Enhancing casein micelle dissociation in diluted skim milk systems using combined processing techniques.

The present work aims to evaluate the dissociation of casein micelles in diluted skim milk (SM) systems after undergoing solvent- or emulsifying salt-based dissociation coupled with ultra-high-pressure homogenization (UHPH). Specifically, Part I evaluated dilute SM solutions combined with varying ethanol concentrations (0- 60%) at varying temperatures (5 - 65°C) in combination with UHPH (100-300 MPa), and Part II evaluated dilute SM solutions combined with varying concentrations (0-100 mM) of either sodium hexametaphosphate (SHMP) or sodium citrate (SC) in combination with UHPH (100-300 MPa). In Part I, high concentrations of ethanol (40-60% vol/vol) at elevated temperatures (45-65°C) achieved extensive dissociation of casein micelles, especially in combination with UHPH at ≥200 MPa, as shown by an ca. 6-fold reduction in sample absorbance and an ca. 3-fold reduction in casein particle size compared with the control (ca. dilute SM, 65°C) under optimum conditions (dilute SM, 60% ethanol, 65°C, ≥ 200 MPa). In Part II, the level of casein micelle dissociation using emulsifying salts (ES) was dependent on the ES type and concentration. Considerable casein micelle dissociation in dilute SM systems was achieved with SHMP concentrations ≥1 mM and SC concentrations ≥10 mM, resulting in decreased sample absorbance (>6-fold decrease in absorbance), bimodal casein size distributions, and increased hydrophobicity (ca. 2-fold increase in intrinsic fluorescence) compared with the control (dilute SM). This dissociation was further enhanced with UHPH (≥200 MPa). These results indicate that both solvent- and ES-based casein dissociation techniques can be optimized when used in combination with UHPH. Together, these processing techniques can be used to extensively dissociate casein micelles with the potential to use these altered systems for value-added applications such as functional ingredients or encapsulation agents.

WHOLE GENOME TARGETED ENRICHMENT AND SEQUENCING OF HUMAN-INFECTING CRYPTOSPORIDIUM spp.

Cryptosporidium spp. are protozoan parasites that cause severe illness in vulnerable human populations. Obtaining pure Cryptosporidium DNA from clinical and environmental samples is challenging because the oocysts shed in contaminated feces are limited in quantity, difficult to purify efficiently, may derive from multiple species, and yield limited DNA (<40 fg/oocyst). Here, we develop and validate a set of 100,000 RNA baits (CryptoCap_100k) based on six human-infecting Cryptosporidium spp. (C. cuniculus, C. hominis, C. meleagridis, C. parvum, C. tyzzeri, and C. viatorum) to enrich Cryptosporidium spp. DNA from a wide array of samples. We demonstrate that CryptoCap_100k increases the percentage of reads mapping to target Cryptosporidium references in a wide variety of scenarios, increasing the depth and breadth of genome coverage, facilitating increased accuracy of detecting and analyzing species within a given sample, while simultaneously decreasing costs, thereby opening new opportunities to understand the complex biology of these important pathogens.

WHOLE GENOME TARGETED ENRICHMENT AND SEQUENCING OF HUMAN-INFECTING CRYPTOSPORIDIUM spp.

Cryptosporidium spp. are protozoan parasites that cause severe illness in vulnerable human populations. Obtaining pure Cryptosporidium DNA from clinical and environmental samples is challenging because the oocysts shed in contaminated feces are limited in quantity, difficult to purify efficiently, may derive from multiple species, and yield limited DNA (<40 fg/oocyst). Here, we develop and validate a set of 100,000 RNA baits (CryptoCap_100k) based on six human-infecting Cryptosporidium spp. ( C. cuniculus , C. hominis , C. meleagridis , C. parvum , C. tyzzeri , and C. viatorum ) to enrich Cryptosporidium spp. DNA from a wide array of samples. We demonstrate that CryptoCap_100k increases the percentage of reads mapping to target Cryptosporidium references in a wide variety of scenarios, increasing the depth and breadth of genome coverage, facilitating increased accuracy of detecting and analyzing species within a given sample, while simultaneously decreasing costs, thereby opening new opportunities to understand the complex biology of these important pathogens.

Pain trajectories and neuropathic pain symptoms following lung cancer surgery: A prospective cohort study.

