Background: Test descriptions from major diagnostic manufacturers do not include ferritin reference intervals (RIs) for individuals aged 60 and older. The absence of older adults-specific RIs contrasts with the widespread use of serum ferritin testing in older adults. We aimed to establish and verify RIs using two common analytical methods. Methods: For this study, 1467 older adults were prospectively enrolled and monitored for morbidity and mortality, and exclusion criteria were applied. Ferritin was measured using chemiluminescent microparticle immunoassay (CMIA) and transferred to an electrochemiluminescence immunoassay (ECLIA) using method comparison. RIs were evaluated using a direct method with a prospective observational study based on healthy individuals according to the Clinical and Laboratory Standards Institute (CLSI) 28-A3c guideline and compared with RIs obtained using an indirect approach based on data obtained in clinical routine outpatients, where normal and abnormal values are supposed to be statistically differentiated to determine RIs. When applied within a countrywide population-based setting in Liechtenstein, the impact of novel RIs on the frequency of abnormal values was analyzed. Results: A total of 386 men and 532 women were included in the direct RI determination. Women (W) had significantly lower ferritin levels than men (M), while age over the age of 60 years had no significant association with ferritin in men and women. RIs were 23-241 ng/mL (W) and 19-396 ng/mL (M) for CMIA and 27-293 ng/mL (W) and 23-480 ng/mL (M) for ECLIA. These RIs are higher than those mentioned in the test descriptions in both tests. In comparison, the indirect method for both assays showed comparably lower reference limits, whereas upper reference limits were only approximately similar. The prevalence of high abnormal ferritin levels was considerably lower with this study's RIs compared with manufacturer RIs. Conclusions: Employing older adults-specific RIs in clinical routine seems to be advisable. This reduces the frequency of abnormal high values in comparison with the widely applied practice of extrapolating RIs obtained from younger age groups to older adults and therefore leads to fewer follow-up investigations.

The ethics of arresting senescence, along with arrest to reversal, share ethical problems. Given the diversity of cultures, religious beliefs, and revenues of us humans around the globe, ethical rules are challenging to implement on an international level. We have uplifted this unsettled topic—and not been clear for a long time—to a chapter level, i.e., this chapter. But we keep it short of meditating on what would happen if rejuvenation became possible one day.

Background Worldwide population is ageing, but little is known regarding risk factors associated with increased mortality in subjectively healthy, community-dwelling older adults. We present the updated results of the longest follow-up carried out on Swiss pensioners and we provide results on potential risk factors associated with mortality before the onset of the COVID-19 pandemic. Materials and methods Within the SENIORLAB study, we collected demographic data, anthropometric measures, medical history, and laboratory parameters of 1467 subjectively healthy, community-dwelling, Swiss adults aged ≥ 60 years over a median follow-up of 8.79 years. The variables considered in the multivariable Cox-proportional hazard model for mortality during follow-up were selected based on prior knowledge. Two separate models for males and females were calculated; moreover, we fitted the old model obtained in 2018 to the complete follow-up data to highlight differences and similarities. Results The population sample included 680 males and 787 females. Age of participants ranged between 60 and 99 years. We experienced 208 deaths throughout the entire follow-up period; no patients were lost at follow-up. The Cox-proportional hazard regression model included female gender, age, albumin levels, smoking status, hypertension, osteoporosis and history of cancer within predictors of mortality over the follow-up period. Consistent findings were obtained also after gender stratification. After fitting the old model, female gender, hypertension, and osteoporosis still showed statistically significant independent associations with all-cause mortality. Conclusions Understanding the predictors of a healthy survival can improve the overall quality of life of the ageing population and simultaneously reduce their global economic burden. Trial registration The present study was registered in the International Standard Randomized Controlled Trial Number registry: https://www.isrctn.com/ISRCTN53778569 (registration date: 27/05/2015).

