only at the smallest temporal scale, a consistent increase in dolphin detections was observed at the impact sites during activities generating impulsive noise. We suggest that this increase in dolphin detections could be explained by changes in vocalization behavior. Marine mammal protection policies focus on the near-field effects of impulsive noise; however, our results emphasize the importance of investigating the far-field effects of anthropogenic disturbances to better understand the impacts of human activities on marine mammal populations.

Funding: Marine Scotland Science and the Marine Alliance for Science and Technology for Scotland (MASTS) pooling initiative, and their support is gratefully acknowledged. MASTS is funded by the Scottish Funding Council (grant reference HR09011) and contributing institutions. 1. The population of bottlenose dolphins in eastern Scotland has undergone significant range expansion since the 1990s, when a Special Area of Conservation was established for the population. 2. Distribution of this population is well described within areas of its range where intensive work has been carried out, such as the inner Moray Firth, St Andrews Bay and the Tay estuary area. However, elsewhere in their range, habitat use is less well understood. 3. In this study, a large‐scale and long‐term passive acoustic array was used to gain a better understanding of bottlenose dolphin habitat use in eastern Scottish waters, complementing and augmenting existing visual surveys. 4. Data from the array were analysed using a three‐stage approach. First, acoustic occupancy results were reported; second, temporal trends were modelled; and third, a spatial–temporal‐habitat model of acoustic occupancy was created. 5. Results from the acoustic occupancy are in agreement with visual studies that found that areas near known foraging locations were consistently occupied. Results from the temporal trend analysis were inconclusive. Habitat modelling showed that, throughout their range, bottlenose dolphins are most likely to be detected closer to shore, and at a constant distance from shore, in deeper water. Postprint

Tobacco burden is significantly greater among those insured by Medicaid, with a smoking prevalence about twice as high as the national average (28% vs. 15%). Over the past decade, smoking prevalence among those insured by Medicaid has remained relatively unchanged while overall smoking prevalence in the United States and among other insurance groups decreased. This indicates need for targeting tobacco control strategies to those insured by Medicaid. In response, the Vermont Tobacco Control Program (VTCP) set out to implement best practice by making its Medicaid cessation benefit more comprehensive and raising awareness and use of the benefit to support members in quitting. The VTCP collaborated with its Medicaid and health department leadership to implement this initiative, learning and adapting processes along the way. The VTCP identified a framework and considerations for programs implementing best practice to expand access and utilization of cessation supports. Elements of success include collaboration, data sharing, and promotion. As a result, the VTCP created an infrastructure that increases access, awareness, and use of cessation supports among Medicaid members and providers. Between 2013 and 2017, the quit ratio among Vermont Medicaid members increased from 8% to 13% and the smoking rate decreased from 36% to 31%.

Growing concern about the impacts of anthropogenic noise on marine life has led to a global increase in the number of acoustic monitoring programmes aiming to quantify underwater soundscapes. However, low-frequency measurements in coastal sites may be affected by flow noise that is not actually present in the environment, but is caused by tidal flow turbulence around the hydrophone. At present, there is no standard way of removing this contaminating noise. This study presents an approach to exclude tidal influences (flow noise and other tidal-related acoustic self-noise) on ambient sound measurements, using data recorded at ten Scottish coastal sites between 2013 and 2017, and with a focus on the 63 and 125 Hz 1/3-octave bands. The annual ambient sound pressure levels (SPL) of the full and “tidal influence excluded” datasets of the three most tidally affected sites were compared against hypothetical noise thresholds. For the 63 Hz 1/3-octave band, results revealed: Site-specific patterns in the amount of data excluded (28.2%–89.2%), decreases in SPL (0.7–8.5 dB), and differences in the percentage of time that noise thresholds were exceeded. The described approach may serve as a standardised way of excluding tidal influence on soundscape descriptors.

