Risk factors for persistent abnormality on chest radiographs at 12-weeks post hospitalisation with PCR confirmed COVID-19.

BACKGROUND: The long-term consequences of COVID-19 remain unclear. There is concern a proportion of patients will progress to develop pulmonary fibrosis. We aimed to assess the temporal change in CXR infiltrates in a cohort of patients following hospitalisation for COVID-19. METHODS: We conducted a single-centre prospective cohort study of patients admitted to University Hospital Southampton with confirmed SARS-CoV2 infection between 20th March and 3rd June 2020. Patients were approached for standard-of-care follow-up 12-weeks after hospitalisation. Inpatient and follow-up CXRs were scored by the assessing clinician for extent of pulmonary infiltrates; 0-4 per lung (Nil = 0, < 25% = 1, 25-50% = 2, 51-75% = 3, > 75% = 4). RESULTS: 101 patients with paired CXRs were included. Demographics: 53% male with a median (IQR) age 53.0 (45-63) years and length of stay 9 (5-17.5) days. The median CXR follow-up interval was 82 (77-86) days with median baseline and follow-up CXR scores of 4.0 (3-5) and 0.0 (0-1) respectively. 32% of patients had persistent CXR abnormality at 12-weeks. In multivariate analysis length of stay (LOS), smoking-status and obesity were identified as independent risk factors for persistent CXR abnormality. Serum LDH was significantly higher at baseline and at follow-up in patients with CXR abnormalities compared to those with resolution. A 5-point composite risk score (1-point each; LOS ≥ 15 days, Level 2/3 admission, LDH > 750 U/L, obesity and smoking-status) strongly predicted risk of persistent radiograph abnormality (0.81). CONCLUSION: Persistent CXR abnormality 12-weeks post COVID-19 was common in this cohort. LOS, obesity, increased serum LDH, and smoking-status were risk factors for radiograph abnormality. These findings require further prospective validation.

Muscle architecture and morphology as determinants of explosive strength.

PURPOSE: Neural drive and contractile properties are well-defined physiological determinants of explosive strength, the influence of muscle architecture and related morphology on explosive strength is poorly understood. The aim of this study was to examine the relationships between Quadriceps muscle architecture (pennation angle [ΘP] and fascicle length [FL]) and size (e.g., volume; QVOL), as well as patellar tendon moment arm (PTMA) with voluntary and evoked explosive knee extension torque in 53 recreationally active young men. METHOD: Following familiarisation, explosive voluntary torque at 50 ms intervals from torque onset (T50, T100, T150), evoked octet at 50 ms (8 pulses at 300-Hz; evoked T50), as well as maximum voluntary torque, were assessed on two occasions with isometric dynamometry. B-mode ultrasound was used to assess ΘP and FL at ten sites throughout the quadriceps (2-3 sites) per constituent muscle. Muscle size (QVOL) and PTMA were quantified using 1.5 T MRI. RESULT: There were no relationships with absolute early phase explosive voluntary torque (≤ 50 ms), but θP (weak), QVOL (moderate to strong) and PTMA (weak) were related to late phase explosive voluntary torque (≥ 100 ms). Regression analysis revealed only QVOL was an independent variable contributing to the variance in T100 (34%) and T150 (54%). Evoked T50 was also related to QVOL and θP. When explosive strength was expressed relative to MVT there were no relationships observed. CONCLUSION: It is likely that the weak associations of θP and PTMA with late phase explosive voluntary torque was via their association with MVT/QVOL rather than as a direct determinant.

Inflammatory phenotyping predicts clinical outcome in COVID-19.

