Heart valve service provision in the United Kingdom and the effect of the COVID 19 pandemic; improved but must do better. A British Heart Valve Society national survey.

BACKGROUND: Outpatient care for patients with heart valve disease (HVD) is best provided by valve clinics delivered by specialists. Modern day practice in the United Kingdom (UK) is currently poorly understood and has not been evaluated for nearly a decade. Furthermore, the COVID 19 pandemic changed the management of many chronic diseases, and how this has impacted patients with heart valve disease is unclear. METHODS: A British Heart Valve Society survey was sent to 161 hospitals throughout the UK. RESULTS: There was a general valve clinic in 46 of the 68 hospitals (68%), in 19 of 23 Heart Centres (83%) and 29 of 45 DGHs (64%). Across all settings, 3824 new patients and 17,980 follow up patients were seen in valve clinics per annum. The mean number of patients per hospital were 197 (median 150, range 48-550) for new patients and 532 (median 400, range 150-2000) for follow up. On the day echocardiography was available in 55% of valve clinics. In patients with severe HVD, serum brain natriuretic peptide (BNP) was measured routinely in 39% of clinics and exercise testing routinely performed in 49% of clinics. A patient helpline was available in 27% of clinics. 78% of centres with a valve clinic had a valve multidisciplinary team meeting (MDT). 45% centres had an MDT co-ordinator and MDT outcomes were recorded on a database in 64%. COVID-19 had a major impact on valve services in 54 (95%) hospitals. CONCLUSIONS: There has been an increase in the number of valve clinics since 2015 from 21 to 68% but the penetration is still well short of the expected 100%, meaning that valve clinics only serve a small proportion of patients requiring surveillance for HVD. COVID-19 had a major impact on the care of patients with HVD in the majority of UK centres surveyed.

Wound healing complications following folded flap palatoplasty in brachycephalic dogs.

OBJECTIVE: To determine the incidence and characteristics of wound healing complications after folded flap palatoplasty (FFP). METHODS: Prospective study of 25 dogs that underwent FFP as a component of corrective multilevel surgery for brachycephalic obstructive airway syndrome. Oropharyngeal re-examination was conducted after a minimum of 28 days post-operatively, unless indicated earlier by the onset of clinical signs. RESULTS: Wound healing complications occurred in nine dogs (36%). Minor and major wound complications were diagnosed at a median of 36 days (1.5-51 days) post-operatively. Eight dogs had major wound complications, four of which showed no associated clinical signs. Two patterns of major wound complications were observed: incisional dehiscence (ID) with caudal retraction of the soft palate mucosa and development of a full-thickness defect (FTD) in the centre of the soft palate. Revision of the soft palate surgery was performed in five dogs, failing again in one dog with ID. Clinical signs resolved in symptomatic dogs after revision surgery to close FTD. CONCLUSION: In this study, wound healing complications were common after FFP and were not associated with significant clinical deterioration. Further research is necessary to determine the value and timing of routine post-operative oropharyngeal examination for assessment of soft palate healing after FFP as well as the indication for and success of approaches to the management of wound healing complications. The two distinct patterns of FFP failure recognised may provide insight into the underlying causes and lead to refinements in folded flap palatoplasty technique.

The Abl-1 Kinase is Dispensable for NK Cell Inhibitory Signalling and is not Involved in Murine NK Cell Education.

Natural killer (NK) cell responsiveness in the mouse is determined in an education process guided by inhibitory Ly49 and NKG2A receptors binding to MHC class I molecules. It has been proposed that inhibitory signalling in human NK cells involves Abl-1 (c-Abl)-mediated phosphorylation of Crk, lowering NK cell function via disruption of a signalling complex including C3G and c-Cbl, suggesting that NK cell education might involve c-Abl. Mice deficient in c-Abl expression specifically in murine NK cells displayed normal inhibitory and activating receptor repertoires. Furthermore, c-Abl-deficient NK cells fluxed Ca2+ normally after triggering of ITAM receptors, killed YAC-1 tumour cells efficiently and showed normal, or even slightly elevated, capacity to produce IFN-γ after activating receptor stimulation. Consistent with these results, c-Abl deficiency in NK cells did not affect NK cell inhibition via the receptors Ly49G2, Ly49A and NKG2A. We conclude that signalling downstream of murine inhibitory receptors does not involve c-Abl and that c-Abl plays no major role in NK cell education in the mouse.