The use of rapid deployment sutureless aortic valve replacement (AVR) has become a viable alternative to conventional AVR especially in intermediate and high-risk patients. However, sutureless AVR has been associated with increased rates of permanent pacemaker (PPM) implantation compared with conventionally implanted aortic valve prostheses. The aim of this study was to determine predictive factors for complete heart block requiring insertion of a PPM post-AVR with a Perceval S sutureless valve (LivaNova, London, UK). Such knowledge will help to improve patient counselling, selection and management of patients undergoing sutureless AVR.A retrospective cohort study assessed all patients who underwent insertion of the Perceval sutureless aortic valve prosthesis between July 2015 and September 2019. Medical records were reviewed for demographic, preoperative electrocardiograph (ECG), and operative features related to postoperative PPM implantation and follow-up in the electrophysiology clinic.One hundred and thirty (130) patients without pre-existing PPM underwent sutureless AVR (66.9% male, average age 74.4±6.6 years). Fifty-seven (57) underwent concomitant cardiac surgical procedures. Eight (8) patients underwent redo cardiac surgery. Nineteen (19) of the 130 (14.6%) patients required insertion of a PPM during their postoperative course. Factors associated with PPM insertion were right bundle branch block (overall n=15, PPM vs No PPM: 8/19 vs 7/111 [42.1 % vs. 6.31 %; p0.01]), longer QRS duration 113.32ms±22.24 ms vs 100.52±20.96 ms (p=0.017) and longer PR Interval 185.166±42.38 ms vs 169.23±25.70 ms (p=0.03).Insertion of rapid deployment sutureless aortic valves in the setting of pre-existing right bundle branch block, prolonged QRS complex and longer PR intervals is associated with increased risk of postoperative PPM requirement. These factors should be considered when preoperatively counselling and postoperatively managing patients when balloon expandable sutureless valves are used.

Objective While there are several cognitive screening tests available for the detection of cortical dementias such as Alzheimer's disease (AD), these are rarely designed to be sensitive to vascular cognitive impairment (VCI). The Brief Memory and Executive Test (BMET) is a screening measure designed to be sensitive to the cognitive profile of both VCI and AD. This study investigated the ability of the BMET to detect AD, and to differentiate between VCI and AD. Methods This study included 150 patients, with either SVD, both with (n = 48) and without VCI (n = 51), or AD (N = 51) and 51 healthy controls. Participants were aged between 40 and 90 years of age and completed both the BMET and the MMSE. Results Receiver operator characteristic (ROC) curve analysis showed as before the BMET is a good predictor SVD. Additionally, the BMET was a good predictor of AD (AUC = 0.96) and performed at least as well as the MMSE (AUC = 0.92) when differentiating AD patients from healthy controls. The BMET had a sensitivity of 86% and specificity of 100% for detecting AD patients from control subjects. Using the difference in cognitive profile between the AD and VCI group, we developed an index score which correctly classified 76% of patients as either having VCI or AD. Conclusion The BMET is a brief and sensitive tool for the detection of cognitive impairment due to both SVD and AD and can be used to aid in the differentiation of the 2 diseases.

The siphonous green alga Codium fragile currently has 10 accepted subspecies, among which is the problematic invasive subsp. fragile. The subspecies are defined on the basis of five polymorphic nucleotides in the plastid rps3–rpl16 spacer region, and this subdivision into subspecies has not been investigated in detail with other DNA markers. Here, we compiled a data set of the green algal DNA barcoding marker tufA that includes 110 C. fragile specimens and an additional 80 specimens of eight related Codium species. Our tufA haplotype tree showed two distinct clades within C. fragile, and the three algorithmic species delimitation methods that were applied agreed that these are likely to represent separate species. The first clade consisted of the invasive subspecies fragile, whereas the second contained the remaining subspecies present among our sequences. Using a newly developed morphometric method to capture fine details of utricle morphology, we show that the two molecular clades also have su...

BACKGROUND In Australia, shockwave lithotripsy (SWL) to treat urinary tract stones is routinely performed with general anaesthesia (GA). We have established a SWL service avoiding GA based outside operating theatres and wish to assess the effectiveness of utilizing modern media on patient satisfaction and analgesic requirements during treatment. METHODS A randomized three-arm trial was performed. Patients were allocated to either watching videos or listening to music on a tablet device, or to getting no media distraction. A total of 95 patients were recruited in a 1:1:1 fashion. Analgesic requirements were recorded during the procedure and patients were asked to fill out a questionnaire with a visual analogue scale to assess their overall pain and satisfaction with the procedure. RESULTS Overall pain scores were decreased - the sound media group reported a mean pain score of 3.52 (P = 0.005), the visual group was 3.62 (P = 0.007), compared to 5.45 in the control group. Analgesic requirements were significantly decreased when compared to the control group (P = 0.05). Overall satisfaction with the procedure was improved in the treatment groups, with the sound group having the best result (P = 0.04). CONCLUSION Modern media can be used as a distraction during SWL in a safe and effective way when treating renal tract stones without GA. Analgesic requirements are decreased significantly, therefore decreasing any potential side-effects and complications. Other departments in Australia should consider using this technique.