Introduction: The neutrophil to lymphocyte ratio (NLR) has increasingly gained interest as an independent and easy to obtain prognostic factor of morbidity and mortality in malignant, immunologic, infectious, and cardiovascular disease. Whereas reference intervals in non-geriatric patients have already been described, such decision aids are so far lacking in the elderly. Thus, reference intervals for the NLR were evaluated in seniors, where diseases with NLR-associated prognosis are frequently encountered. Methods: Within the framework of the SENIORLAB study, subjectively healthy Swiss individuals aged 60 years and older were prospectively included and followed for morbidity and mortality. Participants who had circumstances known to affect the NLR were excluded (i.e., smoking, cancer, steroids, inflammation with CRP>5mg/L, known underlying hematological disease) as were participants, who did not survive during a prespecified follow-up period. Automated blood cell differential was measured with a Sysmex XE-5000 hematology analyzer (Sysmex, Horgen, Switzerland). Double sided 95%-reference intervals (RI) together with their 90% confidence intervals (CI) were calculated according to the Clinical and Laboratory Standards Institute (CLSI) guideline EP28-A3c by means of the robust method. Outliers were eliminated according to Tukey. Results: A total of 976 individuals (441 male/535 female) aged 60 to 99 years and a mean follow-up period of 3.7+/- 0.7 years were included into the study. NLR increased significantly with age (Spearman rank rho= 0.22; p<0.001) and males had a significantly higher median NLR (1.91, interquartile range, IQR [1.5,2.47]) than females (1.73, IQR [1,34,2.25]) (p<0.001). Thus, RI were stratified according to age and gender. In males, RI were 0.98 to 3.22 (90%CI [0.92,1.06] and [3.06,3.39]) at age 60-69 years, 0.95 to 4.28 (90%CI [0.88,1.02] and [3.90,4.69]) at age 70 to 79 years, and 1.01 to 6.43 (90%CI [0.90,1.14] and [5.36,7.66] at age 80 years and older. In females the respective RI's were: 0.83 to 3.38 (90% CI [0.79,0.88] and [3.12,3.66]) at age 60-69 years, 0.84 to 3.58 (90% CI [0.77,0.91] and [3.36,3.82]) at age 70-79 years, as well as 1.09 to 4.76 (90%CI [1.01,1-18] and [4.14,5.48]) at age 80 years and older. Conclusions: In the elderly, age, and sex specific differences in the NLR can be observed. Male sex and older age is associated with higher reference limits. An age and gender specific use of reference intervals for NLR is thus suggested in the elderly.