BACKGROUND: The COVID-19 pandemic has led to more than 760,000 deaths worldwide (correct as of 16th August 2020). Studies suggest a hyperinflammatory response is a major cause of disease severity and death. Identitfying COVID-19 patients with hyperinflammation may identify subgroups who could benefit from targeted immunomodulatory treatments. Analysis of cytokine levels at the point of diagnosis of SARS-CoV-2 infection can identify patients at risk of deterioration. METHODS: We used a multiplex cytokine assay to measure serum IL-6, IL-8, TNF, IL-1ß, GM-CSF, IL-10, IL-33 and IFN-γ in 100 hospitalised patients with confirmed COVID-19 at admission to University Hospital Southampton (UK). Demographic, clinical and outcome data were collected for analysis. RESULTS: Age > 70 years was the strongest predictor of death (OR 28, 95% CI 5.94, 139.45). IL-6, IL-8, TNF, IL-1ß and IL-33 were significantly associated with adverse outcome. Clinical parameters were predictive of poor outcome (AUROC 0.71), addition of a combined cytokine panel significantly improved the predictability (AUROC 0.85). In those ≤70 years, IL-33 and TNF were predictive of poor outcome (AUROC 0.83 and 0.84), addition of a combined cytokine panel demonstrated greater predictability of poor outcome than clinical parameters alone (AUROC 0.92 vs 0.77). CONCLUSIONS: A combined cytokine panel improves the accuracy of the predictive value for adverse outcome beyond standard clinical data alone. Identification of specific cytokines may help to stratify patients towards trials of specific immunomodulatory treatments to improve outcomes in COVID-19.

Acquired immune responses to the seasonal trivalent influenza vaccination in COPD.

Epidemiological data suggest that influenza vaccination protects against all-cause mortality in chronic obstructive pulmonary disease (COPD) patients. However, recent work has suggested there is a defect in the ability of some COPD patients to mount an adequate humoral response to influenza vaccination. The aim of our study was to investigate humoral and cell-mediated vaccine responses to the seasonal trivalent influenza vaccination (TIV) in COPD subjects and healthy controls. Forty-seven subjects were enrolled into the study; 23 COPD patients, 13 age-matched healthy controls (HC ≥ 50) and 11 young healthy control subjects (YC ≤ 40). Serum and peripheral blood mononuclear cells (PBMC) were isolated pre-TIV vaccination and at days 7 and 28 and 6 months post-vaccine for haemagglutinin inhibition (HAI) titre, antigen-specific T cell and antibody-secreting cell analysis. The kinetics of the vaccine response were similar between YC, HC and COPD patients and there was no significant difference in antibody titres between these groups at 28 days post-vaccine. As we observed no disease-dependent differences in either humoral or cellular responses, we investigated if there was any association of these measures with age. H1N1 (r = -0·4253, P = 0·0036) and influenza B (r = -0·344, P = 0·0192) antibody titre at 28 days negatively correlated with age, as did H1N1-specific CD4+ T helper cells (r = -0·4276, P = 0·0034). These results suggest that age is the primary determinant of response to trivalent vaccine and that COPD is not a driver of deficient responses per se. These data support the continued use of the yearly trivalent vaccine as an adjunct to COPD disease management.

Reliability of quadriceps surface electromyography measurements is improved by two vs. single site recordings.

PURPOSE: The reliability of surface electromyography (sEMG) is typically modest even with rigorous methods, and therefore further improvements in sEMG reliability are desirable. This study compared the between-session reliability (both within participant absolute reliability and between-participant relative reliability) of sEMG amplitude from single vs. average of two distinct recording sites, for individual muscle (IM) and whole quadriceps (WQ) measures during voluntary and evoked contractions. METHODS: Healthy males (n = 20) performed unilateral isometric knee extension contractions: voluntary maximum and submaximum (60%), as well as evoked twitch contractions on two separate days. sEMG was recorded from two distinct sites on each superficial quadriceps muscle. RESULTS: Averaging two recording sites vs. using single site measures improved reliability for IM and WQ measurements during voluntary (16-26% reduction in within-participant coefficient of variation, CVW) and evoked contractions (40-56% reduction in CVW). CONCLUSIONS: For sEMG measurements from large muscles, averaging the recording of two distinct sites is recommended as it improves within-participant reliability. This improved sensitivity has application to clinical and research measurement of sEMG amplitude.