BACKGROUND: Persistent postsurgical pain (PPSP) after lung cancer surgery is common and current definitions are based on evaluations at a single time point after surgery. Pain intensity and symptoms may however fluctuate and change over time, and be impacted by multiple and shifting factors. Studies of postoperative recovery patterns and transition from acute to chronic pain are needed for further investigation of preventive measures and treatments to modify unfavourable recovery paths. METHODS: In this explorative study, 85 patients undergoing surgery due to either presumptive or confirmed lung cancer reported pain intensities bi-monthly for 12 months. Pain trajectories during recovery were investigated, using group-based trajectory modelling. Associations with possible risk factors for PPSP, including clinical variables and anxiety and depression score (HADS), were also explored. RESULTS: A trajectory model containing three 12-month pain recovery groups was computed. One group without PPSP fully recovered (50%) within two to three months. Another group with mild-intensity PPSP followed a protracted recovery trajectory (37%), while incomplete recovery was observed in the last group (13%). Acute postoperative pain and younger age were associated with a less favourable recovery trajectory. More neuropathic pain symptoms were observed in patients with incomplete recovery. CONCLUSIONS: Three clinically relevant recovery trajectories were identified, based on comprehensive pain tracking. Higher acute postoperative pain intensity was associated with an unfavourable pain recovery trajectory. SIGNIFICANCE STATEMENT: Understanding the transition from acute to chronic postoperative pain and identifying preoperative risk factors is essential for the development of targeted treatments and the implementation of preventive measures. This study (1) identified distinct recovery trajectories based on frequent pain assessment follow-ups for 12 months after surgery and (2) evaluated risk factors for unfavourable postoperative pain recovery paths. Findings suggest that early higher postoperative pain intensity is associated with an unfavourable long-term recovery path.

Occupational risk of COVID-19 in foreign-born employees in Denmark.

BACKGROUND: Foreign-born workers in high-income countries experience higher rates of COVID-19 but the causes are only partially known. AIMS: To examine if the occupational risk of COVID-19 in foreign-born workers deviates from the risk in native-born employees in Denmark. METHODS: Within a registry-based cohort of all residents employed in Denmark (n = 2 451 542), we identified four-digit DISCO-08 occupations associated with an increased incidence of COVID-19-related hospital admission during 2020-21 (at-risk occupations). The sex-specific prevalence of at-risk employment in foreign born was compared with the prevalence in native born. Moreover, we examined if the country of birth modified the risk of a positive SARS-CoV-2 polymerase chain reaction (PCR) test and COVID-19-related hospital admission in at-risk occupations. RESULTS: Workers born in low-income countries and male workers from Eastern Europe more often worked in at-risk occupations (relative risks between 1.16 [95% confidence interval {CI} 1.14-1.17] and 1.87 [95% CI 1.82-1.90]). Being foreign-born modified the adjusted risk of PCR test positivity (test for interaction P < 0.0001), primarily because of higher risk in at-risk occupations among men born in Eastern European countries (incidence rate ratio [IRR] 2.39 [95% CI 2.09-2.72] versus IRR 1.19 [95% CI 1.14-1.23] in native-born men). For COVID-19-related hospital admission, no overall interaction was seen, and in women, country of birth did not consistently modify the occupational risk. CONCLUSIONS: Workplace viral transmission may contribute to an excess risk of COVID-19 in male workers born in Eastern Europe, but most foreign-born employees in at-risk occupations seem not to be at higher occupational risk than native born.

Quantitative sensory testing, psychological profiles and clinical pain in patients with psoriatic arthritis and hand osteoarthritis experiencing pain of at least moderate intensity.

BACKGROUND: Chronic pain is the hallmark symptom of joint diseases. This study examined the differences in quantitative sensory testing between patients with psoriatic arthritis (PsA), hand osteoarthritis (hand-OA) and a pain-free control group and differences between patients with and without concomitant fibromyalgia (cFM). METHODS: All patients and pain-free controls were assessed using pressure pain thresholds (PPT), temporal summation of pain (TSP), conditioned pain modulation (CPM) and clinical pain intensities. Psychological distress was assessed with the Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, and Pittsburgh Sleep Quality Index. Disability was assessed with the Health Assessment Questionnaire and pain quality with the painDETECT questionnaire. cFM was identified using the revised 2016 American College of Rheumatology diagnostic criteria. RESULTS: Patients with hand-OA (n = 75) or PsA (n = 58) had statistically significant lower PPTs and CPM, greater TSP, and higher scores of psychological distress (p < 0.05) than controls (n = 20). Patients with cFM (58%) had higher scores of depression (p = 0.001), anxiety (p = 0.004), catastrophizing (p = 0.012), disability (p < 0.001), higher painDETECT score (p = 0.001), TSP (p = 0.027), and reduced sleep quality (p = 0.021) when compared to patients without cFM. CONCLUSION: Patients with hand-OA and PsA exhibited signs of pain sensitization and a higher degree of psychological distress and disability than pain-free individuals. Patients with cFM had greater TSP, painDETECT score, disability, catastrophizing, and reduced sleep quality, than patients without, indicating greater degree of pain sensitization, psychological burden, and disability. STATEMENT OF SIGNIFICANCE: This paper shows that a significant proportion of patients with hand osteoarthritis and psoriatic arthritis with moderate pain intensity have significantly increased signs of pain sensitization and markers of psychological distress. A large proportion of these patients fulfil the criteria for concomitant fibromyalgia and these patients show even greater propensity towards pain sensitization and psychological distress.