Despite frequent records from other parts of the North Atlantic, minke whales have never been acoustically recorded in the North Sea. This study investigated the detectability of pulse trains previously associated with this species in other regions, in acoustic data from ten sites along the east coast of Scotland. Since preliminary results confirmed pulse train presence, subsequently, an automated detector was applied to these data to record the seasonal and diel presence of minke whale pulse trains. Minke whales were detected from May to November, with most detections occurring in June, July and October. No acoustic detections were made in December, January or in the month of April, whilst no data were available for February and March. This pattern of acoustic presence supports available visual data and suggested an absence of minke whales from the study area during winter. Minke whale acoustic presence showed a statistically significant diel pattern, with a detection peak during night time. This study established the acoustic detectability of minke whales in the North Sea and highlights the potential of using passive acoustic monitoring to study the seasonal presence and spatial distribution of minke whales in the North Sea and wider Northeast Atlantic.

Underwater noise pollution from shipping is globally pervasive and has a range of adverse impacts on species which depend on sound, including marine mammals, sea turtles, fish, and many invertebrates. International bodies including United Nations agencies, the Arctic Council, and the European Union are beginning to address the issue at the policy level, but better evidence is needed to map levels of underwater noise pollution and the potential benefits of management measures such as ship-quieting regulations. Crucially, corroboration of noise maps with field measurements is presently lacking, which undermines confidence in their application to policymaking. We construct a computational model of underwater noise levels in the Northeast Atlantic using Automatic Identification System (AIS) ship-tracking data, wind speed data, and other environmental parameters, and validate this model against field measurements at 4 sites in the North Sea. Overall, model predictions of the median sound level were within ±3 dB for 93% of the field measurements for one-third octave frequency bands in the range 125 Hz-5 kHz. Areas with median noise levels exceeding 120 dB re 1 μPa and 20 dB above modelled natural background sound were predicted to occur in the Dover Strait, the Norwegian trench, near to several major ports, and around offshore infrastructure sites in the North Sea. To our knowledge, this is the first study to quantitatively validate large-scale modelled noise maps with field measurements at multiple sites. Further validation will increase confidence in deeper waters and during winter months. Our results highlight areas where anthropogenic pressure from shipping noise is greatest and will inform the management of shipping noise in the Northeast Atlantic. The good agreement between measurements and model gives confidence that models of shipping noise can be used to inform future policy and management decisions to address shipping noise pollution.

Background: Extracorporeal shockwave lithotripsy (SWL) is still an important option in the treatment of renal tract stones. SWL is not without its limitations and alternatives should be considered. This study investigates the referral data to a new SWL planning meeting to identify reasons why SWL was not offered.Methods: A review of 12 months of data prospectively collected at a weekly stone meeting was supplemented with a retrospective chart analysis to identify the source of all referrals for SWL. The principal reason for diverting a patient to other stone management was noted.Results: 142 patients (median age 52 years) were referred for SWL over the 12-month period. SWL was not recommended in 40 (28.2%) patients. SWL was most commonly contraindicated due to excessive stone size±position (32.5%), anatomical complexity (25.0%) and radiolucency on x-ray (10.0%). The majority of patients who were diverted away from SWL were referred from an emergency department (32.5%) and the general urology clinics (20.0%).Conclusions: A significant portion of patients referred for SWL prove unsuitable for this method of stone clearance. This highlights an educational gap amongst clinicians regarding the indications and more importantly contraindications for SWL. Only 6.3% of total referrals originated from general practice suggesting a lack of awareness of the process of direct referral for SWL. Improving this with guidelines will relieve demand in outpatient clinics and help streamline patient care.

