Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Determining hemodilution in diagnostic bone marrow aspirated samples in plasma cell disorders by next-generation flow cytometry: Proposal for a bone marrow quality index.

Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p < 0.001), mast cells (AUC = 0.65; p < 0.001), and the BM WBC count (AUC = 0.77; p < 0.05). We generated a novel BMQI that is intrinsic to current NGF protocols, for evaluating quality of diagnostic BM samples and suggest the use of a BMQI scoring system for interpreting results and guiding appropriate actions.

Prevalence of smoldering multiple myeloma based on nationwide screening.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma. Here we define the epidemiological characteristics of SMM in the general population in Iceland. The iStopMM study (ClinicalTrials.gov ID: NCT03327597 ) is a nationwide screening study for multiple myeloma precursors where all residents in Iceland 40 years or older were invited to participate. SMM was defined as 10-60% bone marrow plasma cells and/or monoclonal (M) protein concentration ≥3 g dl-1, in the absence of myeloma-defining events. Of the 80,759 who gave informed consent to participate, 75,422 (93%) were screened. The prevalence of SMM in the total population was 0.53% (95% confidence interval (CI) = 0.49-0.57%) in individuals 40 years or older. In men and women, the prevalence of SMM was 0.67% (95% CI = 0.62-0.73%) and 0.39% (95% CI = 0.35-0.43%), respectively; it increased with age in both sexes. For the 193 individuals with SMM, median age was 70 years (range 44-92 years) and 60% were males. The mean M protein concentration of individuals with SMM was 0.62 g dl-1 (range 0.01-3.5 g dl-1) and 73% had 11-20% bone marrow plasma cell infiltration. The high prevalence of SMM has implications for future treatment policies in multiple myeloma as the evidence supporting treatment initiation at the SMM stage is emerging.

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study.

Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.

Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study.

Multiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81-1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52-1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19.

Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.

Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.

A comparative study of quality and safety of Atlantic cod (Gadus morhua) fillets during cold storage, as affected by different thawing methods of pre-rigor frozen headed and gutted fish.

BACKGROUND: The catch of marine whitefish is typically seasonal, whereas the land-based processing industry has a need for all-year stable supply of raw materials. This challenge can be met by applying fish frozen at sea. When using frozen fish, the methods employed for thawing may influence the safety and quality of the final product. This study aimed to investigate the applicability of novel thawing strategies in order to provide an all-year supply of high-quality and safe cod products. RESULTS: Comparative investigations of quality and safety factors after thawing in water, with and without air circulation, and contact thawing were performed. The parameters included water-holding capacity, thawing loss, drip loss, cooking yield, sensory evaluation and microbiological analyses (including total volatile bases nitrogen). Water thawing with air circulation provided faster thawing than water thawing without air circulation and contact thawing. For all three methods, the quality of the thawed fish was acceptable and the shelf life of the fillets during chilled storage was between 10 and 14 days post-filleting. CONCLUSION: The results show that controlled freezing of cod, followed by appropriate thawing, may provide the processing industry with an all-year delivery of raw materials, without compromising quality and safety of the final product. © 2017 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The Effects of Short-Time Temperature Abuse on the Microbial and Sensory Quality of Chilled Saithe (Pollachius virens) Fillets.

Chilled fish products are highly perishable with a limited shelf life (10 to 14 d). For this reason, the control of the cold chain for fish is essential. This study´s objective was to investigate the effects of short-time temperature abuse during processing on spoilage of chilled saithe (Pollachius virens) fillets. Analysis of microbial growth, freshness grades, and sensory score by Quality Index method, as well as pH, were carried out during a 10-d storage period at 2 ± 2 °C. Before storage, the fillets were kept at 16 °C for 0, 1, and 2 h. The results showed that spoilage of the fillets was accelerated with longer holding time at 16 °C. The 1- and 2-h holding before packing and storage caused a 22% (2 d) and 44% (4 d) loss of shelf life, respectively, compared to fillets that were packed immediately after processing. These findings indicate how bottlenecks and delays during processing may result in loss of microbial and sensory quality of chilled fish products. PRACTICAL APPLICATION: The observations show the importance of maintaining a low temperature in fish, even for a short period such as during processing. Any delays, such as due to buffering or mechanical failure, may accelerate spoilage of chilled products during subsequent storage. This effect is even more pronounced when products are packed in bulk volumes as the cooling rate is much slower than the piece-by-piece cooling rate.