TLR-Stimulated Eosinophils Mediate Recruitment and Activation of NK Cells In Vivo.

Eosinophils like many myeloid innate immune cells can provide cytokines and chemokines for the activation of other immune cells upon TLR stimulation. When TLR-stimulated eosinophils were inoculated i.p. into wild-type mice, and NK cells were rapidly recruited and exhibited antitumour cytotoxicity. However, when mice depleted of CD11c+ cells were used, a marked decrease in the number of recruited NK cells was observed. We postulated that CpG or LPS from the injected eosinophils could be transferred to host cells, which in turn could recruit NK cells. However, by inoculating mice deficient in TLR4 or TLR9 with LPS or CpG-stimulated eosinophils respectively, NK cell recruitment was still observed alongside cytotoxicity and IFNγ production. CpG stimulation of eosinophils produced the pro-inflammatory cytokine IL-12 and the chemokine CXCL10, which are important for NK cell activation and recruitment in vivo. To demonstrate the importance of CXCL10 in NK cell recruitment, we found that CpG-stimulated eosinophils pretreated with the gut microbial metabolite butyrate had reduced expression and production of CXCL10 and IL-12 and concomitantly were poor at recruitment of NK cells and inducing IFNγ in NK cells. Therefore, eosinophils like other innate immune cells of myeloid origin can conceivably stimulate NK cell activity. In addition, products of the gut microbiota can be potential inhibitors of NK cell.

Sex-linked and autosomal microsatellites provide new insights into island populations of the tammar wallaby.

The emerging availability of microsatellite markers from mammalian sex chromosomes provides opportunities to investigate both male- and female-mediated gene flow in wild populations, identifying patterns not apparent from the analysis of autosomal markers alone. Tammar wallabies (Macropus eugenii), once spread over the southern mainland, have been isolated on several islands off the Western Australian and South Australian coastlines for between 10,000 and 13,000 years. Here, we combine analyses of autosomal, Y-linked and X-linked microsatellite loci to investigate genetic variation in populations of this species on two islands (Kangaroo Island, South Australia and Garden Island, Western Australia). All measures of diversity were higher for the larger Kangaroo Island population, in which genetic variation was lowest at Y-linked markers and highest at autosomal markers (θ=3.291, 1.208 and 0.627 for autosomal, X-linked and Y-linked data, respectively). Greater relatedness among females than males provides evidence for male-biased dispersal in this population, while sex-linked markers identified genetic lineages not apparent from autosomal data alone. Overall genetic diversity in the Garden Island population was low, especially on the Y chromosome where most males shared a common haplotype, and we observed high levels of inbreeding and relatedness among individuals. Our findings highlight the utility of this approach for management actions, such as the selection of animals for translocation or captive breeding, and the ecological insights that may be gained by combining analyses of microsatellite markers on sex chromosomes with those derived from autosomes.

The effects of hepatitis C virus core protein on functional responses in the NK cell line YTS.

Hepatitis C virus infection affects more than 170 million people worldwide. More than 80% of the patients are not able to eliminate the virus and progress to a chronic infection that usually culminates in complications such as cirrhosis and/or hepatocellular carcinoma. Although the adaptive immune response has been widely shown to be essential for viral clearance, the role of natural killer (NK) cells is not clearly understood. In this study, the effect of HCV core protein is examined on NK cell function, i.e., cytotoxicity and cytokine secretion. The expression of core protein in the YTS NK cell line led to an increase in the percentage of apoptotic cells soon after transduction. The surviving cells exhibited decreased cytotoxicity associated with decreases in perforin and granzyme B expression. Furthermore, the HCV core protein-transduced YTS NK cells had reduced IFNγ production as well as an altered surface receptor expression pattern. These features may correspond to a state of functional anergy similar to that seen in T cells transduced with HCV core protein. Together, these data suggest that HCV core protein may alter NK cell function.