"Normal" age-related cognitive decline has been associated with cardiovascular risk factors. Framingham Vascular Age is age-normed cardiovascular risk which may help communicate risk to patients and identify those at relatively higher risk. We aim to assess the association between Framingham Vascular Age and cognition. 346 "healthy" participants (57±10 years) without neuropsychiatric disorders or clinical manifestations of cardiovascular disease were studied. Cognition was evaluated using the Brief Memory and Executive Test and Framingham Vascular Age was calculated. The association between Framingham Vascular Age and cognitive performance was determined through General Linear Models to control for covariates. Framingham Vascular age was associated with poorer Memory and Executive Function/Processing Speed indices (p= 0.019 and p

The work was funded under Scottish Government grant MMSS/001/11 and contract CR/2014/04, and supported by National Capability funding from NERC to SMRU (grant no. SMRU1001). Seal at-sea usage maps, location data for individual seals, locations and source levels for vessels, and SPLs from monitoring data used for acoustic validations are available from the Pure repository, https://doi.org/10.17630/89ac9345-240a-41bb-8f53-b3f14bb114c0. 1. Vessels can have acute and chronic impacts on marine species. The rate of increase in commercial shipping is accelerating, and there is a need to quantify and potentially manage the risk of these impacts. 2. Usage maps characterising densities of grey and harbour seals and ships around the British Isles were used to produce risk maps of seal co-occurrence with shipping traffic. Acoustic exposure to individual harbour seals was modelled in a study area using contemporaneous movement data from 28 animals fitted with UHF global positioning satellite telemetry tags and automatic identification system data from all ships during 2014 and 2015. Data from four acoustic recorders were used to validate sound exposure predictions. 3. Across the British Isles, rates of co-occurrence were highest within 50 km of the coast, close to seal haul-outs. Areas identified with high risk of exposure included 11 Special Areas of Conservation (SAC; from a possible 25). Risk to harbour seal populations was highest, affecting half of all SACs associated with the species. 4. Predicted cumulative sound exposure level, cSELs(Mpw), over all seals was 176·8 dB re 1 μPa2 s (95% CI 163·3–190·4), ranging from 170·2 dB re 1μPa2 s (95% CI 168·4–171·9) to 189·3 dB re 1 μPa2 s (95% CI 172·6–206·0) for individuals. This represented an increase in 28·3 dB re 1 μPa2 s over measured ambient noise. For 20 of 28 animals in the study, 95% CI for cSELs(Mpw) had upper bounds above levels known to induce temporary threshold shift. Predictions of broadband received sound pressure levels were underestimated on average by 0·7 dB re 1 μPa (±3·3). 5. Synthesis and applications. We present a framework to allow shipping noise, an important marine anthropogenic stressor, to be explicitly incorporated into spatial planning. Potentially sensitive areas are identified through quantifying risk to marine species of exposure to shipping traffic, and individual noise exposure is predicted with associated uncertainty in an area with varying rates of co-occurrence. The detailed approach taken here facilitates spatial planning with regard to underwater noise within areas protected through the Habitats Directive, and could be used to provide evidence for further designations. This framework may have utility in assessing whether underwater noise levels are at Good Environmental Status under the Marine Strategy Framework Directive. Publisher PDF

L.R. and K.J.P. were supported by Marine Scotland Science and the Marine Alliance for Science and Technology for Scotland (MASTS) pooling initiative and their support is gratefully acknowledged. MASTS is funded by the Scottish Funding Council (grant reference HR09011) and contributing institutions. Passive acoustic monitoring is an efficient way to study acoustically active animals but species identification remains a major challenge. C-PODs are popular logging devices that automatically detect odontocete echolocation clicks. However, the accompanying analysis software does not distinguish between delphinid species. Click train features logged by C-PODs were compared to frequency spectra from adjacently deployed continuous recorders. A generalized additive model was then used to categorize C-POD click trains into three groups: broadband click trains, produced by bottlenose dolphin (Tursiops truncatus) or common dolphin (Delphinus delphis), frequency-banded click trains, produced by Risso's (Grampus griseus) or white beaked dolphins (Lagenorhynchus albirostris), and unknown click trains. Incorrect categorization rates for broadband and frequency banded clicks were 0.02 (SD 0.01), but only 30% of the click trains met the categorization threshold. To increase the proportion of categorized click trains, model predictions were pooled within acoustic encounters and a likelihood ratio threshold was used to categorize encounters. This increased the proportion of the click trains meeting either the broadband or frequency banded categorization threshold to 98%. Predicted species distribution at the 30 study sites matched well to visual sighting records from the region. Postprint

Background and Purpose— A variant in the histone deacetylase 9 ( HDAC9 ) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. Methods— Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. Results— A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P =0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3–0.7; P =0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29–0.77; P =0.003). Conclusions— These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.