Position paper on screening for breast cancer by the European Society of Breast Imaging (EUSOBI) and 30 national breast radiology bodies from Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Israel, Lithuania, Moldova, The Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Spain, Sweden, Switzerland and Turkey.

EUSOBI and 30 national breast radiology bodies support mammography for population-based screening, demonstrated to reduce breast cancer (BC) mortality and treatment impact. According to the International Agency for Research on Cancer, the reduction in mortality is 40 % for women aged 50-69 years taking up the invitation while the probability of false-positive needle biopsy is <1 % per round and overdiagnosis is only 1-10 % for a 20-year screening. Mortality reduction was also observed for the age groups 40-49 years and 70-74 years, although with "limited evidence". Thus, we firstly recommend biennial screening mammography for average-risk women aged 50-69 years; extension up to 73 or 75 years, biennially, is a second priority, from 40-45 to 49 years, annually, a third priority. Screening with thermography or other optical tools as alternatives to mammography is discouraged. Preference should be given to population screening programmes on a territorial basis, with double reading. Adoption of digital mammography (not film-screen or phosphor-plate computer radiography) is a priority, which also improves sensitivity in dense breasts. Radiologists qualified as screening readers should be involved in programmes. Digital breast tomosynthesis is also set to become "routine mammography" in the screening setting in the next future. Dedicated pathways for high-risk women offering breast MRI according to national or international guidelines and recommendations are encouraged. KEY POINTS: • EUSOBI and 30 national breast radiology bodies support screening mammography. • A first priority is double-reading biennial mammography for women aged 50-69 years. • Extension to 73-75 and from 40-45 to 49 years is also encouraged. • Digital mammography (not film-screen or computer radiography) should be used. • DBT is set to become "routine mammography" in the screening setting in the next future.

Influence of smoking and packaging methods on lipid stability and microbial quality of Capelin (Mallotus villosus) and Sardine (Sardinella gibossa).

Lipid and microbial quality of smoked capelin (two groups differing in lipid content) and sardine was studied, with the aim of introducing capelin in the smoked sardine markets. Lipid hydrolysis (phospholipid and free fatty acids) and oxidation index (hydroperoxides and thiobarbituric acid-reactive substances), fatty acid composition, and total viable count were measured in raw and packaged smoked fish during chilled storage (day 2, 10, 16, 22, 28). Lipid hydrolysis was more pronounced in low lipid capelin, whereas accelerated lipid oxidation occurred in high lipid capelin. Muscle lipid was less stable in sardine than capelin. Essential polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) constituted 12% of fatty acids in capelin and 19% in sardine. Vacuum packaging as well as hot smoking retarded bacterial growth, recording counts of ≤log 5 CFU/g compared to ≥log 7CFU/g in cold smoked air packaged. Smoked low lipid capelin was considered an alternative for introduction in smoked sardine markets.

The effects of pre-salting methods on salt and water distribution of heavily salted cod, as analyzed by (1)H and (23)Na MRI, (23)Na NMR, low-field NMR and physicochemical analysis.

The effect of different pre-salting methods (brine injection with salt with/without polyphosphates, brining and pickling) on the water and salt distribution in dry salted Atlantic cod (Gadus morhua) fillets was studied with proton and sodium NMR and MRI methods, supported by physicochemical analysis of salt and water content as well as water holding capacity. The study indicated that double head brine injection with salt and phosphates lead to the least heterogeneous water distribution, while pickle salting had the least heterogeneous salt distribution. Fillets from all treatments contained spots with unsaturated brine, increasing the risk of microbial denaturation of the fillets during storage. Since a homogeneous water and salt distribution was not achieved with the studied pre-salting methods, further optimizations of the salting process, including the pre-salting and dry salting steps, must be made in the future.

Sensory properties of frozen herring (Clupea harengus) from different catch seasons and locations.

UNLABELLED: Freezing of herring (Clupea harengus) for human consumption is increasing in the Nordic herring industry, either onboard the fishing vessels or right after landing. The quality of frozen herring as a raw material does not only depend on the frozen storage conditions applied, but also on compositional features, something which in turn can vary with season and catching ground. To unravel the link between biological variations, basic muscle composition, and sensory properties of frozen herring, a unique herring raw material was caught by commercial fishing vessels at three locations: around Iceland, outside the Norwegian coast, and in Kattegat/Skagerrak. The samplings were done according to a specific scheme and conducted over several seasons and 2 years. The herring was converted into butterfly fillets, packed in cardboard boxes, frozen, and then stored at -20 °C or -80 °C for up to 18 mo. The sensory quality was characterized by objective sensory profiling. It was shown that two generalized sensory variables could be defined from a principal component analysis of the sensory data. Except for the expected pronounced effect from storage time, the most distinct variation followed the lipid content, which in turn varied with season. An unexpected conclusion was that catching location only had a minor affect on the changes in sensory quality of herring during frozen storage. Knowledge about how season and catching location affect herring during frozen storage will be useful for optimizing the utilization of herring for frozen storage for human consumption. PRACTICAL APPLICATION: The results of this study constitute important information for the herring processing industry when handling raw materials with different geographical and seasonal history. The reported information on a highly equal sensory quality of geographically diverse raw materials will give consumers and retailers valuable knowledge on the changes in eating quality to expect after long-term frozen storage under conditions similar to household freezers or refrigerated counters in supermarkets.

The use of digital photographs for the diagnosis of hand osteoarthritis: the AGES-Reykjavik study.

BACKGROUND: The objective of the study was to standardize a method using digital photographs to diagnose and grade hand osteoarthritis (HOA), to compare it with radiographs and clinical examination with regard to prevalence and relation to symptoms, and finally to construct a simple shortened version suitable for use in very large studies, where a global estimate may be preferable. METHODS: High quality photographs with standard distance and hand positioning were analysed for the presence of HOA and subsequently compared with standard radiographs and clinical examination in 381 random participants in the AGES-Reykjavik Study, a large population study. The mean age of the participants was 76 years. RESULTS: Using the photographic method, the most commonly affected joints were the second DIP joints followed by the third DIP joints and second and third PIP joints. Both interobserver (ICC = 0.83) and intraobserver reading agreements (ICC = 0.89) were acceptable. On comparison with radiography and clinical examination, aggregate scores were significantly correlated (R(s) 0.35-0.69), more so in females (R(s) 0.53-0.72) than males. Hand pain in males showed very little association with HOA findings by the three methods but all methods showed a comparable moderate association with hand pain in females. The performance of photography in predicting pain on most days for at least a month in females was comparable to that of radiography and clinical examination (AUC 0.63 p = 0.004). Analysis of intermittent pain yielded similar results for in the DIP and PIP joints (OR 3.2-3.3, p < 0.01), but for the CMC1 joints, both radiography (OR 9.0, p < 0.0001), and clinical examination (OR 9.8, p < 0.0001), had higher predictive odds ratios for pain than photography (OR 3.6, p < 0.0001)., A shortened, rapidly performed form of reading photographs also showed a high degree of correlation with the other methods (R(s) 0.56-0.82). CONCLUSION: High quality hand photographs can be used to diagnose and grade hand osteoarthritis. The method has the advantage of being inexpensive and easy to perform. By using a slightly simplified method of reading, it appears to be highly suitable for use in large studies.

Shrimp processing assessed by low field nuclear magnetic resonance, near infrared spectroscopy, and physicochemical measurements--the effect of polyphosphate content and length of prebrining on shrimp muscle.

The effect of using polyphosphates during prebrining and the effect of prebrining time of cold water shrimp (Pandalus borealis) was studied with low field nuclear magnetic resonance (LF-NMR) transverse relaxation time measurements (benchtop and unilateral) and near infrared (NIR) spectroscopy with the aim of improving shrimp processing. Strong calibrations were obtained for moisture content and water-holding capacity (WHC) using the NIR technique. Multivariate analysis indicated significant correlations between benchtop NMR parameters and moisture content and WHC, as measured with physicochemical methods and NIR spectroscopy. Significant correlations were also observed between NMR parameters and muscle pH, protein content, and phosphate content. The study showed that LF-NMR contribute to improved understanding of the shrimp brining process and to improved process control on-line or at-line, especially in combination with NIR measurements. However, optimization of the unilateral device is necessary.