Fibrotic myopathy of the iliopsoas muscle in a dog.

Fibrotic myopathy of the iliopsoas muscle developed in a dog, following extensive migration of a grass awn within the muscle and adjacent subcutaneous tissue. The dog was initially presented for evaluation of a fluctuant swelling over the right flank region. The clinical and imaging findings were suggestive of iliopsoas fibrotic myopathy and the diagnosis was confirmed by histopathology. This is the third report of iliopsoas fibrotic myopathy in a dog, the first report to describe the postmortem pathologic changes and the first report of iliopsoas fibrotic myopathy subsequent to foreign body migration.

Diagnostic accuracy of acute vestibular syndrome at the bedside in a stroke unit.

Acute vestibular syndrome may be due to vestibular neuritis (VN) or posterior circulation strokes. Bedside ocular motor testing performed by experts is superior to early MRI in excluding strokes. We sought to demonstrate that differentiation of strokes from VN in our stroke unit is reliable. During a prospective study at a tertiary hospital over 1 year, patients with AVS were evaluated in the emergency department (ED) and underwent admission with targeted examination: gait, gaze-holding, horizontal head impulse test (hHIT), testing for skew deviation (SD) and vertical smooth pursuit (vSP). Neuroimaging included CT, transcranial Doppler (TCD) and MRI with MR angiogram (MRA). VN was diagnosed with normal diffusion-weighted images (DWI) and absence of neurological deficits on follow-up. Acute strokes were confirmed with DWI. A total of 24 patients with AVS were enrolled and divided in two groups. In the pure vestibular group (n = 20), all VN (n = 10/10) had positive hHIT and unidirectional nystagmus, but 1 patient had SD and abnormal vertical smooth pursuit (SP). In all the strokes (n = 10/10), one of the following signs suggestive of central lesion was present: negative hHIT, central-type nystagmus, SD or abnormal vSP. Finding one of these was 100% sensitive and 90% specific for stroke. In the cochleovestibular group (n = 4) all had normal DWI, but 3 patients had central ocular motor signs (abnormal vertical SP and SD). Whilst the study is small, classification of AVS in our stroke unit is reliable. The sensitivity and specificity of bedside ocular motor testing are comparable to those previously reported by expert neuro-otologists. Acute cochleovestibular loss and normal DWI may signify a labyrinthine infarct but differentiating between different causes of inner ear dysfunction is not possible with bedside testing.

Multidisciplinary approach to carotid stenting.

BACKGROUND: Stroke neurologists, vascular surgeons, interventional neuroradiologists and interventional cardiologists have embraced carotid angioplasty and stenting (CAS) because of potential advantages over carotid endarterectomy (CEA). At Austin Health, a multidisciplinary neuro-interventional group was formed to standardise indications and facilitate training. The aims of this study were to describe our organisational model and to determine whether 30-day complications and early outcomes were similar to those of major trials. METHODS: A clinical protocol was developed to ensure optimal management. CAS was performed on patients with high medical risk for CEA, with technically difficult anatomy for CEA, or who were randomised to CAS in a trial. RESULTS: From October 2003 to May 2008, 47 patients (34 male, mean age 71.5) underwent CAS of 50 carotid arteries. Forty-three cases had ipsilateral carotid territory symptoms within the previous 12 months. The main indications for CAS were high risk for CEA (n= 17) and randomised to CAS (n= 21). Interventionists were proctored in 27 cases. The procedural success rate was 94% with two cases abandoned because of anatomical problems and one because of on-table angina. Hypotension requiring vasopressor therapy occurred in 12 cases (24%). The duration of follow up was one to 44 months (mean 6.8 months). The 30-day rate of peri-procedural stroke or death was 6% and the one-year rate of peri-procedural stroke or death or subsequent ipsilateral stroke was 10.6%. Restenosis occurred in 13% (all asymptomatic). CONCLUSION: A multidisciplinary approach is a useful strategy for initiating and sustaining a CAS programme.

