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During the COVID-19 outbreak, reports have surfaced of children who present with features of a multisystem inflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome - Paediatric Inflammatory Multisystem Syndrome- temporally associated with SARS-CoV-2 pandemic (PIMS-TS). Initial reports find that many of the children are PCR-negative for SARS-CoV-2, so it is difficult to confirm whether this syndrome is a late complication of viral infection in an age group largely spared the worst consequences of this infection, or if this syndrome reflects enhanced surveillance.Children hospitalised for symptoms consistent with PIMS-TS between 28 April and 8 May 2020, and who were PCR-negative for SARS-CoV-2, were tested for antibodies to viral spike glycoprotein using an ELISA test.Eight patients (age range 7-14 years, 63% male) fulfilled case-definition for PIMS-TS during the study period. Six of the eight patients required admission to intensive care. All patients exhibited significant IgG and IgA responses to viral spike glycoprotein. Further assessment showed that the IgG isotypes detected in children with PIMS-TS were of the IgG1 and IgG3 subclasses, a distribution similar to that observed in samples from hospitalised adult COVID-19 patients. In contrast, IgG2 and IgG4 were not detected in children or adults. IgM was not detected in children, which contrasts with adult hospitalised adult COVID-19 patients of whom all had positive IgM responses.Strong IgG antibody responses can be detected in PCR-negative children with PIMS-TS. The low detection rate of IgM in these patients is consistent with infection having occurred weeks previously and that the syndrome onset occurs well after the control of SARS-CoV-2 viral load. This implies that the disease is largely immune-mediated. Lastly, this indicates that serology can be an appropriate diagnostic tool in select patient groups.

Summary Background Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. Methods The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009–010956–93, and has completed recruitment. Findings Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0–43·5), median progression-free survival was 30 months (95% CI 25–36) with CVD and 20 months (15–28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48–0·75, p

Summary The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re‐induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high‐risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow‐up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16–26) vs. 11 months (9–12), hazard ratio [HR]: 0·40, 95% CI: 0·29–0·56, P

Introduction: Measurement of immunoglobulin free light chains (FLCs) in saliva can serve as a non-invasive biomarker in health and behavioural research. FLCs have been explored in relation to physiological stress but FLC responses to psychological stress and their relationship with infections remain unknown. This study aimed to investigate the impact of exam period stress on salivary FLCs alongside other established biomarkers of stress and whether FLCs relate to symptoms of infection. Methods: 58 healthy adults studying at university completed saliva samples and questionnaires in a period without exams (baseline), and again prior to the start of an exam period. Saliva samples were assessed for FLCs, IgA, cortisol and dehydroepiandrosterone (DHEA). Measures of life events stress, perceived stress, anxiety and depression were completed. Students also reported incidence and severity of symptoms of infection and rated general well-being at baseline, prior to, during and after the exam period. Exercise, sleep and alcohol consumption were also assessed at both timepoints. Results: FLCs secretion rates were significantly lower at the exam period compared to baseline (p

Background Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma. Methods TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35. Findings Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8–13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51–0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group. Interpretation Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy.

Highlights • Early small studies provide mixed evidence for effects of time of vaccination on antibody response. • This is the first large scale randomised trial of different times of vaccination. • Morning vaccination enhances the antibody response to the influenza vaccine. • This simple manipulation is cost neutral and may improve protection from influenza in older adults., Objectives Older adults are less able to produce a protective antibody response to vaccinations. One factor that contributes to this is immune ageing. Here we examined whether diurnal variations in immune responses might extend to the antibody response to vaccination. Design We utilised a cluster-randomised trial design. Setting 24 General Practices (GPs) across the West Midlands, UK who were assigned to morning (9–11 am; 15 surgeries) or afternoon (3–5 pm; 9 surgeries) vaccination times for the annual UK influenza vaccination programme. Participants 276 adults (aged 65+ years and without a current infection or immune disorder or taking immunosuppressant medication). Interventions Participants were vaccinated in the morning or afternoon between 2011 and 2013. Main outcome measures The primary outcome was the change in antibody titres to the three vaccine influenza strains from pre-vaccination to one month post-vaccination. Secondary outcomes of serum cytokines and steroid hormone concentrations were analysed at baseline to identify relationships with antibody responses. Results The increase in antibody levels due to vaccination differed between morning and afternoon administration; mean difference (95% CI) for H1N1 A-strain, 293.3 (30.97–555.66) p = .03, B-strain, 15.89 (3.42–28.36) p = .01, but not H3N2 A-strain, 47.0 (−52.43 to 146.46) p = .35; those vaccinated in the morning had a greater antibody response. Cytokines and steroid hormones were not related to antibody responses. No adverse events were reported. Conclusions This simple manipulation in the timing of vaccine administration to favour morning vaccination may be beneficial for the influenza antibody response in older adults, with potential implications for vaccination strategies generally. Trial registration This trial is registered with the ISRCTN (ISRCTN70898162).

Summary Background Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. Methods The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1–21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. Findings Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18–50), median progression-free survival was 39 months (95% CI 36–42) with lenalidomide and 20 months (18–22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41–0·53]; p

Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/μl) and uncomplicated malaria (3,700/μl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/μl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria.