Investigating biodiversity patterns across scales in freshwater mussels.

Hypotheses relating genomic diversity to community attributes such as abundance and species diversity attract attention from a wide and varied audience because their applications are twofold. First, testing such hypotheses can further a theoretical-and hopefully generalizable-understanding of the forces that assemble communities and create observed patterns of biodiversity. Second, relationships that hold true could ease the burden of data collection for conservation or other urgent applications; for example, a strong correlation between species diversity and genetic diversity could make it possible to use one as a proxy for the other, and focus limited resources on measuring the easier of the two without sacrificing information gained. In a From the Cover article in this issue of Molecular Ecology, Bucholz et al. (2023) explore the relationships between within-species genomic diversity, community relative abundance and community species richness, testing three types of ecological hypotheses in the freshwater mussel communities of the southeastern United States. They find positive relationships between mussel density and species richness, and between genomic diversity within a species and density of that species, but no robust support for the expectation of correlated genomic and species diversity. Their analyses highlight the among-species variability in relationships among these different levels of organization and also the complex ways in which interactions with the broader ecosystem (i.e. unionid mussels require fish hosts for maturation) affect these quantitative relationships, nonetheless pushing forward into the important frontier of community-wide genomic assessment for theoretical and conservation applications.

An integrated biological effects assessment of the discharge water into the Sunndalsfjord from an aluminium smelter.

An integrated biological effects study using field transplanted mussels was applied to determine the potential biological effects of an effluent discharge from an aluminium smelter into a Norwegian fjord. Chemical body burden and biological effects were measured in mussels positioned downstream (1, 2, 5, 10 and 20 km) from the aluminium smelters discharge for a period of 6 weeks. A suite of biomarkers, from whole organism to subcellular responses were measured. Chemical concentrations in mussel tissues were low; however, a change in the PAC (polyaromatic compound) profile from high to low pyrogenic influence provided evidence of exposure to the smelter's effluent. Overall, the biological responses observed where greater in the mussels positioned closest to the smelter (1-5 km). Lowest chemical accumulation and biomarker responses were observed in mussels positioned 10 km from the smelter and were considered as the reference field population. Mussels located furthest from the smelter (20 km) exhibited significant biomarker responses and suggested a different contaminant source within the fjord. The integrated biological response index (IBR) was applied and reflected the expected level of exposure to the smelters discharge, with highest IBR calculated in mussels positioned closest to the discharge (1-5 km). Principal component analysis (PCA) also differentiated among mussel groups, with the most impacted located closest to the smelter. Not one chemical factor could explain the biological responses observed in mussels, but the presence of PAH16, PAH41 and metals Mn, Ni and Cr were the main contributors measured to the higher stress seen in the mussels from the 1 and 5 km groups.

Investigation of pain sensitivity following 3 nights of disrupted sleep in healthy individuals.

BACKGROUND: Poor quality sleep is a common complaint among people with chronic pain. The co-occurrence of poor sleep quality and chronic pain often comes with increased pain intensity, more disability and a higher cost of healthcare. Poor sleep has been suggested to affect measures of peripheral and central pain mechanisms. To date, sleep provocations are the only models proven to affect measures of central pain mechanisms in healthy subjects. However, there are limited studies investigating the effect of several nights of sleep disruption on measures of central pain mechanisms. METHODS: The current study implemented three nights of sleep disruption with three planned awakenings per night in 30 healthy subjects sleeping at home. Pain testing was conducted at the same time of day at baseline and follow-up for each subject. Pressure pain thresholds were assessed bilaterally on the infraspinatus and gastrocnemius muscles. Using handheld pressure algometry, suprathreshold pressure pain sensitivity and area were also investigated on the dominant infraspinatus muscle. Cuff-pressure pain detection and tolerance thresholds, temporal summation of pain and conditioned pain modulation were investigated using cuff-pressure algometry. RESULTS: Temporal summation of pain was significantly facilitated (p = 0.022), suprathreshold pain areas (p = 0.005) and intensities (p < 0.05) were significantly increased, and all pressure pain thresholds were decreased (p < 0.005) after sleep disruption compared to baseline. CONCLUSIONS: The current study found that three consecutive nights of sleep disruption at home induced pressure hyperalgesia and increased measures of pain facilitation in healthy subjects, which is consistent with previous findings. SIGNIFICANCE: Poor quality of sleep is often experienced by patients with chronic pain, with the most common complaint being nightly awakenings. This exploratory study is the first to investigate changes in measures of central and peripheral pain sensitivity in healthy subjects after sleep disruptions for three consecutive nights without any restrictions on total sleep time. The findings suggest that disruptions to sleep continuity in healthy individuals can induce increased sensitivity to measures of central and peripheral pain sensitization.

Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer's Disease.

OBJECTIVE: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship. METHODS: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of ß-amyloid (Aß42/Aß40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status. RESULTS: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aß42/Aß40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample. CONCLUSION: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology.

Increased synovial galectin-3 induce inflammatory fibroblast activation and osteoclastogenesis in patients with rheumatoid arthritis.

OBJECTIVE: Galectin-3 (Gal-3) has been suggested as a proinflammatory mediator in rheumatoid arthritis (RA). We aimed to study clinical and pathogenic aspects of Gal-3 in RA. METHOD: Plasma samples from healthy controls (n = 48) and patients with newly diagnosed, early RA were assayed for soluble Gal-3. In patients with chronic RA (n = 18), Gal-3 was measured in both plasma and synovial fluid. Synovial fluid mononuclear cells were used to purify fibroblast-like synoviocytes (FLSs) and osteoclasts. Monocultures of FLSs and autologous co-cultures of FLSs and peripheral blood mononuclear cells were established and co-incubated with a Gal-3 inhibitor. RESULTS: Patients with early and chronic RA had persistently increased plasma levels of Gal-3 compared with controls. However, changes in plasma Gal-3 at the level of individuals were associated with long-term disease activity. In seropositive early RA patients, all patients with decreasing plasma Gal-3 from 0 to 3 months had low disease activity after 2 years (p < 0.05). Gal-3 levels in synovial fluid were markedly elevated. In vitro, co-incubation with a Gal-3 inhibitor (GB1107, 10 µM) led to a significant reduction in both interleukin-1ß and tumour necrosis factor-α secretion from FLS monocultures (both p < 0.05) and decreased monocyte-derived osteoclastogenesis compared with controls (both p < 0.05). CONCLUSIONS: Our findings underscore the role of Gal-3 regarding disease activity and tissue destruction in RA. An initial decrease in plasma Gal-3 levels predicted decreased long-term disease activity. Correspondingly, a Gal-3 inhibitor decreased the activity of inflammatory FLSs and osteoclastogenesis in patients with RA.

Serum 14-3-3η as predictor of clinical remission and progression of structural damage in early rheumatoid arthritis following a treat-to-target strategy in a randomized controlled trial.

OBJECTIVE: 14-3-3η is a proinflammatory mediator critical to joint destruction in rheumatoid arthritis (RA). We aimed to evaluate serum 14-3-3η for predicting disease activity and radiographic progression in patients with early RA in the double-blinded, randomized OPERA trial. METHOD: 180 patients with early RA were randomized to receive methotrexate (MTX) + adalimumab or MTX + placebo in combination with glucocorticoid injections into swollen joints. Disease activity was measured using the 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP). Clinical remission was defined as DAS28-CRP < 2.6. X-rays of hands and feet were evaluated by the Total Sharp van der Heijde score (TSS). Radiographic progression was defined as exceeding the smallest detectable change (1.8 TSS-units). Serum 14-3-3η was determined by enzyme-linked immunosorbent assay. Multivariate logistic regression models were used to identify predictors of DAS28-CRP remission at 6 months and radiographic progression at 12 months. RESULTS: Baseline 14-3-3η was a borderline significant independent predictor of radiographic progression at 12 months (odds radio = 1.02, 95% confidence interval 1.00-1.03, p = 0.05). In anti-cyclic citrullinated peptide antibody (ACPA)-negative patients, a moderate/high baseline 14-3-3η concentration increased the risk of radiographic progression at 12 months [4/51 (8%) vs 3/9 (33%), χ2 = 4.823, p = 0.028]. No value of 14-3-3η for predicting achievement of clinical remission was found. CONCLUSION: Serum 14-3-3η was a borderline significant predictor of radiographic progression, particularly in ACPA-negative patients, but not of predicting achievement of clinical remission. Optimal cut-off levels of 14-3-3η for predicting radiographic progression in RA need further clarification.

Baseline serum levels of IgA anti-cyclic citrullinated protein antibodies in early rheumatoid arthritis predict radiographic progression after 11 years of treatment: a secondary analysis of the CIMESTRA study.