Thoracoscopic-assisted lung lobectomy in the dog: report of two cases.

The benefits and application of thoracoscopy with selective ventilation, as an adjunct to thoracotomy, in facilitating pleural exploration and lung lobectomy in two dogs are presented. Similar thoracoscopic-assisted procedures are commonly used in human patients because there is better exposure and they are technically less demanding than thoracoscopy alone, while causing less postoperative morbidity than conventional thoracotomy. There are no previous reports of thoracoscopic-assisted surgery in the veterinary literature. In the cases described, thoracoscopic-assisted mini-thoracotomy was an effective, minimally-invasive approach for ipsilateral hemithorax exploration and lung lobectomy.

Nasal vascular hamartoma in a Domestic Shorthair cat.

A nasal mass in a Domestic Shorthair cat was causing facial deformity, sneezing and intermittent epistaxis. Biopsy samples obtained previously had been non-diagnostic. Computed tomography images revealed an irregular, contrast-enhancing mass occupying a large portion of the righthand side of the nasal cavity. Previously described criteria for malignancy were not present. A ventral surgical approach combined with temporary, ipsilateral, common carotid arterial occlusion provided excellent access for debulking the lesion and collecting samples for histopathology. A nasal vascular hamartoma was diagnosed and clinical signs resolved postoperatively. This is the first documentation of this abnormality in the cat. Hamartomatous abnormalities should be included on the list of differential diagnoses for feline nasal mass lesions. The prognosis for hamartomatous lesions postoperatively is good, in keeping with their limited propensity for growth after maturity.

Microbial water pollution: a screening tool for initial catchment-scale assessment and source apportionment.

The European Union Water Framework Directive requires that Management Plans are developed for individual River Basin Districts. From the point of view of faecal indicator organisms (FIOs), there is a critical need for screening tools that can provide a rapid assessment of the likely FIO concentrations and fluxes within catchments under base- and high-flow conditions, and of the balance ('source apportionment') between agriculture- and sewage-derived sources. Accordingly, the present paper reports on: (1) the development of preliminary generic models, using water quality and land cover data from previous UK catchment studies for assessing FIO concentrations, fluxes and source apportionment within catchments during the summer bathing season; (2) the calibration of national land use data, against data previously used in the models; and (3) provisional FIO concentration and source-apportionment assessments for England and Wales. The models clearly highlighted the crucial importance of high-flow conditions for the flux of FIOs within catchments. At high flow, improved grassland (and associated livestock) was the key FIO source; FIO loadings derived from catchments with high proportions of improved grassland were shown to be as high as from urbanized catchments; and in many rural catchments, especially in NW and SW England and Wales, which are important areas of lowland livestock (especially dairy) farming, ≥ 40% of FIOs was assessed to be derived from agricultural sources. In contrast, under base-flow conditions, when there was little or no runoff from agricultural land, urban (i.e. sewerage-related) sources were assessed to dominate, and even in rural areas the majority of FIOs were attributed to urban sources. The results of the study demonstrate the potential of this type of approach, particularly in light of climate change and the likelihood of more high-flow events, in underpinning informed policy development and prioritization of investment.

End-of-life decision-making in individuals with locked-in syndrome in the acute period after brainstem stroke.

Locked-in syndrome (LIS) is commonly associated with a poor prognosis, particularly if the aetiology is stroke. Dealing with individuals with LIS and a poor prognosis raises the issue of introducing end-of-life discussions with the patient and/or family in the acute period of the illness. Existing literature regarding LIS provides little guidance about end-of-life decision-making in the acute management phase. We aim to provide some guidance for clinicians holding end-of-life discussions in the acute management period. We report two cases of relatively young individuals with LIS secondary to brainstem stroke. Both cases had a very poor prognosis and end-of-life discussions were commenced by the treating team in the acute phase. Despite the severity of their conditions, in neither case were end-of-life discussions well tolerated by the family in the weeks following admission. We suggest that LIS patients and their families, who have chosen to persist with full medical management after diagnosis of LIS, should be provided with sufficient time to adjust to the catastrophic changes that have occurred before further end-of-life discussions are pursued. Education and support are likely to be highly beneficial in the acute period post stroke as they allow the patient and family to develop a realistic understanding of the likely outcomes of their decisions.