Respect for the dead and the ethics of anatomy.

Dead bodies are not persons but nor are they just things. What, ethically speaking, do the living owe the dead when it comes to using their bodies in anatomy? The article begins with the general question of respect for the dead. It distinguishes between why we should respect the dead, how we should respect them, and the weight to be given to respect. It sets out an account of the reason to respect the dead based on their interests. The article then turns to how the dead should be respected and the importance of doing so. Specifically, it considers three ethical issues in anatomy: the role of the family, the use of unclaimed bodies, and the public display of bodies donated for that purpose. This article claims that what it is to respect the dead is substantially determined by their wishes. Nonetheless the article argues that respect is consistent with allowing the family to veto anatomical use even when the deceased has consented because respect for the dead does not require following all their possible wishes. Respect is also consistent with using unclaimed bodies to which no one--deceased or family--has consented because the interests of the dead do not directly require consent and the interests of the family are unlikely to be relevant. Finally, the article does not see anything disrespectful in the public display of the bodies of those who have consented.

Contribution of FcRn binding to intestinal uptake of IgG in suckling rat pups and human FcRn-transgenic mice.

Immunoglobulin G (IgG) is transcytosed across intestinal epithelial cells of suckling mammals by the neonatal Fc receptor (FcRn); however, the contribution of FcRn vs. FcRn-independent uptake to serum IgG levels had not been determined in either rat pups or human (h)FcRn-expressing mice (Tg276 and Tg32). In isoflurane-anesthetized rodents, serum levels were determined after regional intestinal delivery of human monoclonal antibodies (hIgG) with either wild-type (WT) Fc sequences or variants engineered for different FcRn binding affinities. Detection of full-length hIgG was by immunoassay; intestinal hFcRn and hIgG localization was by immunocytochemistry. High (µg/ml) serum levels of hIgG were detected after proximal intestinal delivery (0.1-10 mg/kg) in 2-wk-old rats. Human FcRn was visualized in epithelial cells of Tg276 mice, but low serum hIgG levels (<10 ng/ml) were obtained. In rat pups, intraintestinal hIgG1 WT administration resulted in dose-related and saturable uptake, whereas uptake of a low FcRn-binding affinity variant was nonsaturable. There were no differences in hIgG levels from systemic and hepatic portal vein serum samples, and intense hIgG immunostaining was noted in villi enterocytes and within lymphatic lacteal-like vessels. This study demonstrated that FcRn-mediated uptake in rat pups accounted for ~80% of serum hIgG levels and that IgG enters the circulation via the lymph and not the hepatic portal vein. The remaining uptake though the immature intestine is nonreceptor mediated. Intestinal epithelial cell hFcRn expression occurred in Tg276 mice, but receptor-mediated transport of IgG was not observed. The suckling rat pup intestine is a mechanistic model of FcRn-IgG-mediated transcytosis.

Comparison of MRI and DXA to measure muscle size and age-related atrophy in thigh muscles.

OBJECTIVES: Magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA) were used to examine the thigh lean mass in young and old men and women. METHODS: A whole-body DXA scan was used to estimate thigh lean mass in young (20 men; 22.4±3.1y; 18 women; 22.1±2.0y) and older adults (25 men; 72.3±4.9y; 28 women; 72.0±4.5y). Thigh lean mass determined with a thigh scan on the DXA or full thigh MRI scans were compared. RESULTS: Although the thigh lean mass quantified by DXA and MRI in young and older participants were correlated (R(2)=0.88; p<0.001) the magnitude of the differences in thigh lean mass between young and old was smaller with DXA than MRI (old vs. young men 79.5±13.1% and 73.4±11.2%; old vs. young women 88.6±11.8% and 79.4±12.3%, respectively). Detailed analysis of MRI revealed 30% smaller quadriceps muscles in the older than young individuals, while the other thigh muscles were only 18% smaller. CONCLUSIONS: DXA underestimates the age-related loss of thigh muscle mass in comparison to MRI. The quadriceps muscles were more susceptible to age-related atrophy compared with other thigh muscles.

Can digital health apps provide patients with support to promote structured diabetes education and ongoing self-management? A real-world evaluation of myDiabetes usage.

Objective: Structured diabetes education has evidenced benefits yet reported uptake rates for those referred to traditional in-person programmes within 12 months of diagnosis were suboptimal. Digital health interventions provide a potential solution to improve diabetes education delivery at population scale, overcoming barriers identified with traditional approaches. myDiabetes is a cloud-based interactive digital health self-management app. This evaluation analysed usage data for people with type 2 diabetes focusing on digital structured diabetes education. Methods: Descriptive quantitative analyses were conducted on existing anonymised user data over 12 months (November 2019-2020) to evaluate whether digital health can provide additional support to deliver diabetes education. Data was divided into two equal 6-month periods. As this overlapped the onset of COVID-19, analyses of its effect on usage were included as a secondary outcome. All data was reported via myDiabetes. Users were prescribed myDiabetes by National Health Service healthcare primary care teams. Those who registered for app use within the study period (n = 2783) were assessed for eligibility (n = 2512) and included if activated. Results: Within the study period, n = 1245/2512 (49.6%) registered users activated myDiabetes. No statistically significant differences were observed between gender (p = 0.721), or age (p = 0.072) for those who activated (59.2 years, SD 12.93) and those who did not activate myDiabetes (57.6 years, SD 13.77). Activated users (n = 1119/1245 (89.8%)) viewed 11,572 education videos. No statistically significant differences were observed in education video views across age groups (p = 0.384), gender (p = 0.400), diabetes treatment type (p = 0.839) or smoking status (p = 0.655). Comparison of usage pre-COVID-19 and post-COVID-19 showed statistically significant increases in app activity (p ≤0.001). Conclusion: Digital health is rapidly evolving in its role of supporting patients to self-manage. Since COVID-19 the benefits of digital technology have become increasingly recognised. There is potential for increasing diabetes education rates by offering patients a digital option in combination with traditional service delivery which should be substantiated through future research.

Consent and the use of the bodies of the dead.

Gametes, tissue, and organs can be taken from the dying or dead for reproduction, transplantation, and research. Whole bodies as well as parts can be used for teaching anatomy. While these uses are diverse, they have an ethical consideration in common: the claims of the people whose bodies are used. Is some use permissible only when people have consented to the use, actually wanted the use, would have wanted the use, not opposed the use, or what? The aim of this article is to make progress in answering these questions. Initially I assume knowledge of people's desires in order to test whether consent is directly required by their rights without worrying about mistaken uses against their wishes. I claim consent is not directly required by people's rights. If we know people wanted or would want a use, their rights permit the use, but if we know they wanted or would want not to be used, their rights do not permit the use. The knowledge assumption is then dropped and the question becomes how to decide what to do when the wishes of rightholders are not known. I suggest working out what to do when wishes are known and then adjusting, on the basis of whatever evidence there is, for probability and strength of desire. There are other considerations too, for instance about default rules. The key general comment here is that, in setting rules, the costs to rightholders in not getting what they want needs to be taken into account. The final section tries to show that, in setting these rules, mistaken uses are not to be taken as worse than mistaken failure to use.

Unravelling the mechanisms driving multimorbidity in COPD to develop holistic approaches to patient-centred care.

COPD is a major cause of morbidity and mortality worldwide. Multimorbidity is common in COPD patients and a key modifiable factor, which requires timely identification and targeted holistic management strategies to improve outcomes and reduce the burden of disease.We discuss the use of integrative approaches, such as cluster analysis and network-based theory, to understand the common and novel pathobiological mechanisms underlying COPD and comorbid disease, which are likely to be key to informing new management strategies.Furthermore, we discuss the current understanding of mechanistic drivers to multimorbidity in COPD, including hypotheses such as multimorbidity as a result of shared common exposure to noxious stimuli (e.g. tobacco smoke), or as a consequence of loss of function following the development of pulmonary disease. In addition, we explore the links to pulmonary disease processes such as systemic overspill of pulmonary inflammation, immune cell priming within the inflamed COPD lung and targeted messengers such as extracellular vesicles as a result of local damage as a cause for multimorbidity in COPD.Finally, we focus on current and new management strategies which may target these underlying mechanisms, with the aim of holistic, patient-centred treatment rather than single disease management.

Tendinous tissue properties after short- and long-term functional overload: Differences between controls, 12 weeks and 4 years of resistance training.

AIM: The potential for tendinous tissues to adapt to functional overload, especially after several years of exposure to heavy-resistance training, is largely unexplored. This study compared the morphological and mechanical characteristics of the patellar tendon and knee extensor tendon-aponeurosis complex between young men exposed to long-term (4 years; n = 16), short-term (12 weeks; n = 15) and no (untrained controls; n = 39) functional overload in the form of heavy-resistance training. METHODS: Patellar tendon cross-sectional area, vastus lateralis aponeurosis area and quadriceps femoris volume, plus patellar tendon stiffness and Young's modulus, and tendon-aponeurosis complex stiffness, were quantified with MRI, dynamometry and ultrasonography. RESULTS: As expected, long-term trained had greater muscle strength and volume (+58% and +56% vs untrained, both P < .001), as well as a greater aponeurosis area (+17% vs untrained, P < .01), but tendon cross-sectional area (mean and regional) was not different between groups. Only long-term trained had reduced patellar tendon elongation/strain over the whole force/stress range, whilst both short-term and long-term overload groups had similarly greater stiffness/Young's modulus at high force/stress (short-term +25/22%, and long-term +17/23% vs untrained; all P < .05). Tendon-aponeurosis complex stiffness was not different between groups (ANOVA, P = .149). CONCLUSION: Despite large differences in muscle strength and size, years of resistance training did not induce tendon hypertrophy. Both short-term and long-term overload demonstrated similar increases in high-force mechanical and material stiffness, but reduced elongation/strain over the whole force/stress range occurred only after years of overload, indicating a force/strain specific time-course to these adaptations.

Contagious Disease and Self-Defence.

This paper gives a self-defence account of the scope and limits of the justified use of compulsion to control contagious disease. It applies an individualistic model of self-defence for state action and uses it to illuminate the constraints on public health compulsion of proportionality and using the least restrictive alternative. It next shows how a self-defence account should not be rejected on the basis of past abuses. The paper then considers two possible limits to a self-defence justification: compulsion of the non-culpable and over-inclusive compulsion. The paper claims that objections to compelling the non-culpable do not greatly restrict the scope of the self-defence justification. The over-included are, however, innocent bystanders, and methods such as compulsory quarantine, vaccination, and screening are not justified in self-defence.

Should Children Be Given Priority in Kidney Allocation?

Kidneys for transplantation are scarce, and many countries give priority to children in allocating them. This paper explains and criticizes the paediatric priority. We set out the relevant ethical principles of allocation, such as utility and severity, and the relevant facts to do with such matters as sensitization and child development. We argue that the facts and principles do not support and sometimes conflict with the priority given to children. We next consider various views on how age or the status of children should affect allocation. Again, these views do not support priority to children in its current form. Since distinctions based on age ought to be positively justified, the failure of all these attempts at justification implies that the priority to children is ethically mistaken. Finally, the paper points to evidence that the paediatric priority reduces the overall supply of kidneys, at least in the United States. Paediatric priority is a real-world policy that seems discriminatory, in some places probably reduces the supply of organs, has no robust official defence, and is unsupported by mainstream ethical principles. Consequently, it should be ended.

Managing complex respiratory patients in the community: an evaluation of a pilot integrated respiratory care service.

INTRODUCTION: In the UK, there is significant variation in respiratory care and outcomes. An integrated approach to the management of high-risk respiratory patients, incorporating specialist and primary care teams' expertise, is the basis for new integrated respiratory services designed to reduce this variation; however, this model needs evaluating. METHODS: To evaluate an integrated service managing high-risk respiratory patients, electronic searches for patients with asthma and chronic obstructive pulmonary disease at risk of poor outcomes were performed in two general practitioner (GP) practices in a local service-development initiative. Patients were reviewed at joint clinics by primary and secondary care professionals. GPs also nominated patients for inclusion. Reviews were delivered to best standards of care including assessments of diagnosis, control, spirometry, self-management, education, medication, inhaler technique and smoking cessation support. Follow-up of routine clinical data collected at 9-months postclinic were compared with seasonally matched 9-months prior to integrated review. RESULTS: 82 patients were identified, 55 attended. 13 (23.6%) had their primary diagnosis changed. In comparison with the seasonally adjusted baseline period, in the 9-month follow-up there was an increase in inhaled corticosteroid prescriptions of 23.3%, a reduction in short-acting ß2-agonist prescription of 33.3%, a reduction in acute respiratory exacerbations of 67.6%, in unscheduled GP surgery visits of 53.3% and acute respiratory hospital admissions reduced from 3 to 0. Only 4 patients (7.3%) required referral to secondary care. Health economic evaluation showed respiratory-related costs per patient reduced by £231.86. CONCLUSIONS: Patients with respiratory disease in this region at risk of suboptimal outcomes identified proactively and managed by an integrated team improved outcomes without the need for hospital referral.

Isolation of glycophorin with deoxycholate.

In a previous communication we reported that human erythrocyte glycophorin prepared by the lithium diiodosalicylate phenol procedure contains approximately 10 mol of lithium diiodosalicylate per mol of glycophorin, and further we showed that this bound lithium diiodosalicylate is difficult to remove by detergents or organic solvents (Romans, A.Y. and Segrest, J.P. (1978) Biochim. Biophys. Acta 511, 297-301). In the present communication we report an alternative purification procedure for glycophorin in which sodium deoxycholate is substituted for lithium diiodosalicylate; the sodium deoxycholate is subsequently removed by gel filtration. Utilizing this procedure, 25-30 mg glycophorin are obtained per gram of lyophilized erythrocyte ghosts. The glycophorin prepared by the sodium deoxycholate procedure, after a single gel filtration step, contains less than 1 mol of sodium deoxycholate per mol glycophorin and is colorless compared with glycophorin prepared by the lithium diiodosalicylate procedure, which has a distint reddish-brown cast.

Discal attachments of the human temporomandibular joint.

BACKGROUND: Despite its clinical significance, the anatomy of the human temporomandibular joint (TMJ) and its relationship to the lateral pterygoid muscle remains poorly described and often misrepresented in standard texts. The aim of this study was to describe how the anterior and posterior attachments of the TMJ disc vary between lateral, central and medial regions of the joint. METHODS: Ten left TMJs were removed en bloc from cadavers and serial sections were made at 3-4mm intervals. Observations were made to ascertain the anterior and posterior attachments of the disc and the joint structures were traced from standardized photographs. RESULTS: Laterally, the capsule and lateral discal ligament merged prior to their attachment at the condylar pole. Medially, muscle fibres, capsule and the disc converged on the medial pole of the condyle. There was no evidence that fibres of the upper head of the lateral pterygoid muscle inserted directly into the disc. The upper head inserted into the condyle either directly at the pterygoid fovea or via a central tendon or indirectly via the capsule. Posteriorly, the superior part of the posterior attachment of the disc attached to the cartilaginous meatus and tympanic part of the temporal bone. The inferior part of the posterior attachment of the disc attached to the posterior surface of the condyle. In four joints, this attachment was folded beneath the posterior band of the disc, creating a wedge-shaped flap that ran medio-laterally. CONCLUSION: This study is in broad agreement with other anatomical TMJ studies but there are two main points of difference. Firstly, a true muscle insertion of the superior head of the lateral pterygoid muscle to the disc was not observed. Secondly, a wedge-shaped flap of retrodiscal tissue was identified between the condyle and the disc.