BACKGROUND: Free light chains (FLCs) have a range of biological functions and may act as a broad marker of immunesuppression and activation and inflammation. Measurement of salivary FLCs may provide practical advantages in a range of clinical populations. The aim of the present study was to develop normal reference ranges of FLCs in saliva and assess the effects of acute exercise on FLC levels in younger and older adults.METHODS: Saliva FLC concentrations and secretion rates were measuredin young (n = 88, aged 18-36) and older (n = 53, aged 60-80) adults. To assess FLC changes in response to acute exercise, young adults completed a constant work-rate cycling exercise trial at 60% VO2max (n = 18) or a 1 h cycling time trial (TT) (n = 10) and older adults completed an incremental submaximal treadmill walking exercise test to 75% HRmax (n = 53). Serum FLCs were measured at baseline and in response to exercise.RESULTS: Older adults demonstrated significantly higher levels of salivary FLC parameters compared with young adults. Median (5-95th percentile) concentrationswere 0.45 (0.004- 3.45) mg/L for kappa and 0.30 (0.08-1.54) mg/L for lambda in young adults; 3.91 (0.75-19.65) mg/L for kappa and 1.00 (0.02-4.50) mg/L for lambda in older ad ults. Overall median concentrations of salivary kappa and lambda FLCs were 10-fold and 20-fold lower than serum, respectively. Reductions in salivary FLC concentrations and secretion rates were observed immediately post- and at 1 h post exercise, but were only significant for the older cohort; FLCs began to recover between post and 1 h post-exercise. No changes in serum FLCs were observed in response to exercise.

Immunoglobulins are essential for combating infectious disease although very high levels can indicate underlying pathology. The present study examined associations between secretory immunoglobulin A (sIgA) in saliva and mortality rates in the general population. Participants were 639 adults from the eldest cohort of the West of Scotland Twenty-07 Study aged 63 years at the time of saliva sampling in 1995. From unstimulated 2-minute saliva samples, saliva volume and S-IgA concentration were measured, and S-IgA secretion rate determined as their product. Mortality data were tracked for 19 years. Cox proportional hazard models were applied to compute hazard ratios (HR) for all-cause mortality from sIgA secretion rate. Associations were adjusted for gender, assay batch, household occupational group, smoking, medication usage, and self-reported health. There was a negative association between log sIgA secretion rate and all-cause mortality, HR = 0.81, 95%CI = 0.73-0.91, p < .001. Further analysis of specific causes of mortality revealed that the all-cause association was due to an underlying association with cancer mortality and, in particular with cancers other than lung cancer. The HR for non-lung cancer was 0.68 (95%CI= 0.54 to 0.85) implying a 32% reduction in mortality risk per standard deviation rise in log sIgA secretion rate. Effects were stronger for men than women. For deaths from respiratory diseases, sIgA secretion had a non-linear relationship with mortality risk whereby only the very lowest levels of secretion were associated with elevated risk. SIgA concentration revealed a similar but weaker pattern of association. In the present study, higher secretion rates of sIgA were associated with a decreased risk of death from cancer, specifically non-lung cancer, as well as from respiratory disease. Thus, it appears that sIgA plays a protective role among older adults, and could serve as a marker of mortality risk, specifically cancer mortality.

Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to distinguish monoclonal gammopathies that result in the development of kidney disease from those that are benign. By definition, patients with MGRS have B-cell clones that do not meet the definition of multiple myeloma or lymphoma. Nevertheless, these clones produce monoclonal proteins that are capable of injuring the kidney resulting in permanent damage. Except for immunoglobulin light chain amyloidosis with heart involvement in which death can be rapid, treatment of MGRS is often indicated more to preserve kidney function and prevent recurrence after kidney transplantation rather than the prolongation of life. Clinical trials are rare for MGRS-related kidney diseases, except in immunoglobulin light chain amyloidosis. Treatment recommendations are therefore based on the clinical data obtained from treatment of the clonal disorder in its malignant state. The establishment of these treatment recommendations is important until data can be obtained by clinical trials of MGRS-related kidney diseases.

Objectives : To assess the diagnostic accuracy and clinical utility of a simplified low cost method for measuring absolute and percentage CD4 counts with flow cytometry. Design : A CD4 counting method (Blantyre count) using a CD4 and CD45 antibody combination with reduced blood and reagent volumes. Diagnostic accuracy was assessed by measuring agreement of the index test with two other assays (TruCount and FACSCount). Clinical utility was investigated by comparing CD4 counts with the new assay with WHO clinical staging in patients with HIV. Setting : Research laboratories and antiretroviral therapy clinic at a medical school and large government hospital in southern Malawi. Participants : Assay comparisons were performed on consecutive blood samples sent for CD4 counting from 129 patients with HIV. Comparison of CD4 count with staging was conducted on 253 consecutive new patients attending the antiretroviral therapy clinic. Main outcome measures : Limits of agreement with 95% confidence intervals between index test and reference standards. Results : The limits of agreement for Blantyre count and TruCount were excellent (cell count −48.9 to 27.0 cells/μl for absolute counts in the CD4 range 350 cells/μl. Conclusions : This simplified method of counting CD4 cells with flow cytometry has good agreement with established commercial assays, is affordable for routine clinical use in Africa, and could improve clinical decision making in patients with HIV.

The purpose of this review is to determine the effects of psychosocial stress on antibody response to vaccination in humans, consider possible mechanisms, and identify agenda for future research. Studies of the association between stress and vaccination response in humans were reviewed. There is evidence of a negative association between stress and antibody response to vaccination, which is most apparent with thymus-dependent vaccines and when measured at extended times after vaccination. Preliminary findings implicate the hypothalamic-pituitary-adrenal axis and sympathetic nervous system as potential mechanisms, although a role for unhealthy behaviours cannot be discounted at this stage. Results to date are sufficiently indicative to direct future research to untangling their theoretical ramifications, as well as realising their clinical implications.