OBJECTIVE: Smoking and periodontitis are risk factors for developing rheumatoid arthritis (RA), suggesting a break of tolerance on mucosal surfaces. Immunoglobulin A (IgA) antibodies are part of the mucosal immune system. The dominant autoantibodies in RA are anti-cyclic citrullinated protein antibodies (ACPAs), and IgG and IgA subclasses exist simultaneously. This study aimed to investigate the association of ACPA IgA subtypes with disease activity and long-term radiographic outcomes in RA, compared with ACPA IgG. METHOD: Total ACPA IgG, IgA, IgA1, and IgA2 were quantified in serum from patients with early RA (n = 97). Patient characteristics, IgM rheumatoid factor (IgM-RF) status, clinical and biochemical disease activity scores, and radiographic status evaluated by total Sharp score (TSS), were assessed at baseline and after 2 and 11 years of treatment. RESULTS: All patients with ACPA IgA also had ACPA IgG. ACPA IgA positivity was associated with IgM-RF and male gender. Both ACPA IgA and IgG levels at baseline were weakly associated with disease activity markers. Baseline ACPA IgA and IgG did not show a linear correlation with radiographic status after 10 years, but could predict radiographic progression (ΔTSS ≥ 5 from 0 to 11 years), with positive likelihood ratios of 3.7 and 4.0, respectively. CONCLUSION: ACPA IgA and IgG were weakly associated with disease activity in early RA. RA patients with a ΔTSS ≥ 5 after 11 years of treatment had higher ACPA IgG and ACPA IgA levels at baseline; however, none of the ACPA subtypes was superior in predicting long-term radiographic progression.

Prenatal exposure to airborne polychlorinated biphenyl congeners and male reproductive health.

STUDY QUESTION: Is fetal exposure to lower-chlorinated polychlorinated biphenyls (LC-PCBs) in indoor air of private homes built with PCB-containing materials associated with semen characteristics and testicular volume in adult men? SUMMARY ANSWER: We observed only marginal and inconsistent associations between maternal exposure to PCBs in indoor air and semen quality, testicular size and reproductive hormones in the adult offspring. WHAT IS KNOWN ALREADY: Recent studies have shown LC-PCBs to exhibit endocrine-disrupting properties and increase the risk of cryptorchidism. Although exposure to LC-PCBs in indoor air is relatively common, the long-term impact of prenatal exposure on male reproductive health has not yet been investigated. STUDY DESIGN, SIZE, DURATION: In this cohort study, participants were men (18+ years) whose mothers carried them while living in one of two residential areas where indoor air had been contaminated by LC-PCB evaporating from building materials in subsets of the apartments. Men were considered prenatally exposed if their mother had lived in a PCB-contaminated apartment and unexposed if their mother had lived in an uncontaminated apartment for a minimum of 1 year during the 3.6 years before conception or during the first trimester. Mothers of prenatally unexposed men could not have lived in a contaminated apartment at any point. Recruitment lasted from 2017 to 2019. In total, 73 exposed and 111 unexposed men gave a blood and semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Percentage differences in semen volume, sperm concentration, total sperm count, morphologically normal spermatozoa, progressively motile spermatozoa and DNA fragmentation index (DFI) between prenatally exposed and unexposed men were estimated using negative binomial regression. Associations with total and calculated free testosterone (CFT), LH and FSH were modeled using the linear regression. Odds of small testicular volume was estimated with logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, the results of this study were conflicting. No differences in semen volume, sperm concentration, testosterone and CFT were observed between the groups, but there were slight indications of lower total sperm count, increased FSH and risk of small testicles, alongside lower sperm DFI and a higher proportion of normal spermatozoa in men exposed to LCB-PCBs from indoor air during fetal life. There is no apparent biologically plausible explanation for the apparently improved measures of DNA fragmentation and morphology, and these findings may have occurred purely by chance. LIMITATIONS, REASONS FOR CAUTION: Owing to the indirect measure of exposure, lack of adjustment for paternal factors, the potential for self-selection due to known exposure status and fertility issues, inability to take time spent away from the residence, limited statistical power and lack of comparable literature, independent replication of the study in larger cohorts is warranted. WIDER IMPLICATIONS OF THE FINDINGS: While our findings may appear reassuring for the large number of people residing and/or working in buildings with indoor air contaminated with LC-PCBs, further efforts to understand the full range of health consequences of fetal LC-PCB exposure are needed. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Independent Research Fund Denmark (ref no. 6110-00085B), Bispebjerg Hospital, Landsbyggefonden, Realdania (ref. no. PRJ-2017-00176), Grundejernes Investeringsfond (ref. no. 18-58) and Helsefonden (ref. no. 16-B-01-22 and 21-B-0412). K.S.H. was supported by FFIKA, Focused Research Effort on Chemicals in the Working Environment, from the Danish Government. The authors declare that they have no financial, personal or professional competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Effect of initiating biologics compared to intensifying conventional DMARDs on clinical and MRI outcomes in established rheumatoid arthritis patients in clinical remission: Secondary analyses of the IMAGINE-RA trial.

