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One of the most ambitious endeavors in the field of diabetes technology is non-invasive glucose sensing. In the past decades, a number of different technologies have been assessed, but none of these have found its entry into general clinical use. We report on the development of a table-top confocal Raman spectrometer that was used in the home of patients with diabetes and operated for extended periods of time unsupervised and without recalibration. The system is based on measurement of glucose levels at a 'critical depth' in the skin, specifically in the interstitial fluid located below the stratum corneum but above the underlying adipose tissue layer. The region chosen for routine glucose measurements was the base of the thumb (the thenar). In a small clinical study, 35 patients with diabetes analyzed their interstitial fluid glucose for a period of 60 days using the new critical-depth Raman (CD-Raman) method and levels were correlated to reference capillary blood glucose values using a standard finger-stick and test strip product. The calibration of the CD-Raman system was stable for > 10 days. Measurement performance for glucose levels present at, or below, a depth of ~250μm below the skin surface was comparable to that reported for currently available invasive continuous glucose monitors. In summary, using the CD-Raman technology we have demonstrated the first successful use of a non-invasive glucose monitor in the home.

Objectives Knowledge about self-perceived health can help us understand the health status and needs among migrants and ethnic minorities in the European Union (EU) which is essential to improve equity and integration. The objective was to examine and compare self-perceived health among migrant and ethnic minority groups in the EU countries. Methods Publications were ascertained by a systematic search of PUBMED and EMBASE. Eligibility of studies was based on the abstracts and the full texts. Additional articles were identified via the references. The final number of studies included was 17. Results Publications were identified in 5 out of the 27 EU countries. In regard to self-perceived health, most migrants and ethnic minority groups appeared to be disadvantaged as compared to the majority population even after controlling for age, gender, and socioeconomic factors. Only limited cross-country comparisons could be carried out, still they revealed a parallel pattern of self-perceived health among similar migrant/ethnic minority groups. Conclusions Policies to improve social and health status, contextual factors, and access to healthcare among migrants and ethnic minorities are essential to reduce ethnic inequalities in health.

Parkinson’s disease (PD) is a progressive neurodegenerative condition. One of the unmet medical needs in PD, are tools for better diagnosis, prognosis, and efficacy of treatment, which reflects the disease course of the individual patient. Alpha-Synuclein (α-Synuclein) is a hallmark of synucleinopathies such as PD, where α-Synuclein aggregates are deposited. Calpain-1 is an enzyme, located in the presynaptic terminal, and shown to be active as an early event related to aggregation of α-Synuclein. The aim of this study was to develop and evaluate a competitive ELISA, targeting a Calpain-1 specific cleavage site of α-Synuclein, named α-Syn-C, and evaluate it in serum from patients diagnosed with PD and comparing to healthy matched donors. A monoclonal antibody was raised against the α-Synuclein fragment generated by cleavage of Calpain-1 and employed in an ELISA assay. The assay was developed, technically evaluated, and quantified in two independent cohorts of patients diagnosed with PD and compared to the healthy donors. The discovery cohort showed α-Syn-C was significantly upregulated in patients with PD compared to healthy donors ( p  =0.0007), with a diagnostic value of AUC = 0.83. The evaluation cohort showed similar results with an ability to differentiate PD patients from healthy donors ( p  < 0.0001) with an AUC = 0.85. These findings are exploratory and hypothesis generating, indicating the α-Syn-C biomarker may be useful in managing PD patients, and needs to be validated in larger cohorts and longitudinal studies.