Fine-scale information on the occurrence of coastal cetaceans is required to support regulation of offshore energy developments and marine spatial planning. In particular, the EU Habitats Directive requires an understanding of the extent to which animals from Special Areas of Conservation (SAC) use adjacent waters, where survey effort is often sparse. Designing survey regimes that can be used to support these assessments is especially challenging because visual sightings are expected to be rare in peripheral parts of a population's range. Consequently, even intensive visual line-transect surveys can result in few encounters. Static passive acoustic monitoring (PAM) provides new opportunities to extend survey effort by using echolocation click detections to quantify levels of occurrence of coastal dolphins, but this does not provide information on species identity. In NE Scotland, assessments of proposed offshore energy developments required information on spatial patterns of occurrence of bottlenose dolphins in waters in and next to the Moray Firth SAC. Here, we illustrate how this can be achieved by integrating data from broad-scale PAM arrays with presence-only data from visual surveys. Generalized estimating equations were used with PAM data to model the occurrence of dolphins in relation to depth, distance to coast, slope, and sediment, and to predict the spatial variation in the cumulative occurrence of all dolphin species across a 4 × 4 km grid of the study area. Classification tree analysis was then applied to available visual sightings data to estimate the likely species identity of dolphins sighted in each grid cell in relation to local habitat. By multiplying these probabilities, it was possible to provide advice on spatial variation in the probability of encountering bottlenose dolphins from this protected population at a regional scale, complementing data from surveys that estimate average density or overall abundance within a region.

Underwater noise from human activities appears to be rising, with ramifications for acoustically sensitive marine organisms and the functioning of marine ecosystems. Policymakers are beginning to address the risk of ecological impact, but are constrained by a lack of data on current and historic noise levels. Here, we present the first nationally coordinated effort to quantify underwater noise levels, in support of UK policy objectives under the EU Marine Strategy Framework Directive (MSFD). Field measurements were made during 2013–2014 at twelve sites around the UK. Median noise levels ranged from 81.5–95.5 dB re 1 μPa for one-third octave bands from 63–500 Hz. Noise exposure varied considerably, with little anthropogenic influence at the Celtic Sea site, to several North Sea sites with persistent vessel noise. Comparison of acoustic metrics found that the RMS level (conventionally used to represent the mean) was highly skewed by outliers, exceeding the 97th percentile at some frequencies. We conclude that environmental indicators of anthropogenic noise should instead use percentiles, to ensure statistical robustness. Power analysis indicated that at least three decades of continuous monitoring would be required to detect trends of similar magnitude to historic rises in noise levels observed in the Northeast Pacific.

Cerebral small vessel disease (SVD) is associated with deficits in working memory, with a relative sparing of long-term memory; function may be influenced by white matter microstructure. Working and long-term memory were examined in 106 patients with SVD and 35 healthy controls. Microstructure was measured in the uncinate fasciculi and cingula. Working memory was more impaired than long-term memory in SVD, but both abilities were reduced compared to controls. Regression analyses found that having SVD explained the variance in memory functions, with additional variance explained by the cingula (working memory) and uncinate (long-term memory). Performance can be explained in terms of integrity loss in specific white matter tract associated with mnemonic functions., Highlights • Working and long-term memory are both impaired in SVD compared to healthy adults. • SVD explained a significant proportion of the variance in both mnemonic functions. • Variance in working memory was explained by microstructure of the cingula. • Variance in long-term memory was explained by microstructure of the uncinate.

This work was supported by Moray Offshore Renewables Ltd. and Beatrice Offshore Wind Ltd. as part of their consent application. Offshore wind farm developments may impact protected marine mammal populations, requiring appropriate assessment under the EU Habitats Directive. We describe a framework developed to assess population level impacts of disturbance from piling noise on a protected harbour seal population in the vicinity of proposed wind farm developments in NE Scotland. Spatial patterns of seal distribution and received noise levels are integrated with available data on the potential impacts of noise to predict how many individuals are displaced or experience auditory injury. Expert judgement is used to link these impacts to changes in vital rates and applied to population models that compare population changes under baseline and construction scenarios over a 25. year period. We use published data and hypothetical piling scenarios to illustrate how the assessment framework has been used to support environmental assessments, explore the sensitivity of the framework to key assumptions, and discuss its potential application to other populations of marine mammals. Publisher PDF