OBJECTIVES: To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission. METHOD: One-hundred patients with established RA, Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP) < 3.2, and no swollen joints (hereafter referred to as 'in clinical remission') who received csDMARDs underwent clinical evaluation and MRI of the wrist and second to fifth metacarpophalangeal joints every 4 months. They followed a 2 year MRI treatment strategy targeting DAS28-CRP ≤ 3.2, no swollen joints, and absence of MRI osteitis, with predefined algorithmic treatment escalation: first: increase in csDMARDs; second: adding a biologic; third: switch biologic. MRI osteitis and Health Assessment Questionnaire (HAQ) (co-primary outcomes) and MRI combined inflammation and Simplified Disease Activity Index (SDAI) (key secondary outcomes) were assessed 4 months after treatment change and expressed as estimates of group differences. Statistical analyses were based on the intention-to-treat population analysed using repeated-measures mixed models. RESULTS: Escalation to first biologic compared to csDMARD escalation more effectively reduced MRI osteitis (difference between least squares means 1.8, 95% confidence interval 1.0-2.6), HAQ score (0.08, 0.03-0.1), MRI combined inflammation (2.5, 0.9-4.1), and SDAI scores (2.7, 1.9-3.5). CONCLUSIONS: Treat-to-target-based treatment escalations to biologics compared to escalation in csDMARDs more effectively improved MRI inflammation, physical function, and clinical disease activity in patients with established RA in clinical remission. Treatment escalation in RA patients in clinical remission reduces clinical and MRI-assessed disease activity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01656278.

No difference in antidepressant prescription in rheumatoid arthritis and controls. Results from a population-based, matched inception cohort.

OBJECTIVE: Depression occurs at least two times more often in rheumatoid arthritis (RA) patients than in controls, but little is known about the treatment of depression in RA. The primary objective of this study was to compare the 1 year period prevalence of antidepressant prescription in patients with RA versus controls. METHOD: We included a retrospective inception cohort of 509 patients with incident RA and 2545 frequency-matched population controls ascertained from 1995 to 2002. The cohort was followed until 31 December 2017 and linked with nationwide Danish registers. From the Danish National Prescription Register, we obtained information on redeemed prescriptions of antidepressants (Anatomical Therapeutic Chemical code N06A). RESULTS: We did not demonstrate significant differences in the 1 year period prevalence ratios and the incidence rate ratios for either antidepressant prescription or the frequency of hospital admissions with depressive episode. The most frequent indication for antidepressant prescription in patients with RA was depression. Cox regression analyses showed no association between RA and antidepressant prescription. CONCLUSION: We found no significant differences in the occurrence of antidepressant prescription in patients with RA versus matched controls. The main indication for antidepressant prescription in RA was depression.

"To have and then lose the safety net" - Female cancer survivors' experiences of the process of becoming ready to return to work.

BACKGROUND: Validation studies have not been able to confirm the stage-specific understanding as operationalised in the readiness for return to work (RRTW) questionnaire. OBJECTIVE: To explore retrospectively how working female cancer survivors experienced the process of becoming ready to RTW during and beyond participation in an occupational rehabilitation intervention and thereby expand the understanding of the RRTW construct. METHODS: A qualitative research design was employed. Thirteen female cancer survivors were included for semi-structured interviews one to two years after they had completed active treatment and returned to work. The RRTW construct guided data generation and analysis. Content analysis was performed in four analytical steps that combined a concept-driven and a data-driven analytic strategy. RESULTS: Three themes were identified; "To have and then lose the safety net", "Realise a changed life situation", "Strive to balance work and everyday life". In a time span of approximately one to two years (from receiving treatment, being enrolled in an intervention and to gradually returning to work); the identified themes were interdependent of each other as one theme gradually evolved to the next theme in the process of engaging in sustained work participation. CONCLUSIONS: The present study points towards continuous development of the RRTW construct and whether the addition of a preparedness dimension would improve validity.

Necessary duration of follow-up to assess complications of mesh in hernia surgery: a time-lapse study based on 460 explants.