Patients with chronic kidney disease (CKD) have increased risk of development of end-stage renal disease (ESRD) and early mortality. Fibrosis is the central pathogenic process in CKD and is caused by dysregulated extracellular matrix (ECM) remodeling. The laminin γ1 chain (LAMC1) is a core structural protein present in the basement membrane of several organs, including the kidneys. We hypothesized that dysregulation of LAMC1 remodeling could be associated with a higher risk of adverse clinical outcomes in patients with CKD. A novel immunoassay targeting LG1M, a specific MMP-9-generated neo-epitope fragment of LAMC1, was developed and used to measure the levels of the fragment in urine and serum from 492 patients from the Renal Impairment in Secondary Care (RIISC) study, a prospective cohort of patients with high-risk CKD. Patients were monitored for a median follow-up time of 3.5 years. Associations between serum and urine LG1M levels and progression of CKD at 12 months were assessed by a multivariable logistic regression model. The association with ESRD or mortality was assessed by Kaplan-Meier survival curves and Cox proportional hazards regression. Forty-six (11%) of the 416 patients who reached 12-month follow-up had progression of CKD; during the study follow-up, 125 patients (25.4%) developed ESRD and 71 patients (14.4%) died. Serum and urine levels of LG1M correlated with baseline eGFR (r = -0.43, p<0.0001 and r = -0.17, p = 0.0002, respectively). Serum levels of LG1M were higher in patients with one-year progression of CKD compared to those who did not progress (p<0.01). Baseline serum levels of LG1M were associated with development of ESRD (HR 3.2, 95% CI 1.99-5.2 for patients in the highest LG1M tertile compared to patient in the lowest tertile). Baseline urinary levels of LG1M (uLG1M) were significantly associated with mortality (HR 5.0, 95% CI 2.8-8.9, p<0.0001 for patients in the highest LG1M tertile compared to patients in the lowest tertile). Urine LG1M was retained in the model for prediction of mortality (HR per standard deviation of uLG1M: 1.01, 95% CI 1.00-1.02, p = 0.001). LG1M, a marker of basement membrane remodeling, is increased in serum and urine of patients with CKD and levels are associated with one-year disease progression, development of ESRD, and mortality.

Rheumatic joints have an altered cartilage turnover. Cartilage intermediate layer protein 1 (CILP-1) is secreted from articular chondrocytes and deposited into the cartilage extracellular matrix. We developed an immunoassay targeting a Matrix Metalloproteinase (MMP)-generated neo-epitope of CILP-1, named CILP-M. Human articular cartilage was cleaved with proteolytic enzymes and CILP-M levels were measured. We also quantified CILP-M in two studies from patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and osteoarthritis (OA) and explored the monitoring and prognostic potential of CILP-M in TNF-α inhibitory treatment and modified Stoke AS Spine Score (mSASSS) progression. CILP-M was generated by MMP-1, -8 and -12. In the discovery study, CILP-M was significantly higher in patients with RA, AS and OA than healthy donors (p < 0.01, p < 0.001, p < 0.05) with an area under the curve (AUC) between the diseased groups and healthy donors > 0.95 (p < 0.001). In the validation study, patients with RA and AS had significantly higher CILP-M levels than healthy controls (p < 0.001) and AUC > 0.90 (p < 0.001). Patients with AS treated with TNF- α inhibitory treatment in the validation study had significantly lower CILP-M levels after treatment (p = 0.004). CILP-M may provide useful insights into cartilage degradation processes in rheumatic diseases.

Extracellular matrix (ECM) remodeling of the skin is a continuous process necessary for maintaining tissue homeostasis. Type VI collagen (COL6) is characterized as a beaded filament, located in the dermal ECM, where COL6-α6-chain has been demonstrated upregulated in atopic dermatitis. The aim of this study was to develop and validate a competitive ELISA, targeting the N-terminal of COL6-α6-chain, named C6A6, and evaluate its associations with the dermatological condition’s atopic dermatitis, psoriasis, hidradenitis suppurativa, systemic lupus erythematosus, systemic sclerosis, urticaria, vitiligo, and cutaneous malignant melanoma in comparison, to healthy controls. A monoclonal antibody was raised and employed in an ELISA assay. The assay was developed, technically validated, and evaluated in two independent patient cohorts. Cohort 1 showed C6A6 was significantly elevated in patients with atopic dermatitis ( p  < 0.0001), psoriasis ( p  < 0.0001), hidradenitis suppurativa ( p  = 0.0095), systemic lupus erythematosus ( p  = 0.0032) and melanoma ( p  < 0.0001) compared to healthy donors. Cohort 2 confirmed C6A6 being upregulated in atopic dermatitis compared to healthy controls ( p  < 0.0001), but also associated with disease severity (SCORAD, p  = 0.046) and lowered in patients receiving calcineurin inhibitors ( p  = 0.014). These findings are hypothesis generating, and the utility of the C6A6 biomarker for disease severity and treatment response needs to be validated in larger cohorts and longitudinal studies.