Summary 1. Understanding which environmental factors drive foraging preferences is critical for the development of effective management measures, but resource use patterns may emerge from processes that occur at different spatial and temporal scales. Direct observations of foraging are also especially challenging in marine predators, but passive acoustic techniques provide opportunities to study the behaviour of echolocating species over a range of scales. 2. We used an extensive passive acoustic data set to investigate the distribution and temporal dynamics of foraging in bottlenose dolphins using the Moray Firth (Scotland, UK). Echolocation buzzes were identified with a mixture model of detected echolocation inter-click intervals and used as a proxy of foraging activity. A robust modelling approach accounting for autocorrelation in the data was then used to evaluate which environmental factors were associated with the observed dynamics at two different spatial and temporal scales. 3. At a broad scale, foraging varied seasonally and was also affected by seabed slope and shelf-sea fronts. At a finer scale, we identified variation in seasonal use and local interactions with tidal processes. Foraging was best predicted at a daily scale, accounting for site specificity in the shape of the estimated relationships. 4. This study demonstrates how passive acoustic data can be used to understand foraging ecology in echolocating species and provides a robust analytical procedure for describing spatiotemporal patterns. Associations between foraging and environmental characteristics varied according to spatial and temporal scale, highlighting the need for a multi-scale approach. Our results indicate that dolphins respond to coarser scale temporal dynamics, but have a detailed understanding of finer-scale spatial distribution of resources.

Objective: To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD). Methods: In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined. Results: Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85. Conclusions: This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions.

Background and Purpose— Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utility in detecting cognitive impairment in sporadic small vessel disease. This study assesses the BMET and the MoCA as clinical tools for detecting mild cognitive deficits in CADASIL. Methods— Sixty-six prospectively recruited patients with CADASIL, and 66 matched controls completed the BMET, with a subset of these also completing the MoCA. Receiver operating characteristic curves were calculated to examine the sensitivity and specificity of clinical cutoffs for the detection of vascular cognitive impairment and reduced activities of daily living. Results— Patients with CADASIL showed more cognitive impairment overall and were poorer on both executive/processing and memory indices of the BMET relative to controls. The BMET showed good accuracy in predicting vascular cognitive impairment (85% sensitivity and 84% specificity) and impaired instrumental activities of daily living (92% sensitivity and 77% specificity). The MoCA also showed good predictive validity for vascular cognitive impairment (80% sensitivity and 78% specificity) and instrumental activities of daily living (75% sensitivity and 76% specificity). The most important background predictor of vascular cognitive impairment was a history of stroke. Conclusions— The results indicate that the BMET and the MoCA are clinically useful and sensitive screening measures for early cognitive impairment in patients with CADASIL.

Objectives: In addition to neuropsychological difficulties, patients with cerebral small vessel disease (SVD) can have reduced activities of daily living and a poorer quality of life compared to healthy adults. The Brief Memory and Executive Test (BMET), is a cognitive screening tool designed to be sensitive to the neuropsychological profile of patients with SVD. While the BMET is sensitive to the cognitive consequences of SVD, it is unclear how well scores on this measure relate to functional outcomes. The aims of this study are to investigate the relationship between scores on the BMET and functional outcomes (activities of daily living and quality of life) in SVD, and to compare this with other commonly used cognitive screening tools. Methods: This study included 184 participants with SVD (mean age=63.2; SD=9.9) and 299 healthy controls (mean age=62.4; SD=13.8) who were tested using the BMET, Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Stroke Specific - Quality of Life Scale (SS-QoL), Geriatric Depression Scale (GDS), and measures of both instrumental activities of daily living (IADL) and basic activities of daily living (BADL). Results: After controlling for covariates the scores on the BMET, but not the MoCA or MMSE, were significantly related to poorer IADL and quality of life in the SVD group. In addition to the BMET scores, symptoms of depression were found to be significant associated with functional outcome. Conclusion: These results support the clinical utility of using of the BMET, in combination with a standardized depression questionnaire, during the early assessment of patients with SVD. (JINS, 2016, 22, 1–9)