PURPOSE: Risk of complications following hernia repair is the key parameter to assess risk/benefit ratio of a technique. As mesh devices are permanent, their risks are life-long. Too many reports in the past assessed mesh safety prematurely after short follow-ups. We aimed to explore what length of follow up would reveal the full extent of complications. METHODS: Time lapses between implantation and excision were analyzed in 460 cases of meshes excised for complications after hernia repair. Patterns of percentage growth and time lapses at 50th and 95th percentiles were used to compare groups of different hernia type, age, gender and reason for excision. RESULTS: The 50th and 95th case percentiles in the dataset were at 3.75 and 15.0 years between mesh implantation and excision. For hernia types, the longest time lapses were for groin hernias (4.0 and 16.11 years at 50th and 95th percentiles). The shortest were for umbilical hernias (2.16 and 9.68 years). Males had later excisions than females (4.11 and 16.1 vs. 2.47 and 9.79 years). Younger patients (< 45 y.o.) had later excisions than older patients (4.12 and 17.68 vs. 3.37 and 10.0 years). Out of all subgroups, the longest time lapses were for groin hernias in younger males (4.77 and 18.89 years) and for mesh erosion into organs (4.67 and 17.0 years). CONCLUSIONS: Follow-up of more than 15 years is needed to fully assess complications after mesh hernia repair. Especially longer periods are needed to detect mesh erosion into organs and complications in younger males. Presently, short observations and lack of reporting standard in the literature prohibit accurate assessment of complication risks. We propose to use cumulative incidence for standardized risk reporting (y% risk at x years). This will show time-dependent patterns and allow comparisons between different techniques and studies of variable duration. Standardization will also help to predict long-term risks beyond shorter (practical) follow-ups and facilitate real-time monitoring during surveillance.

Developmental stage and morphology of the competent blastocyst are associated with sex of the child but not with other obstetric outcomes: a multicenter cohort study.

STUDY QUESTION: Are transfer day, developmental stage and morphology of the competent blastocyst in pregnancies leading to live birth associated with preterm birth, birthweight, length at birth and sex of the child? SUMMARY ANSWER: A high score in blastocyst developmental stage and in trophectoderm (TE) showed a significant association with the sex of the child, while no other associations with obstetric outcomes were observed. WHAT IS KNOWN ALREADY: The association between blastocyst assessment scores and obstetric outcomes have been reported in small single-center studies and the results are conflicting. STUDY DESIGN, SIZE, DURATION: Multicenter historical cohort study based on exposure data (transfer day (blastocyst developmental stage reached by Day 5 or Day 6)) blastocyst developmental stage (1-6) and morphology (TE and inner cell mass (ICM): A, B, C)) and outcome data (preterm birth, birthweight, length at birth, and sex of the child) from women undergoing single blastocyst transfer resulting in a singleton pregnancy and live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from 16 private and university-based facilities for clinical services and research were used. A total of 7246 women, who in 2014-2018 underwent fresh-embryo transfer with a single blastocyst or frozen-thawed embryo transfer (FET) with a single blastocyst resulting in a singleton pregnancy were identified. Linking to the Danish Medical Birth Registry resulted in a total of 4842 women with a live birth being included. Cycles with pre-implantation genetic testing and donated gametes were excluded. The analyses were adjusted for female age (n = 4842), female BMI (n = 4302), female smoking (n = 4290), parity (n = 4365), infertility diagnosis (n = 4765), type of treatment (n = 4842) and center (n = 4842); some analyses additionally included gestational age (n = 4368) and sex of the child (n = 4833). MAIN RESULTS AND THE ROLE OF CHANCE: No statistically significant associations between blastocyst assessment scores (transfer day, developmental stage, TE, ICM) and preterm birth (8.3%) or birthweight (mean 3461.7 g) were found. The adjusted association between blastocysts with a TE score of C and a TE score of A and length at birth (mean 51.6 cm) were statistically significant (adjusted mean difference 0.4 cm (95% CI: 0.02; 0.77)). Blastocysts transferred with developmental stage score 5 compared to blastocysts transferred with score 3 had a 34% increased probability of being a boy (odds ratio (OR) 1.34 (95% CI: 1.09; 1.64). Further, TE score B blastocysts compared to TE score A blastocysts had a 31% reduced probability of being a boy (OR 0.69 (95% CI: 0.60; 0.80)). LIMITATIONS, REASONS FOR CAUTION: It is possible that some residual confounding remains. WIDER IMPLICATIONS OF THE FINDINGS: Blastocyst selection during ART does not appear to introduce any negative effects on obstetric outcome. Therefore, clinicians and patients can be reassured that the assessment scores of the selected blastocyst will not in themselves pose a risk of preterm birth or affect birthweight and the length at birth. STUDY FUNDING/COMPETING INTEREST(S): Unrestricted grant from Gedeon Richter Nordics AB, Sweden. None of the authors have any competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Women's perceptions of fertility assessment and counselling 6 years after attending a Fertility Assessment and Counselling clinic in Denmark.