Convalescere: a latin word for 'to recover' with linguistics reaching into current English - says it all: the revival of patients from COVID-19 infection to a healthy (virus-free?) life. [[1]Lopez-Otin C. Kroemer G. Hallmarks of health.Cell. 2021; 184: 33-63Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar,[2]Conti A.A. Historical evolution of the cocept of health in Western medicine.Acta Biomed. 2018; 83: 352-354Google Scholar]. Even after a poorly defined waiting period of one month, blood banks collect blood plasma during the dynamics of recovery: donor recruitment impossible without med lab assessment of fitness (Table 1) [[3]Bloch E.M. Shoham S. Tobian A.A. coautors Deployment of convalescent plasma for the prevention and treatment of COVID-19.J Clin Invest. 2020; 130: 2757-2765Crossref PubMed Scopus (550) Google Scholar]. Whereas the safety of apheresis plasma donation was scrutinized during the development of this technique and persists to be acknowleged since inception, the safety procedures required for convalescent blood plasma (CBP) donation are questionable. [[4]Joyner M.J. Wright R.S. Casadevall A. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients.J Clin Invest. 2020; 130 (coautors): 4791-4797Crossref PubMed Scopus (275) Google Scholar].Table 1Proposed med lab tests within reference intervals to estimate fitness for donation of convalescent plasma.clinical chemistryhematologyimmunologymicrobiologystandard: CRP, ferritin, creatinine, LDH, ALT, CK, bilirubinhb, RBC count, ABO histo-blood typeIg levels (polyclonal, IgG,IgM, IgA, SARS-CoV-2 Ig titers), C5a, SC5b-9regular blood donation tests (**HIV, HCV, HBV, syphiliss.)High titered SARS-CoV levels (hyperimmune); different commercially available assays.LDH lactate dehydrogenase.ALT alanine aminotransferase.CK creatine kinase.** HIV, HCV, HBV, syphiliss. Open table in a new tab High titered SARS-CoV levels (hyperimmune); different commercially available assays. LDH lactate dehydrogenase. ALT alanine aminotransferase. CK creatine kinase. The infant-Covid-19 group study [[5]Khanna N. Weisser M. Buser A. Efficacy of COVID-19 pathogen inactivated convalescent plasma for patients with moderate to severe acute COVD-19: a case matched control study.Blood. 2020; 136 (coautors): 29-30Crossref Google Scholar,[6]Libster R. Pérez Marc G.P. Group I-C Early high-titer plasma therapy to prevent severe Covid-19 in older adults.New Engl J Med. 2021; Crossref PubMed Scopus (588) Google Scholar] clearly showed that early administration of high-titer CBP can reduce progression of COVID-19. Ever since CBP was asserted with other infectious diseases than SARS-CoV 2, specific sets of lab assays were required to meet donation requirements; as of 2020, under the pressure of treating an ever increasing number of younger COVID 19 patients [7Huang L. Zhang X. Xu A. Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: a prospective contact-tracing study.J Infect Public Health. 2020; (coauthors)Google Scholar, 8Jafari R. Kouchaksrael S. Hosseini R. Nayeb M. Ranbajar A. Convalescent plasma:an old trick for the treatment of COVID-19.J Pedr Rev. 2020; 8: 209-210Crossref Google Scholar, 9Felsenstein S. Willis E. Lythgoe H. McCann L. Cleary A. Mahmood K. et al.Presentation, treatment response and short-term outcomes in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS).J Clin Med. 2020; 14Google Scholar] we cannot remain inactive to apply simple procedures prior to CBP, this fresh-frozen semi- stable blood product remaining remote from pharmaceutical approaches as those seen for polyconal and/or monoclonal antibodies (abs) [[10]Weinreich D.M. Sivapalasingam S. Norton T. Investigators T REGN-COV2, a Neutralizing Antibody Cocktail.New Engl J Med. 2020; : 17Google Scholar]. Pathogen inactivation is has now been achieved applying such methods as Amotosalen UVA which blocks DNA and RNA replication - this Intercept Blood System is used for blood plasma, without compromising anti SARS-CoV-2 activity [[5]Khanna N. Weisser M. Buser A. Efficacy of COVID-19 pathogen inactivated convalescent plasma for patients with moderate to severe acute COVD-19: a case matched control study.Blood. 2020; 136 (coautors): 29-30Crossref Google Scholar]. Thus, the containment of anti-SARS-CoV 2 antibodies in CBP produced by the convalescing donor or added as spike, is more and more perceived as bringing therapeutic efficacy to some patients receiving CBP [[11]Lung T. Risch L. Risch M. Sakem B. Wurzner R. Nydegger U. The utility of complement assays in clinical immunology: a comprehensive review.J Autoimmun. 2018; 95: 191-200Crossref PubMed Scopus (5) Google Scholar,[12]Lung T. Kazatchkine M. Risch L. Risch M. Nydegger U. A consideration of convalescent plasma and plasmaderivatives in the care of severely- ill patients with COVID 19.Transfus Apher Sci. 2020; 59Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. In addition, glycan constitution of the abs seems to confer virotoxicity: afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity [[13]Larsen M.D. de Graaf E.L. Sonneveld MEea Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity.Science. 2020; : eabc8378PubMed Google Scholar]. The polyclonal machinery in humans which synthesizes abs can best be screened using a pan-immunoglobulin assay quantifying specificities towards receptor-binding domain of the SARS-CoV-2 S1-subunit of the spike protein [[14]Schaffner A. Risch L. Risch M. Characterization of a pan-immunoglobulin assay quantifying antibodies directed against the receptor binding domain of the SARS-CoV-2 S1-subunit of the spike protein: a population-based study.J Clin Med. 2020; 9 (coauthors): 3989Crossref Scopus (29) Google Scholar] or assays based on PCR neutralization [[15]Danh K. Karp D.C. Tsai C. Detection of SARS-CoV-2 neutralizing antibodies with a cell-free PCR assay. medRxiv, 2020Crossref Scopus (0) Google Scholar]. We have recently proposed that CBP contains as yet to be defined components different from anti-SARS-CoV-2 abs; one may underline this assumption adressing the GIS (geographic information system) approach forwarded by Topol et al. [[16]Topol E. Individualized medicine from prewomb to tomb.Cell. 2014; 157: 241-253Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar]. This can be completed with data-driven Bayesian networks estimated to uncover complex interrelationships and confounding effects [[12]Lung T. Kazatchkine M. Risch L. Risch M. Nydegger U. A consideration of convalescent plasma and plasmaderivatives in the care of severely- ill patients with COVID 19.Transfus Apher Sci. 2020; 59Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,[17]Cippa P.E. Cugnata F. Di Serio C. A data-driven approach to identify risk profiles and protective drugs in COVID-19.Proc Natl Acad Sci U S A. 2020; 118 (coauthors)Crossref PubMed Scopus (29) Google Scholar]. Recovery from COVID-19, including expiration of SARS-CoV-2 load, may in fact depend on metabolome and proteome including different components from abs alone and scoop from multiple and superimposed layers of innate and acquired immune events; recovery also takes hold of such components as α1−antitrypsin, C1 esterase inhibitor, metalloproteinase or shed IL- receptors: their putative convalescing potential might get lost to the convalescing/recovering COVID 19 patient. The involvement of the DNA ladder, here coding for ABO histo-blood groups and complement in COVID -19 just begins to be considered on a patients` chart [[18]Valenti L. Griffini S. Cugno M. Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19.J Autoimmun. 2021; (coautors)Crossref Scopus (40) Google Scholar,[19]Ellinghaus D. Degenhardt F. Karlsen T.H. The ABO blood group loccus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. medRxiv, 2020Google Scholar]. The medicalized smartphone [[20]Topol E. The patient will see you now. Basic Books, New York2015Google Scholar] software on a bracelet, programmed to clear a convalescent COVID-19 patient to qualify for plasma donation, may enable advance us to recruit sufficient CBP donors - should this treatment become part of good medical practice.

Recent updates in the diagnosis and management of chronic inflammatory conditions can be brought together to better understand autoimmune diseases (ADs). With organ-specific or organ-limited and systemic ADs, physicians often are faced with a dilemma when making a diagnosis and may feel a kind of embarrassment when a more distinct nosological entity cannot be found. ADs often overlap with other diseases and good diagnostic procedures for ADs only become evidence-based when refined histopathologic, immunopathologic, and general laboratory analyses are available. Immunofluorescence analyses, Western blotting, CUT & RUN technology allow localization of the site of autoantibody-reactivity on the relevant DNA sequence. The Polymerase chain reaction technology and CRISPR-Cas9, the new gene editor using pools of synthetic non-coding RNAs in screening experiments, are expected to lead to advances in the diagnosis of ADs. The current use of mRNA as a vaccine against COVID-19 has increased confidence in the use of mRNA or long non-coding RNAs in the treatment strategy for ADs. The integration of new knowledge about innate immunity, the complement system, vaccinology, and senescence into the care of patients with ADs expands the therapeutic arsenal of disease-modifying drugs and allows for the repurposing of anti-cytokine monoclonal/biosimilar antibodies, originally designed for chronic inflammatory diseases, for ADs. This review article brings together some of the most relevant ideas; a case report included in this review highlights the difficulty of distinguishing between ADs, chronic inflammation, and/or granular disease.

Abstract Objectives Mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) possess diagnostic and prognostic capabilities in a variety of diseases. We aimed to establish reference intervals (RI) for platelet indices (PI) in seniors. Methods We established direct and indirect RI for MPV, PDW, and PCT in selected reference individuals aged 60 years and older. Abnormal PI were assessed in a population-based setting in the Principality of Liechtenstein, where 37.7% of the whole nation’s population aged 60 years and older had PI determined by hematology analyzers from Sysmex (Horgen, Switzerland). Results Among 689 female and 542 male participants, MPV and PDW did not exhibit age- and gender-specific differences, whereas PCT in females also displayed no age-specific differences. Age- and sex-independent RI were 9.3–12.5 fl for MPV and 10.1–16.7% for PDW, whereas the age-independent RI for PCT in women was 0.18–0.37. In males, age-specific RI for PCT were 0.16–0.30 (age 60–69), 0.15–0.33 (age 70–79), and 0.14–0.33 (age 80 and older). The population-based frequency of abnormal PI results was 0.8% (MPV), 1.1% (PDW), and 24.4% (PCT). Conclusions Applying novel RI for PI reveals that only approximately 1% of patients exhibit abnormal MPV and PDW. Abnormal PCT is observed much more frequently.

Youth, working age and the elderly: On a timeline, chronological age (CA) and biological age (BA) may dissociate; nosological entities manifest themselves at different BAs. In determining which disease corresponds to a given age decade, statistical registries of causes of death are unreliable and this does not change with SARS CoV-2 infection. Beyond adolescence, ageing metrics involve estimations of changes in fitness, including prediction models to estimate the number of remaining years left to live. A substantial disparity in biomarker levels and health status of ageing can be observed: the difference in CA and BA in the large cohorts under consideration is glaring. Here, we focus more closely on ageing and senescence metrics in order to make information available for risk analysis non the least with COVID-19, including the most recent risk factors of ABO blood type and 3p21.31 chromosome cluster impacting on C5a and SC5b-9 plasma levels. From the multitude of routine medical laboratory assays, a potentially meaningful set of assays aimed to best reflect the stage of individual senescence; hence risk factors the observational prospective SENIORLABOR study of 1,467 healthy elderly performed since 2009 and similar approaches since 1958 can be instantiated as a network to combine a set of elementary laboratory assays quantifying senescence.

BACKGROUND A combined indicator for the determination of vitamin B12 status (4cB12) that employs four markers of vitamin B12 status (i.e., holotranscobalamin, HoloTC; vitamin B12, B12; methyl malonic acid, MMA; and homocysteine, Hcy) has been proposed for the comprehensive assessment of B12 status. We aimed to compare recently published 2- (2cB12) and 3-parameter (3cB12) cB12 equations missing one or two markers of B12 status with the established four-parameter cB12 (4cB12). METHODS In 3,614 routine samples in which HoloTC, B12, MMA, Hcy and serum folate were measured, cB12 was assessed with 4cB12, as well as with four 3cB12 and six 2cB12 equations. Diagnostic accuracy (AUC) curves were calculated by receiver operating characteristic (ROC) curve analysis with the four-parameter equation (4cB12) as an index. Furthermore, we investigated whether calculating cB12 in addition to a 2-step algorithm employing the same parameters would add diagnostic value for the diagnosis of vitamin B12 deficiency. RESULTS HoloTC showed the highest diagnostic accuracy among the single markers (AUC = 0.94). The cB12 equation using HoloTC and MMA (2cB12HoloTC/MMA) had the highest AUC among the 2-parameter equations (0.98). Among the 3-parameter equations, 3cB12HoloTC/MMA/Hcy and 3cB12HoloTC/B12/MMA revealed an AUC of 0.99, which was significantly higher than that of 2cB12HoloTC/MMA (p < 0.01). Calculating 2cB12HoloTC/MMA in addition to using a stepwise algorithm employing HoloTC and MMA for diagnosis of vitamin B12 deficiency increased the positive likelihood ratio from 12.1 to 42.6. CONCLUSIONS cB12 calculated with two or three markers of B12 status provides a good approximation of the 4cB12 equation. A 2cB12 equation employing the same parameters improved diagnostic accuracy compared to the use of a 2-step diagnostic algorithm alone. Our results suggest, that laboratories should consider enriching their reports by additionally reporting a corresponding 2cB12 or 3cB12 to results obtained in stepwise diagnostic algorithms.

Four biomarkers are commonly employed to diagnose B12 deficiency: vitamin B12 (B12), holotranscobalamin (HoloTC), methylmalonic acid (MMA), and homocysteine (Hcy). 4cB12, a combined index of the B12 status, has been suggested to improve the recognition of B12 deficiency. We aimed to evaluate the four different markers for detecting B12 deficiency, as determined by 4cB12. Within a large, mixed patient population, 11,833 samples had concurrent measurements of B12, HoloTC, MMA, and Hcy. 4cB12 was calculated according to the methods described by Fedosov. Diagnostic cutoffs as well as diagnostic accuracy for the detection of B12 deficiency were assessed with receiver operating characteristic (ROC) analysis. The median age was 56 years, and women accounted for 58.8% of the samples. Overall, the area under the curve (AUC) for the detection of subclinical B12 deficiency was highest for HoloTC (0.92), followed by MMA (0.91), B12 (0.9) and Hcy (0.78). The difference between HoloTC and B12 was driven by a significantly higher AUC for HoloTC (0.93) than for B12 (0.89), MMA (0.91), and Hcy in women 50 years and older (0.79; p<0.05 for all). In the detection of subclinical B12 deficiency, there were no significant differences in the AUCs of HoloTC, B12, and MMA among men and women <50 years. In conclusion, in women<50 years and in men, HoloTC, MMA, or Hcy do not appear superior to B12 for the detection of B12 deficiency. For women 50 years and older, HoloTC seems to be the preferred first-line marker for the detection of subclinical B12 deficiency.

The pathogenesis and immunopathological damage of severe forms of COVID-19 resemble acute autoimmune disease sparked by SARS-CoV-2, including an early systemic overproduction of proinflammatory cytokines. Such immunopathological features provide a rationale for the use of passive immunotherapy with convalescent plasma as a source of neutralizing anti-viral antibodies and of anti-inflammatory plasma components. While convalescent plasma therapy is now being evaluated in prospective clinical trials, we further consider the therapeutic potential of human hyper immune globulins, and of heterologous, engineered and monoclonal neutralizing antibodies as anti-viral agents to treat COVID-19. Good medical practice procedures are still needed and is why we also discuss the potential use of polyclonal polyspecific immunoglobulins (IVIG), a therapeutic plasma derivative, with potent anti-inflammatory activity, in severe forms of Covid-19.

Background. - Hemoglobin A1c (HbA1c) is an accurate index of fluctuation in glycemia over the 2-3 months prior to quantitative assessment. During this time, hemoglobin (Hb) slowly glycates until it shows the properties of advanced glycation end-products. Glycation kinetics is intensified by prolonged glucose exposure. In subjects undergoing oral glucose tolerance testing (OGTT), immediately after ingestion, glucose is ostensibly transported by the glucose transporter 1 (GLUT1) to erythrocyte corpuscular hemoglobin. The earliest significant measurable level of hemoglobin glycation associated with this transportation is still not clear. Subjects and methods. - We attempted to explore the early impact of short-term glucose load on HbA1c levels, because it is now known that transmembrane GLUT1-mediated glucose transport occurs immediately. A total of 88 participants (46 patients and 42 clinically healthy controls) underwent fasting plasma glucose quantitation during an OGTT. HbA1c, revealed by a monoclonal anti-glycation epitope antibody and adiponectin, was quantitated before (T0) and 2 hours (T120) after 80 g glucose ingestion. Results. - Wilcoxon test revealed that the HbA1c values did not significantly vary (P = 0.15) during the OGTT, whereas glucose concentration varied strongly between T0 and T120. Discussion. - It is well known that quantitative estimation of HbA1c is informative for clinical care, independently of glucose level. The molecular mechanisms and dynamics by which glucose enters/exits red blood cells are incompletely known and may differ between individuals. We here show, for the first time, that HbA1c levels do not significantly increase during OGTT, supporting the view that non-enzymatic glycation of hemoglobin occurs slowly and that glycation during the 2 hours of an OGTT is insignificant. (C) 2020 Labormedizinisches zentrum Dr. Risch. Publie par Elsevier Masson SAS.