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Data sharing: The PHOSP-COVID study protocol, consent form, definition, and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online. UK Biobank information can be released once necessary approvals have been obtained. Other data (eg, the R code and protocol) will be made available on reasonable request to the corresponding author. Copyright © 2023 The Author(s). Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council. UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

Data sharing statement This is an Open Access article under the CC BY 4.0 license The ISARIC4C protocol, data sharing and publication policy are available at https://isaric4c.net. ISARIC4C's Independent Data and Material Access Committee welcomes applications for access to data and materials (https://isaric4c.net). The PHOSP-COVID protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online: https://phosp.org/resource/. Access to these materials can be granted by contacting phosp@leicester.ac.uk and Phospcontracts@leicester.ac.uk. All data used in this study is available within ODAP and accessible under reasonable request. Data access criteria and information about how to request access is available online: https://phosp.org/resource/. If criteria are met and a request is made, access can be gained by signing the eDRIS user agreement. Supplementary data are available online at https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00584-9/fulltext#supplementaryMaterial . Copyright © 2022 The Author(s). Background: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. Funding: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript. This work is supported by the following grants: The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute for Health and Care Research (grant references: MR/V027859/1 and COV0319). ISARIC4C is supported by grants from the National Institute for Health and Care Research (award CO-CIN-01) and the Medical Research Council (grant MC_PC_19059) Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research (grant reference: C18616/A25153). Other grants which have supported this work include: the UK Coronavirus Immunology Consortium [funder reference:1257927], the Imperial Biomedical Research Centre (NIHR Imperial BRC, grant IS-BRC-1215-20013), the Health Protection Research Unit (HPRU) in Respiratory Infections at Imperial College London and NIHR HPRU in Emerging and Zoonotic Infections at University of Liverpool, both in partnership with Public Health England, [NIHR award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], Health Data Research UK (HDR UK) [grant code: 2021.0155], Medical Research Council [grant code: MC_UU_12014/12], and NIHR Clinical Research Network for providing infrastructure support for this research. FL is supported by an MRC clinical training fellowship [award MR/W000970/1]. LPH is supported by Oxford NIHR Biomedical Research Centre. AART is supported by a BHF Intermediate Clinical Fellowship (FS/18/13/33281). SLRJ receives support from UKRI, GCRF, Rosetrees Trust, BHIVA, EDCTP, Globvac. JDC has grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis and Insmed. RAE holds a NIHR Clinician Scientist Fellowship (CS-2016-16-020). AH is currently supported by UK Research and Innovation. NIHR and NIHR Manchester BRC. BR receives support from BHF Oxford Centre of Research Excellence, NIHR Oxford BRC and MRC. SJD is funded by an NIHR Global Research Professorship [NIHR300791]. DW is supported by an NIHR Advanced Fellowship. AH has received support from MRC and the Coronavirus Immunology Consortium (MR/V028448/1). LVW has received support from UKRI, GSK/Asthma + Lung UK and NIHR for this study. MGS has received support from NIHR UK, MRC UK and Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool. JKB is supported by the Wellcome Trust (223164/Z/21/Z) and UKRI (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1, and MC_PC_20029). PJMO is supported by a NIHR Senior Investigator Award [award 201385]. LT is supported by the Wellcome Trust [clinical career development fellowship grant number 205228/Z/16/Z], the Centre of Excellence in Infectious Diseases Research (CEIDR) and the Alder Hey Charity.

Data sharing statement: PHOSP-COVID: The protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, requests for data access and other relevant study materials are available online at https://www.phosp.org. COVIDENCE UK: De-identified participant data will be made available upon reasonable request to the corresponding author. Supplementary data is available online at: https://www.sciencedirect.com/science/article/pii/S2666776223000546?via%3Dihub#appsec1 . Copyright © 2023 The Author(s). Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders. PHOSP-COVID: This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the study at all of the 65 NHS trusts/Health boards and 25 research institutions across the UK, as well as all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland, and Public Health England, and support from the ISARIC Coronavirus Clinical Characterisation Consortium. We thank Kate Holmes at the NIHR Office for Clinical Research Infrastructure (NOCRI) for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well NOCRI for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer's Research UK, Asthma + Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations, and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. COVIDENCE UK: We thank all participants of COVIDENCE UK, and the following organisations who supported study recruitment: Asthma UK/British Lung Foundation, the British Heart Foundation, the British Obesity Society, Cancer Research UK, Diabetes UK, Future Publishing, Kidney Care UK, Kidney Wales, Mumsnet, the National Kidney Federation, the National Rheumatoid Arthritis Society, the North West London Health Research Register (DISCOVER), Primary Immunodeficiency UK, the Race Equality Foundation, SWM Health, the Terence Higgins Trust, and Vasculitis UK.

Scrub typhus and Queensland tick typhus (QTT)-rickettsial infections endemic to tropical Australia-can cause life-threatening disease. This retrospective study examined the clinical course of all patients with laboratory-confirmed scrub typhus or QTT admitted to the intensive care unit (ICU) of a tertiary referral hospital in tropical Australia between 1997 and 2019. Of the 22 patients, 13 had scrub typhus and nine had QTT. The patients' median (interquartile range [IQR]) age was 50 (38-67) years; 14/22 (64%) had no comorbidity. Patients presented a median (IQR) of seven (5-10) days after symptom onset. Median (IQR) Acute Physiology and Chronic Health Evaluation II scores were 13 (9-17) for scrub typhus and 13 (10-15) for QTT cases (P = 0.61). Following hospital admission, the median (IQR) time to ICU admission was five (2-19) hours. The median (IQR, range) length of ICU stay was 4.4 (2.9-15.9, 0.8-33.8) days. Multi-organ support was required in 11/22 (50%), 5/22 (22%) required only vasopressor support, 2/22 (9%) required only invasive ventilation, and 4/22 (18%) were admitted for monitoring. Patients were ventilated using protective lung strategies, and fluid management was conservative. Standard vasopressors were used, indications for renal replacement therapy were conventional, and blood product usage was restrictive; 9/22 (41%) received corticosteroids. One patient with QTT died, and two (8%) additional patients with QTT developed purpura fulminans requiring digital amputation. Death or permanent disability occurred in 3/9 (33%) QTT and 0/13 scrub typhus cases (P = 0.055). Queensland tick typhus and scrub typhus can cause multi-organ failure requiring ICU care in otherwise well individuals. Queensland tick typhus appears to have a more severe clinical phenotype than previously believed.

IntroductionAboriginal and Torres Strait Islander Australians living in remote locations suffer disproportionately from chronic hepatitis B (CHB). Defining the temporospatial epidemiology of the disease-and assessing the ability of local clinicians to deliver optimal care-is crucial to improving patient outcomes in these settings.MethodsThe demographic, laboratory and radiology findings in all patients diagnosed with CHB after 1990, and presently residing in remote Far North Queensland (FNQ), tropical Australia, were correlated with their management and clinical course.ResultsOf the 602 patients, 514 (85%) identified as Aboriginal and Torres Strait Islander Australians, 417 (69%) of whom had Torres Strait Islander heritage. Among the 514 Aboriginal and Torres Strait Islander Australians, there were only 61 (12%) born after universal postnatal vaccination was introduced in 1985. Community CHB prevalence varied significantly across the region from 7/1707 (0.4%) in western Cape York to 55/806 (6.8%) in the Eastern Torres Strait Islands. Although 240/602 (40%) are engaged in care, with 65 (27%) meeting criteria for antiviral therapy, only 43 (66%) were receiving this treatment. Among 537 with complete data, 32 (6%) were cirrhotic, of whom 15 (47%) were engaged in care and 10 (33%) were receiving antiviral therapy. Only 64/251 (26%) in whom national guidelines would recommend hepatocellular carcinoma (HCC) surveillance are receiving screening, however, only 20 patients have been diagnosed with HCC since 1999.ConclusionVaccination has had a dramatic effect on CHB prevalence in FNQ in only a generation. However, although engagement in care is the highest in Australia, this is not translating into initiation of antiviral therapy in all those that should be receiving it, increasing their risk of developing cirrhosis and HCC. New strategies are necessary to improve the care of Indigenous Australians living with CHB to reduce the morbidity and mortality of this preventable disease.

Objective Otitis media with effusion (OME) is a major cause of childhood hearing impairment (HI) in the developing world, but its prevalence has never been quantified in Nepal. This study therefore set out to determine the proportion of cases of OME complicated by HI and to identify associated factors. Methods This was a cross-sectional prevalence survey carried out in rural, urban and Tibetan schools in and around Pokhara, Nepal. HI was the primary outcome, and was defined as a middle-frequency pure tone average >25 dB on audiological testing. The study population was defined as children aged four years and older, attending primary school and with a diagnosis of OME. Results One hundred and eleven schoolchildren with a combined total of 172 ears affected by OME underwent audiometric assessment. HI was most prevalent in the rural Nepali population; 27% (95%CIs 18–38%) had HI, with a mean hearing loss of 22 dB (15–25 dB). In the Tibetan population, 16% (8–29%) had HI, with a mean loss of 17 dB (12–22 dB). The urban Nepali population had the least HI; 4% (1–13%) were affected, with a mean loss of 16 dB (15–19 dB). The difference in prevalence between the urban and rural Nepali populations was statistically significant (p > 0.05). Logistic regression analysis did not identify any associated factors. Conclusions HI is a common complication of OME in Nepal. There is hitherto-unreported variation between populations in the number of cases of OME complicated by HI. This study identified higher rates of morbidity amongst rural populations but was unable to identify associated factors.

In January 1990, a virus was isolated from ovarian fluid of steelhead Oncorhynchus mykiss from the Tokal Creek Hatchery in the southern portion of Puget Sound, Washington. A unique cytopathic effect, characterized by well-defined plaques consisting of aggregates of multinucleate and vacuolated cells, was observed in five of seven cell lines inoculated with the virus. The virus grew best at 10 and 14°C, although it also replicated well at 6°C. It was resistant to incubation for 2 h at pH 3, 5, 7, and 9, but not at pH 2. The virus contained a single-stranded RNA genome, and particles were often found as a lattice-like matrix of unenveloped, round-toicosahedral-shaped nucleocapsids that were 25–30 nm in diameter and had a 16-nm-diameter core. Based on this information, we have classified the virus as the: Tokal Creek steelhead virus and believe it to be the first reported picorna-like virus (possibly of the genus Enterovirus) of salmonids.

Editor—Albright hereditary osteodystrophy (AHO) is an autosomal dominant disorder characterised by short stature, a round face with a low, flat nasal bridge, brachymetaphalangism, particularly of the fourth and fifth digits, obesity, subcutaneous calcification, and variable degrees of mental retardation. Patients may show end organ resistance to parathyroid hormone (PTH), known as pseudohypoparathyroidism type Ia (PHPIa). Patients with PHPIa may have hypocalcaemia, hyperphosphataemia, and raised PTH levels and show an absent or blunted cAMP response to exogenous PTH.1Resistance to other hormones such as thyroid stimulating hormone (TSH) and luteinising hormone have also been reported. Other patients with AHO have a normal biochemical profile with a normal cAMP response to a PTH infusion, known as pseudopseudohypoparathyroidism (PPHP). PHPIa and PPHP both result from inactivating mutations of the GNAS1 gene on chromosome 20. The PHPIa and PPHP phenotypes have been observed to segregate within the same family and thus represent variable expressivity of the same mutation. There is an apparent parent of origin effect: PHPIa usually results from maternal inheritance of a GNAS1 mutation while paternal transmissions give rise to offspring with PPHP.2 GNAS1 has 13 exons and mutations associated with AHO occur throughout the gene.3-8 The new mutation rate at GNAS1 is unknown, but de novo occurrence of mutations has been proven in a number of families5-7 (our own unpublished observations). We now describe a family comprising two affected sibs whose presentation was complicated by gastrointestinal symptoms not previously associated with Albright hereditary osteodystrophy. Neither parent showed any features of AHO. Patient 1 was born at term to non-consanguineous Cypriot parents. She developed persistent diarrhoea on the second day of life, resulting in episodes of dehydration, metabolic acidosis, and failure to thrive. At 4 months of age, her barium meal was normal …

Direct sequencing of the emerin gene in 22 families with Emery-Dreifuss muscular dystrophy (EMD) revealed mutations in 21 (95%), confirming that emerin mutations can be identified in the majority of families with X-linked EMD. Most emerin mutations result in absence of the protein. In this study three mutations (a missense mutation Pro183Thr and two in-frame deletions removing residues 95-99 and 236-241, respectively) were unusual in being associated with expression of mutant protein. The phenotype in these families was compared in detail with the clinical features in cases with typical null mutations. For the in-frame deletions there were no significant differences. In the family with the missense mutation the phenotype was milder. Age at onset was later for first symptoms and for development of ankle contractures and muscle weakness. These findings have diagnostic implications as well as pointing to functionally important regions of the emerin protein.