The collection of visual and acoustic data was funded by the UK Department of Energy & Climate Change, the Scottish Government, Collaborative Offshore Wind Research into the Environment (COWRIE) and Oil & Gas UK. Digital aerial surveys were funded by Moray Offshore Renewables Ltd and additional funding for analysis of the combined data sets was provided by Marine Scotland. Collaboration between the University of Aberdeen and Marine Scotland was supported by MarCRF. 1. Robust estimates of the density or abundance of cetaceans are required to support a wide range of ecological studies and inform management decisions. Considerable effort has been put into the development of line-transect sampling techniques to obtain estimates of absolute density from aerial- and boat-based visual surveys. Surveys of cetaceans using acoustic loggers or digital cameras provide alternative methods to estimate relative density that have the potential to reduce cost and provide a verifiable record of all detections. However, the ability of these methods to provide reliable estimates of relative density has yet to be established. 2. These methodologies were compared by conducting aerial visual line-transect surveys (n = 10 days) and digital video strip-transect surveys (n = 4 days) in the Moray Firth, Scotland. Simultaneous acoustic data were collected from moored echolocation detectors (C-PODs) at 58 locations across the study site. Density surface modelling (DSM) of visual survey data was used to estimate spatial variation in relative harbour porpoise density on a 4 × 4 km grid. DSM was also performed on the digital survey data, and the resulting model output compared to that from visual survey data. Estimates of relative density from visual surveys around acoustic monitoring sites were compared with several metrics previously used to characterise variation in acoustic detections of echolocation clicks. 3. There was a strong correlation between estimates of relative density from visual surveys and digital video surveys (Spearman's ρ = 0·85). A correction to account for animals missed on the transect line [previously calculated for visual aerial surveys of harbour porpoise in the North Sea was used to convert relative density from the visual surveys to absolute density. This allowed calculation of the first estimate of a proxy for detection probability in digital video surveys, suggesting that 61% (CV = 0·53) of harbour porpoises were detected. There was also a strong correlation between acoustic detections and density with Spearman's ρ = 0·73 for detection positive hours. 4. These results provide confidence in the emerging use of digital video and acoustic surveys for studying the density of small cetaceans and their responses to environmental and anthropogenic change. Publisher PDF

A common cause of neuropsychological impairment in older adults is cerebral small vessel disease (SVD), but little is known as to whether lack of awareness of neuropsychological impairment is a feature of this clinical condition. In this study, we investigated awareness deficits in a well-phenotyped population of patients with SVD (n= 45; 21 with defined concomitant neuropsychological impairment) and made comparisons with 24 Alzheimer's disease (AD) patients and a further 80 control participants. Awareness of performance on a range of neuropsychological measures was examined based on the Brief Memory and Executive Test Battery (BMET) (Brookes, Hannesdottir, Lawrence, Morris, & Markus, 2012), exploring the relationship between awareness and memory and executive function. The results revealed significant awareness deficits in both the SVD and AD groups. When splitting the SVD group into those with or without concomitant neuropsychological impairment, only those with neuropsychological impairment showed reduced awareness. For the SVD group, executive function was significantly correlated with awareness but memory was not. By comparison, memory was significantly correlated with awareness in the AD group, with executive function showing a trend but remaining non-significant. The results show that lack of awareness of deficit is a clinical feature of SVD and indicate that there are distinct neuropsychological associations with awareness deficit for SVD and AD.

Background: cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment (VCI). Despite this, there is a paucity of rapid simple screening tools to identify cognitive impairment in SVD and differentiate it from other common dementia types. Objective: to validate a new screening test for cognitive impairment in SVD, the Brief Memory and Executive Test (BMET) battery, and examine its ability to detect SVD and differentiate it from Alzheimer's disease (AD). Subjects: 45 patients with SVD, 27 patients with AD and 80 normal controls. Methods: the BMET includes brief tests of executive functioning and processing speed, with comparative tests of memory and orientation. Group discrimination was calculated using discriminant function analysis. Results: the BMET took an average of 10 min to administer. It showed high sensitivity (91%) and specificity (85%) in differentiating SVD patients with cognitive impairment from AD patients. As a comparison the mini-mental state examination had lower sensitivity (63%) and specificity (62%). Conclusions: the BMET is a simple and quick to administer clinical tool for the detection of VCI in SVD and its differentiation from AD impairment. Further multicentre studies are required to evaluate and compare it with other existing screening tests.