Critical role of Qa1b in the protection of mature dendritic cells from NK cell-mediated killing.

Molecular interactions in natural killer (NK) cell-mediated killing of dendritic cells (DC) have under recent years come under scrutiny. Upon stimulation with IFN-gamma or lipopolysaccharide, DC become relatively resistant to NK cell-mediated lysis. In the present study, we investigated the role of Qa1(b) on DC and its receptor NKG2A on NK cells in the protection of mature DC from NK cells. We demonstrate that while both NKG2A+ and NKG2A- NK cells can efficiently lyse unstimulated DC, NKG2A+ NK cells but not NKG2A- NK cells are largely impaired in their ability to lyse mature DC. Similarly, mature DC from mice expressing H-2D(b), whose leader peptide sequence binds and stabilizes Qa1(b), were resistant to NK cell-mediated killing, suggesting that stable Qa1(b) expression contributes to the protection of mature DC. This finding was further validated by the demonstration that addition of the Qdm leader peptide could protect TAP1-/- DC from NK cell-mediated lysis both in vitro and in vivo. The present data suggest that stable expression of Qa1 on the surface of mature DC contributes to the protection of DC from NK cell-mediated lysis.

Timing of clinically significant microembolism after carotid endarterectomy.

PURPOSE: Post-operatively detected transcranial Doppler (TCD) embolic signals (ES) are associated with an increased risk of carotid endarterectomy (CEA) stroke/TIA. The aims here were to quantify this risk and determine the most efficient monitoring protocol. METHODS: Sequential patients undergoing CEA (enrolled in a randomised, blinded, placebo-controlled trial of peri-operative dextran therapy) had 30-min TCD monitoring in the first post-operative hour. 30-min monitoring was also performed 2-3, 4-6 and 24-36 h post-operatively. First post-operative hour ES counts were correlated with peri-operative ipsilateral carotid stroke/TIA to determine the size of a clinically significant ES load and the magnitude of the associated risk. The exact Cochran-Armitage test for trend in proportions was used to determine when a clinically significant ES load was first detected. RESULTS: 141 patients (mean age 69.3 years, 72% male) were monitored during the first post-operative hour. An ES count >10 per recording was identified as the best overall predictor of ipsilateral stroke/TIA (sensitivity 72%, specificity 89%). 3/119 (2.5%) patients with 0-10 ES had ipsilateral carotid events compared to 8/22 (36.4%) patients with 11-115 ES (OR = 22.1, 95% CI 4.5, 138.4, p < 0.0001). 13/18 (72%) of subjects with >10 ES were identified in the first post-operative hour with no significant increase in the number of new cases over the subsequent 24-36 post-operative h (p = 0.354). CONCLUSION: Patients with clinically significant post-operative microembolism had an approximately 15 times higher risk of ipsilateral stroke/TIA and most were identified during a 30-min study in the first post-operative hour.

Mycophenolate mofetil substitution for cyclosporine-dependent myasthenia gravis and nephrotoxicity.

Severe autoimmune myasthenia gravis is difficult to manage and may require immunosuppression with cyclosporine. However, cyclosporine dependency is associated with the risk of nephrotoxicity. Mycophenolate mofetil is a non-nephrotoxic alternative which should be considered to rescue cyclosporine-dependent, severe myasthenia gravis sufferers with renal impairment from progression to end-stage renal failure. However, the evidence is limited and studies have not assessed the outcome of a direct substitution in these cyclosporine-dependent patients. We study three such patients who successfully converted to mycophenolate mofetil, and briefly examine the evidence behind this option. We believe that total cyclosporine withdrawal is feasible, but strongly recommend overlapping mycophenolate mofetil treatment with cyclosporine.