Current predominant theories for the pathogenesis of intracranial saccular aneurysms have a congenital or a degenerative basis. Complementing these theories, the predilection of intracranial aneurysms for the human species has been attributed to a variety of human neurovascular morphological traits, which however, on closer scrutiny are not unique to the human species. Human evolution to a bipedal primate has required significant adaptation in several organ systems, with significant consequent biological costs. We hypothesize that susceptibility to intracranial aneurysms is part of this latter cost of adopting an upright stance with respect to the neurovascular systems. Evidence supporting the above hypothesis, is presented. [Neurol Res 1996; 18: 33–38]

Urease secretion by Helicobacter species may be a mechanism for survival against acid in the stomach. However, since the bacteria reside predominantly underneath the overlying mucus layer on the mucosa, the major exposure to acid is likely to be during transit across the gastric lumen upon initial colonisation. It is probable, therefore, that urease inhibition during this period may interfere with gastric mucosal colonisation. We have studied the role of urease in the colonisation of naive, infant ferrets with H. mustelae (Hm) using four different approaches: (a) challenge with a urease negative mutant, (b) challenge with Hm grown in the presence of a urease inhibitor, (c) dosing of animals with a urease inhibitor prior to challenge and (d) dosing of animals with inhibitor after suppression of Hm with a bismuth salt.

When I recently flicked through my old hospital notebooks, I discovered the scribblings of a lunatic: 69 y/o Cauc female c/o 2/52 Hx SOBOE + productive cough. ↑To, ohaemoptysis, ochest pain, o↓kg, onight sweats, oPND, oorthopneoa. PMHx STEMI – revascularised PC, ↑BP. SHx Ex-smoker; 30 pack yrs. DHx verapamil, aspirin, simvastatin, NKDA It will not come as news that medicine is awash with technical terms. The Oxford Handbook contains a list of just under 300 acronyms; not an exhaustive list, but the bare minimum needed to survive as a junior doctor. What alarms me is how easily and eagerly students become inured to this alien …

Two new cell lines developed from chinook salmon with plasmacytoid leukaemia have been found to be producing a virus. The virus has been identified as a retrovirus based on: type of c.p.e. induced in culture; morphology and density of the particle; presence of Mn(2+)-dependent, poly(rA)-directed reverse transcriptase activity which was associated with a density of 1.16 to 1.18 g/ml in sucrose; electrophoretic pattern of the polypeptides from purified virions; elevated [3H]UTP labelling of RNA in the cell cultures occurring at a density of 1.16 to 1.18 g/ml in sucrose. This report describes the first isolation of a retrovirus from a salmonid cell line.

We compared myosin samples isolated from iliac-femoral arteries of control and renal (stenosis) hypertensive dogs to determine the effects of increased blood pressure on the characteristics of the myosin. The ratio of 204-kd (SM-1) to 200-kd (SM-2) myosin heavy chains was approximately 1:0.75 for myosin from the iliac-femoral artery of normotensive dogs. This was not altered significantly in response to hypertension. Both SM-1 and SM-2 myosin heavy chains cross-reacted with antibody against smooth muscle myosin on Western blot analysis. In addition to these heavy chains, purified myosin from both groups showed a very faint protein band slightly below the 200-kd myosin heavy chain on electrophoresis on a highly porous sodium dodecyl sulfate-polyacrylamide gel. This protein band cross-reacted with antibody against nonmuscle myosin but not with smooth muscle myosin antibody. The 20- and 17-kd light chains of myosin isolated from normotensive and hypertensive dogs gave similar results on isoelectric focusing. Peptide maps of tryptic digests of heavy chains revealed both quantitative and qualitative differences. The Ca(2+)-activated myosin ATPase activity measured in high salt (0.5 mol/L KCl) was similar for myosin from both groups, whereas the potassium (ethylenedinitrilo)tetraacetic acid-stimulated ATPase of myosin from hypertensive animals was higher than that from normotensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)

The objective of this study was to determine whether unregulated self-medication in an ambulatory surgery population was a significant problem in terms of the incidence and nature of drugs detected. We asked 67 consecutive patients who presented for elective ambulatory surgery at a university medical center to volunteer for serum and urine testing with the assurance of confidentiality. All patients denied nonprescription drug use. Initial testing was for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine (PCP), tetrahydrocannabinol (THC) and alcohol. Of the 64 patients who agreed to be tested, 16 patients tested positive for at least one of the above substances; 4 patients demonstrated residua of 2 or 3 substances. No distinctive characteristic of those with evidence of drug use could be identified. We believe that the 25% of patients who tested positive in this group is a conservative estimate of possible unrecognized drug use. We have demonstrated a significant incidence of substance abuse in the ambulatory surgery environment. These findings have serious safety implications, and a higher awareness of possible nonprescription drug use in this environment is needed in medical and support personnel.

Greater choice is always better for patients, right? The regulatory body for doctors in the United Kingdom, the General Medical Council, certainly thinks so. At the heart of their guidance for doctors is the principle that patients have the right to self determination. The doctor’s role is to inform, counsel, and empower but not to choose on the patient’s behalf. UK policymakers also aspire to promote patient choice. Reforms of the National Health Service aim to transform it from state monopoly to a diverse healthcare marketplace, where patient-consumers can shop around for the doctors, hospitals, and treatments they want. The result is that, increasingly, doctors and healthcare systems are divesting themselves of responsibility for decision making. By …

The open-loop characteristics of the carotid sinus baroreceptor reflex control of pulsatile arterial pressure-flow relations were studied in halothane-anesthetized dogs. Pressures and flows were measured in the ascending aorta, the celiac, mesenteric, renal, and iliac arteries and were used to compute values of regional vascular impedance and hydraulic power. The carotid sinuses were bilaterally isolated and perfused under conditions of controlled mean pressure with a constant sinusoidal component. Measurements were made with the vagi intact and after bilateral vagotomy. Maximum values of open-loop gain averaged -0.78 +/- 0.08 before and -1.42 +/- 0.20 after vagotomy. Vagotomy produced significant increases in the variation of all hemodynamic variables with carotid sinus pressure that were nonuniformly affected in the various regional vascular beds. Aortic and regional vascular impedance showed significant variations with carotid sinus pressure that were augmented by vagotomy. Aortic impedance exhibited a minimum at the normal set point. These results indicate that a) carotid sinus baroreflexes are well preserved with halothane anesthesia, b) thoracic baroreceptor-mediated reflexes exert significant hemodynamic effects on systemic hemodynamics around normal set point values of arterial pressure, c) systemic baroreceptors exert control over large as well as small vessel properties, and d) the baroreceptor-mediated reflexes produce significant influences on hydraulic power and its components.

In the absence of peripheral chemoreceptors, the effects of graded hypoxemia on the carotid sinus control of central and regional hemodynamics were studied in anesthetized mongrel dogs. Baroreceptor stimulation was effected by carotid sinus isolation and perfusion under controlled pressure. Blood flows were measured in the aorta and the celiac, mesenteric, left renal, and right iliac arteries. Carotid sinus reflex set-point pressures were well maintained until hypoxemia was severe. Carotid sinus reflex set-point gain was maximal during mild hypoxemia. Reflex operating point regional flows were unaffected by hypoxemia. A factorial analysis of overall reflex increases in mean aortic pressure, flow, and power during reduced baroreceptor stimulation showed potentiation by increasing hypoxemia. Corresponding effects of baroreceptor stimulation and hypoxemia on aortic resistance and heart rate were additive. Celiac, renal, and iliac blood flows increased during both hypoxemia and reduced baroreceptor stimulation. Only in the celiac bed were blood flow changes independent of concomitant changes in cardiac output. Thus, at maximum sympathetic stimulation (low carotid sinus pressure) during hypoxemia, the cardiovascular system maintained both central and regional blood flows at high systemic blood pressures independent of the peripheral chemoreceptors.

The regional differentiation of carotid sinus control of arterial pressure-flow relationships was studied in chloralose-anesthetized dogs. Simulatneous pressure-flow measurements were made in the ascending aorta, the celiac artery, the cranial mesenteric artery, the renal artery, and the femoral artery. The carotid sinuses were bilaterally isolated and perfused with pulsatile pressure. The open-loop reflex gain was not symmetrical about and was maximum at pressures below the closed loop operating point pressure. Changes in both peripheral resistance and cardiac output contributed significantly to the open-loop gain with the former predominating. Aortic impedance for frequencies above 3 Hz was at a minimum at the closed-loop operating point and increased for both higher and lower values of carotid sinus pressure. For the frequency range from 3 to 9 Hz, regional impedance in all of the beds varied inversely with carotid sinus pressure. The sensitivity of the various beds to changes in carotid sinus pressure around the operating point increased in the order celiac less than mesenteric less than renal less than femoral. Following vagotomy, operating point values of regional resistance and sensitivity were significantly increased. This fact suggests that the aortic arch receptors exert a significant influence on regional vascular impedance at operating point pressures. The fraction of cardiac output in the celiac, mesenteric, and renal beds was nearly independent of carotid sinus pressure before and after vagotomy, but that in the femoral bed increased with carotid sinus pressure. These results demonstrate the nonuniform nature of carotid sinus and aortic arch baroreceptor control of regional blood flow.

Summary During animal evolution the circulatory system has shown a progressive modification in structure, function and short-term control. Short-term circulatory control has evolved from the limitation of a rising blood pressure via a reflex bradycardia to bidirectional control of blood pressure by appropriate reflex changes in heart rate, vascular resistance and impedance. Relevant experimental data ranges from extensive in mammals to nugatory in invertebrates. Baroreceptor research in intervening animal groups is varied, being particularly sparse in birds. This research is reviewed. There are few interspecies comparisons of baroreceptor physiology. Available data is complicated by variation in the techniques employed for assessing baroreceptor function. In non-mammalian research the correlation of heart rate changes to pharmacologically induced changes in blood pressure predominate. In mammalian baroreceptor research methods based upon the ability of discrete baroreceptor sites to effect changes in the peripheral vasculature are more prevalent. All methods are susceptible to modification by other experimental variables, particularly the anaesthetic state of the animal. Available evidence shows a consistent response of a decreasing heart rate to baroreceptor loading throughout the vertebrates, with a progressive increase in the ability of the baroreceptors to change peripheral vascular resistance. These findings are consistent with the known, progressive trend from cholinergic to adrenergic control of the vascular system during evolution. Known baroreceptor sites appear to be located so as to protect the end-organ or-organs primarily at risk from inappropriate blood pressure changes; namely the gill vasculature in the fish, pulmonary circulation in the Amphibia and Reptilia, and the brain and heart in higher animal groups. It is postulated that the carotid sinus baroreceptors have developed in the Mammalia as a second functional baroreceptor site to provide extra protection against hypoperfusion of vital organs, particularly the heart and brain. In humans the dynamic aspects of cardiovascular carotid sinus control, particularly of skeletal muscle flow and integration with cardiopulmonary baroreceptors, may represent a specific response to the adoption of an upright stance. Extremes of environmental stress encountered in contemporary life may exceed the limitation of baroreceptor function in humans, as, for example, during gravitational loading particularly following periods of weightlessness and modification by endurance training.

The effects of bilateral thoracotomy upon the operating characteristics of the carotid sinus reflex were examined in 11 vagotomized dogs. Pressure-flow relationships in the aorta, celiac, mesenteric, renal, and femoral arteries were studied as a function of pressure in the isolated carotid sinuses. These relationships were analyzed to give the carotid sinus reflex operating point values and sensitivities of pressure, flow, impedance, and power for each regional vascular bed. Following thoracotomy there was a significant fall in the closed-loop operating point pressure (CLOP) (p

The open-loop carotid sinus baroreflex control of arterial pressure-flow relations were compared in mongrel dogs and racing greyhounds (GH) anesthetized with alpha-chloralose. The carotid sinuses were bilaterally isolated and perfused under controlled pressure. Pulsatile pressure and flow were simultaneously measured in the ascending aorta, the celiac, superior mesenteric, left renal, and right iliac arteries. Open-loop set point values of mean arterial pressure were higher in GH before and after vagotomy. Reflex gains were similar before vagotomy but lower in GH after vagotomy. The overall range of control of arterial pressure was the same before vagotomy but smaller in GH after vagotomy. The variation of mean arterial pressure with mean carotid sinus pressure in GH was shifted toward higher pressure levels similar to resetting. The overall effects of vagotomy on carotid sinus baroreceptor reflex responses were smaller in GH. Operating point values of regional resistance were generally smaller in GH. Operating point sensitivities of regional resistance were the same except for the iliac bed, which was more sensitive in GH. These results document significant regional differences in the baroreceptor control of regional hemodynamics between mongrels and greyhounds that could contribute to altered responses especially to "hypertensive" perturbations.

The open-loop carotid sinus reflex control of systemic haemodynamics was studied in an acute dog preparation with isolated perfused carotid sinuses at three end-tidal halothane levels of 0.66 +/- 0.02% (HI); 0.88 +/- 0.02% (H2); and 1.17 +/- 0.02% (H3), in order to investigate the dose dependency of the carotid sinus reflex operating characteristics for halothane. Corresponding to the above halothane levels were reflex operating point pressures (set point pressures) of 104.9 +/- 2.9, 103.3 +/- 4.1 and 76.0 +/- 3.8 mmHg, respectively. Carotid sinus reflex gain decreased significantly with progressively increasing halothane levels (1.4. +/- 0.18; 0.84 +/- 0.12; 0.48 +/- 0.09), as did the range of reflex changes in systemic arterial pressure for equal overall changes in carotid sinus pressure (87.1 +/- 7.9; 64.1 +/- 7.4; 33.6 +/- 5.1 mmHg; P less than 0.01). For halothane levels below approximately 0.9%, this depression was not dependent upon changes in mean systemic arterial pressure. The relationship between reflex gain and halothane concentration could be described by a first-order exponential which suggested virtual ablation of the carotid sinus reflex control of mean arterial pressure at an end-tidal halothane concentration exceeding about 1.6%.

Arterial baroreceptor function was assessed in trained, chronically instrumented dogs by measuring the systemic haemodynamic responses to brachiocephalic artery occlusion (BCO). BCO was carried out in awake dogs and repeated at end-tidal halothane levels of 0.75 +/- 0.01% (H1), 0.94 +/- 0.02% (H2) and 1.13 +/- 0.02% (H3). Before BCO, at H1 only the increased heart rate and decreased stroke volume were significantly different from awake controls (P less than 0.01). Mean atrial pressure and cardiac output at H2 and H3 were significantly lower than in the awake controls (P less than 0.05). The pressor response to BCO fell progressively with increasing halothane levels, the decrease being significant at the H2 and H3 levels (P less than 0.001). There was a good linear correlation between the pressor response to BCO as a percentage of the response in awake animals, and the end-tidal halothane levels (r = -0.816, P less than 0.001). This indicated a sensitive dose-dependent modification of the haemodynamic response to BCO by halothane. However, halothane levels existed between about 0.7-0.8%, at which levels the average pressor response to BCO was not significantly different from awake values.

Changes in the structure of the gonad, skin, interrenal, liver, kidney, stomach, gill and pituitary gland, as well as blood cortisol and haematocrit values were investigated in adult pink salmon during their migration through the Fraser and Thompson Rivers to the spawning grounds. At the commencement of their freshwater migration the gonads of both males and females were in an advanced state of development, the pituitary contained a large complement of well-granulated gonadotrops, and hypertrophy was evident in the interrenal tissue and in the epidermis of the skin. At this time, no change from the normal sexually immature salmon was evident in the structure of the gill, liver or stomach. Sclerosis of the glomeruli was noted in the kidney. The plasma cortisol level was consistent with concentrations in unstressed salmon. Migration of the fish through a turbulent section of the Fraser River evoked a marked increase in both blood cortisol concentration and in interrenal nuclear diameters. On arrival at the spawning grounds, 10–15 days after entry into fresh water, a general but not marked deterioration of the tissues was evident. The results are discussed in relation to the spawning migration of other species of Pacific salmon.

The authors show that a steady state two-dimensional finite difference model has been developed to describe the roll casting process, incorporating a variable heat transfer coefficient through the ...

The application of the various aspects of systems theory has increased steadily over the last 10 years and has proved useful in such diverse fields as surgical services (Spratt et al. 1974), public health (Haas 1974), education (Harrington 1966), nephrology (Bigelow et al. 1973), medical information (Davis 1973), behavior (Shooster 1974), internal medicine (Guyton et al. 1972), metaphysics (Gayer 1972), and sociology (Attinger & Millendorfer 1968). More recently, rystems analysis has been applied to anaesthetic systems in the engineering literature (Smith & Schwede: 1972) and has begun to appear in the anaesthesia literature (Brows 1973). The anaesthetist in the operating room is part of a complex system. In its simplest form the latter involves the anaesthetist, the anaesthesia delivery system, the patient and the surgeon. This discussion is intended to introduce the anaesthetist to some of the terminology and techniques common to the systems analysis approach. Examples have been drawn from biological aystems in man which have proved useful to describe in feedback control terms. Where possible, the examples used are those most relevant to anaesthesiology.

Central and regional cardiovascular responses to step changes in carotid sinus pressure were evaluated in dogs before and after increasing carotid sinus reflex set point pressure, by approximately 30%, via an intravenous infusion of angiotensin II at three anesthetic levels (isoflurane). With respect to overall cardiovascular behavior, angiotensin inhibited both the interaction of carotid sinus baroreceptor stimulation and anesthesia upon mean arterial pressure and total resistance, together with the inverse relationship between iliac resistance and carotid sinus pressure. At the set point pressure of the carotid sinus reflex, angiotensin increased set point levels of aortic, celiac, mesenteric and renal resistances, reduced corresponding set point flows, and increased the range of arterial pressure control together with the maximum capacity of the carotid sinus reflex to increase mean aortic pressure and power for all anesthetic levels. Angiotensin increased the set point sensitivity of mean arterial pressure (gain), heart rate, iliac blood flow, aortic, celiac, mesenteric and renal resistance, to changes in carotid sinus pressure for intermediate anesthetic levels. While reflex gain was unchanged by angiotensin, peak gain was significantly increased at lower anesthetic levels. The maximum capacity of the carotid sinus reflex to decrease mean aortic pressure and power was reduced. Thus, intravenous angiotensin infusion producing moderate increases in mean arterial pressure facilitates the ability of the carotid sinus baroreceptors to control mean arterial pressure and heart rate, and results in an increased overall vasoconstrictor capacity. Corresponding increased ability to control regional blood flow was confined to the iliac bed.

The characteristics of the carotid sinus baroreceptor (CSB) reflex control of arterial pressure-flow relations were studied in young (18 mo) and old (10.5 yr) racing greyhounds anesthetized with chloralose. Pressure and flow were simultaneously measured in the ascending aorta, the celiac, superior mesenteric, renal, and iliac arteries under steady-state conditions of pulsatile perfusion of the isolated carotid sinuses before and after bilateral cervical vagotomy. Operating-point (OP) values of mean pressure were not significantly different between the young or old greyhounds, but OP values of cardiac output were lower and of peripheral resistance were higher in the older animals. OP values of regional resistances were higher in the older animals, but only those of the celiac and mesenteric beds were significantly different. Values of OP sensitivity of central hemodynamic variables were not decreased in the older animals. OP values of renal and iliac resistance sensitivity tended to be lower in the older animals. The overall range of control of the various hemodynamic variables by the CSB was lower in the older group only in the case of iliac resistance. The characteristics of the CSB were not uniformly depressed in the older animals but were relatively well maintained compared with those of the younger group.

Studies were conducted in halothane-anesthetized dogs to evaluate the interaction of mean and pulsatile components of carotid sinus perfusion pressure on the control of regional pressure-flow relations. Pressure and flow were measured simultaneously in the ascending aorta, celiac, mesenteric, renal, and iliac arteries. The carotid sinuses were bilaterally isolated and perfused under controlled conditions. Mean (CSP) and pulsatile components (CSPP) of carotid sinus pressure were varied systemically. Values of mean aortic pressure (AP) at the operating point (AP = CSP) decreased with increasing CSPP (127 +/- 5 at CSPP = 0 to 103 +/- 5 at CSPP = 60). Reflex gains at the operating point also decreased with increasing CSPP (-1.35 +/- 0.16 for CSPP = 0 to -0.92 +/- 0.18 for CSPP = 60). Changes in cardiac output and peripheral resistance nonuniformly contributed to these responses, with the former predominating at low CSPP and the later at high CSPP. Operating-point values of regional resistance generally decreased with increasing CSPP but to different degrees in the various beds. With increasing CSPP amplitude, regional resistance sensitivity at the operating point (i.e., slope) increased in the celiac and decreased in the mesenteric, renal, and iliac vascular beds. Separate changes in mean and pulsatile components of carotid sinus pressure about the normal operating point produce quantitatively similar changes in systemic hemodynamic variables.