STUDY QUESTION: What are women's perceptions and experience of fertility assessment and counselling 6 years after attending a Fertility Assessment and Counselling (FAC) clinic in Denmark? SUMMARY ANSWER: Women viewed the personalized fertility knowledge and advice they received as important aids to decision-making and they felt the benefits outweighed the risks of receiving personalized fertility information. WHAT IS KNOWN ALREADY: Many young people wish to become parents in the future. However, research demonstrates there is a gap in women's and men's knowledge of fertility and suggests they may be making fertility decisions based on inaccurate information. Experts have called for the development of interventions to increase fertility awareness so that men and women can make informed fertility decisions and achieve their family-building goals. Since 2011, the FAC clinic in Copenhagen, Denmark has provided personalized fertility assessment and guidance based on clinical examination and evaluation of individual risk factors. Available qualitative research showed that attending the FAC clinic increased fertility awareness and knowledge and was experienced as a catalyst for change (e.g. starting to conceive, pursuing fertility treatment, ending a relationship) in women 1-year post-consultation. STUDY DESIGN SIZE DURATION: The study was a 6-year follow-up qualitative study of 24 women who attended the FAC clinic between January and June 2012. All women were interviewed during a 2-month period from February to March 2018 at Rigshospitalet, their home or office, in Copenhagen, Denmark. Interviews were held in English and ranged between 60 and 94 min (mean 73 min). PARTICIPANTS/MATERIALS SETTING METHODS: Invitations to participate in an interview-based follow-up study were sent to 141 women who attended the FAC clinic in 2012. In total, 95 women read the invitation, 35 confirmed interest in participating and 16 declined to participate. Twenty-five interviews were booked and 24 interviews held. Interviews followed a semi-structured format regarding reasons for attending the FAC clinic, if/how their needs were met, and perceptions of fertility assessment and counselling. Data were analysed using thematic analysis. MAIN RESULTS AND THE ROLE OF CHANCE: At the follow-up interview, women were on average 39.5 years old. Ten were currently single or dating and 14 were married/cohabiting. All were childless when they attended the FAC clinic. At the follow-up interview, 21 women were parents (14 women with one child; 6 with two children; 1 with three children) and the remaining three women intended to have children in the future. The most common reason for originally attending the FAC clinic was to determine how long they could delay childbearing. Most of the women now believed their needs for attending had been met. Those who were dissatisfied cited a desire for more exact ('concrete') information as to their remaining years of fertility, although acknowledged that this was likely not realistic. Women stated that they had felt reassured as to their fertility status after attending the FAC clinic whilst receiving the message that they could not delay childbearing 'too long'. Women viewed personalized fertility knowledge as an important aid to decision-making but cautioned about developing a false sense of security about their fertility and chance of conceiving in the future based on the results. Although women were generally satisfied with their experience, they wished for more time to discuss options and to receive additional guidance after their initial meeting at the FAC clinic. LIMITATIONS REASONS FOR CAUTION: Participants were from a group of Danish women attending the FAC clinic and interviews were conducted in English, which means they are not representative of all reproductive-aged women. Nevertheless, the study group included a broad spectrum of women who achieved parenthood through different means (heterosexual/lesbian relationship, single parent with donor, co-parent) with various family sizes, and women who were currently childless. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides support for an individualized approach to fertility education, assessment and counselling provided at a time when the information is relevant to the individual and their current fertility decision-making. The findings suggest that although satisfied with their visit to the FAC clinic, the women wished for more information and guidance after this visit, suggesting that the current intervention may need to be expanded or new interventions developed to meet these additional needs. STUDY FUNDING/COMPETING INTERESTS: E.K. was funded by an ESHRE Travel/Training grant by ReproUnion, co-financed by the European Union, Interreg V OKS. J.B. reports that the risk evaluation form used at the Fertility Assessment Clinic was inspired by the Fertility Status Awareness Tool FertiSTAT that was developed at Cardiff University for self-assessment of reproductive risk. J.B. also reports personal fees from Merck KGaA, Merck AB, Theramex, Ferring Pharmaceuticals A/S and a research grant from Merck Serono Ltd outside the submitted work. A.N.A. has received personal fees from both Merck Pharmaceuticals and Ferring and grants from Roche Diagnostics outside the submitted work. The other authors report no conflicts of interest.