Clinical application of transcranial Doppler monitoring for embolic signals.

A major advantage of transcranial ultrasound is its suitability for continuous monitoring. Microembolic signals (MES) are brief, high-intensity transients that occur when particulate microemboli or gaseous microbubbles pass through the ultrasound beam. These MES have been detected in several clinical scenarios, but rarely in age-matched controls. The detection of MES provides important pathophysiological information in a variety of disorders, but their clinical importance and possible therapeutic implications are still under debate. The present article summarizes the significance of MES in different clinical settings and outlines some of the problems to be resolved so that transcranial ultrasound can be applied in clinical practice.

Symptomatic and asymptomatic carotid stenosis: just when we thought we had all the answers.

The management of symptomatic and asymptomatic carotid stenosis has been a hotly debated topic for decades. The publication of four randomized controlled trials of carotid endarterectomy has clarified many of the issues. Patients with symptomatic carotid stenosis >70% benefit most with an absolute risk reduction of 17% over 2 years with numbers needed to treat of 3-6, whereas in patients with asymptomatic carotid stenosis >60%, the absolute risk reduction is 1% per annum (numbers needed to treat = 14-17). There is doubt about the benefit in women >70 years of age with asymptomatic stenosis. Carotid angioplasty and stenting is in its infancy and may one day supplant carotid endarterectomy as the treatment of choice; however, currently indications for this procedure include participation in randomized controlled trials, surgically inaccessible stenosis, in patients with combined symptomatic carotid and symptomatic coronary artery disease or in patients with severe co-morbidities that preclude formal carotid endarterectomy.

Carotid endarterectomy for asymptomatic carotid stenosis.

BACKGROUND: Carotid endarterectomy (CEA) is of proven benefit in recently-symptomatic patients with severe carotid stenosis. Its role in asymptomatic stenosis is still debated. The Asymptomatic Carotid Surgery Trial (ACST) more than doubled the number of patients randomised to CEA trials. This revised review incorporates the recently published ACST results. OBJECTIVES: Our objective was to determine the effects of CEA for patients with asymptomatic carotid stenosis. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (searched May 2004), MEDLINE (1966 to May 2004), EMBASE (1980 to June 2004), Current Contents (1995 to January 1997), and reference lists of relevant articles. We contacted researchers in the field to identify additional published and unpublished studies. SELECTION CRITERIA: All completed randomised trials comparing CEA to medical treatment in patients with asymptomatic carotid stenosis. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed trial quality. Attempts were made to contact investigators to obtain missing information. MAIN RESULTS: Three trials with a total of 5223 patients were included. In these trials, the overall net excess of operation-related perioperative stroke or death was 2.9%. For the primary outcome of perioperative stroke or death or any subsequent stroke, patients undergoing CEA fared better than those treated medically (relative risk (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.83). Similarly, for the outcome of perioperative stroke or death or subsequent ipsilateral stroke, there was benefit for the surgical group (RR 0.71, 95% CI 0.55 to 0.90). For the outcome of any stroke or death, there was a non-significant trend towards fewer events in the surgical group (RR 0.92, 95% CI 0.83 to 1.02). Subgroup analyses were performed for the outcome of perioperative stroke or death or subsequent carotid stroke. CEA appeared more beneficial in men than in women and more beneficial in younger patients than in older patients although the data for age effect were inconclusive. There was no statistically significant difference between the treatment effect estimates in patients with different grades of stenosis but the data were insufficient. AUTHORS' CONCLUSIONS: Despite about a 3% perioperative stroke or death rate, CEA for asymptomatic carotid stenosis reduces the risk of ipsilateral stroke, and any stroke, by approximately 30% over three years. However, the absolute risk reduction is small (approximately 1% per annum over the first few years of follow up in the two largest and most recent trials) but it could be higher with longer follow up.