Dupuytren Disease (DD) is a chronic progressive disease that can cause disabling hand deformities. The most common treatments have either high complication rates or high early recurrence rates. Dupuytren lacks a staging biomarker profile to inform the development of preventive therapeutics to improve long-term outcomes. This multi-omic study aimed to create a DD blood proteomic biomarker profile by comparing DD plasma with that of a healthy control group. We measured circulating collagen metabolism peptides and found normal Collagen I synthesis but impaired Collagen I degradation in DD. We measured 6995 serum protein aptamers and identified 68 proteins that showed statistically significant differences compared with the control group. We developed two Diagnostic Proteomic Risk Scores (DPRS) based on hypothesis-free and hypothesis-based analyses. In independent data, our hypothesis-free and hypothesis-based DPRS distinguished Dupuytren from control subjects with accuracies of 76.5% and 70.6%, respectively. Our hypothesis-based DPRS also distinguished DD subjects with different disease progression rates by age at their first corrective procedure (p = 0.0018). This pilot study is the first to provide evidence to suggest that Collagen I accumulation in DD results from impaired degradation rather than increased collagen synthesis. It also describes novel DPRS that have potential use as diagnostic and staging biomarker panels for Dupuytren disease.

Abstract This study aimed to determine the optimal supply of lactation feed during the transition period to minimize farrowing duration (FD) and maximize colostrum yield (CY) and quality with the overall aim of reducing piglet mortality. A total of 48 sows were stratified for body weight and assigned to six levels of feed supply (1.8, 2.4, 3.1, 3.7, 4.3, and 5.0 kg/d) from day 108 of gestation until 24 h after the onset of farrowing. The number of total born, live-born, and stillborn piglets; birth time and birth weight of each piglet; and frequency of farrowing assistance (FA) was recorded, and blood samples were obtained from newborn piglets at birth. Live-born piglets were further weighed at 12 and 24 h after birth to record weight gain, which in turn was used to estimate intake and yield of colostrum. Colostrum samples were collected at 0, 12, 24, and 36 h after the onset of farrowing. FD was shortest (4.2 h) at intermediate (3.7 kg/d), longest (7.1 to 7.6 h) at low (1.8 and 2.4 kg/d), and intermediate (5.6 to 5.7 h) at high (4.3 and 5.0 kg/d) feed intake (P = 0.004; mean comparison). FA was lowest (0.7% to 0.8%) at intermediate feed intake (3.7 and 4.3 kg/d) and substantially elevated (4.3% to 4.7%) at both lower and higher feed intake (P = 0.01; mean comparison). The cubic contrast revealed 4.1 kg/d as the optimal feed intake to achieve the shortest FD and to minimize FA. Newborn piglets from second-parity sows were less vital than piglets from gilts as evaluated by blood biochemical variables immediately after birth. CY was greatest at 3.1 kg/d (P = 0.04), whereas the cubic contrast revealed 3.0 kg/d as the optimal feed intake to maximize CY. Concentrations of colostral components were affected by the diet, parity, and their interaction except for lactose concentrations. In conclusion, the study demonstrated the importance of proper feed level during the transition period on sow productivity. Moreover, this study estimated 4.1 and 3.0 kg/d as the optimal feed intake during the transition period to improve farrowing characteristic and CY, respectively, and these two feed intake levels supplied daily 38.8 MJ metabolizable energy (ME) and 23.9 g standardized ileal digestible (SID) lysine (3.0 kg/d) or 53.0 MJ ME and 32.7 g SID lysine (4.1 kg/d). The discrepancy of optimal feed intake for optimal farrowing and colostrum performance suggests that it may be advantageous to lower dietary lysine concentration in the diet fed prepartum.

Achromobacter species are increasingly isolated from the respiratory tract of cystic fibrosis patients and often a chronic infection is established. How Achromobacter sp. adapts to the human host remains uncharacterised. By comparing longitudinally collected isolates of Achromobacter sp. isolated from five CF patients, we have investigated the within-host evolution of clonal lineages. The majority of identified mutations were isolate-specific suggesting co-evolution of several subpopulations from the original infecting isolate. The largest proportion of mutated genes were involved in the general metabolism of the bacterium, but genes involved in virulence and antimicrobial resistance were also affected. A number of virulence genes required for initiation of acute infection were selected against, e.g. genes of the type I and type III secretion systems and genes related to pilus and flagellum formation or function. Six antimicrobial resistance genes or their regulatory genes were mutated, including large deletions affecting the repressor genes of an RND-family efflux pump and a beta-lactamase. Convergent evolution was observed for five genes that were all implicated in bacterial virulence. Characterisation of genes involved in adaptation of Achromobacter to the human host is required for understanding the pathogen-host interaction and facilitate design of future therapeutic interventions.

Abstract Context Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents. Objective This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders. Participants Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document. Evidence Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available. Conclusion Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks.