A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results: We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion: This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Impact on Health-Related quality of life after wearing compression garment or not for six months in women with mild breast cancer-related arm lymphedema. A cross-sectional study.

BACKGROUND: Women with mild breast cancer-related arm lymphedema (BCRAL) mostly receive treatment with compression garments and instructions in self-care to prevent the progression of lymphedema. However, wearing a compression garment may be experienced as negative and may affect health-related quality of life (HRQOL) more than the lymphedema itself. The aim of this study was to investigate if there is a difference in lymphedema-specific HRQOL, between women with mild BCRAL wearing compression garments or not for 6 months. MATERIAL AND METHODS: Participants with mild BCRAL (Lymphedema relative volume <10%) rated their HRQOL by the Lymphedema Quality of Life Inventory (LyQLI), 6 months after diagnosis and being randomized to compression group (CG) or non-compression group (NCG). Both groups received self-care instructions, and the CG was treated with a standard compression garment, compression class 1. Data from 51 women (30 in the CG and 21 in the NCG), were analyzed. RESULTS: Both the CG and the NCG experienced a low negative impact on HRQOL in physical, psychosocial, and practical domains (score <1). However, the CG experienced a higher negative impact on median HRQOL in the practical domain compared to the NCG, 0.23/0.08 respectively, (p = 0.026). In the specific items, more participants in the CG reported a negative impact on HRQOL compared to the NCG in employment activities 23%/0%, (p = 0.032), embarrassment by lymphedema/compression garments 33%/5%, (p = 0.017), feeling discomfort/embarrassment while doing sports and hobbies 30%/5%, (p = 0.034) and having to answer questions about the lymphedema 27%/0% (p = 0.015). CONCLUSION: Overall, the lymphedema-specific HRQOL was high after 6 months in women with mild lymphedema, with only a minor difference between the groups. Some women may however perceive practical and emotional issues with the compression garment. These aspects should be considered in patient education and when planning/evaluating treatment. Trial registration: ISRCTN51918431.

Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells.

The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD +to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss-of-function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.

Apolipoprotein L1 (APOL1) cation current in HEK-293 cells and in human podocytes.

Two heterozygous missense variants (G1 and G2) of Apolipoprotein L1 (APOL1) found in individuals of recent African ancestry can attenuate the severity of infection by some forms of Trypanosoma brucei. However, these two variants within a broader African haplotype also increase the risk of kidney disease in Americans of African descent. Although overexpression of either variant G1 or G2 causes multiple pathogenic changes in cultured cells and transgenic mouse models, the mechanism(s) promoting kidney disease remain unclear. Human serum APOL1 kills trypanosomes through its cation channel activity, and cation channel activity of recombinant APOL1 has been reconstituted in lipid bilayers and proteoliposomes. Although APOL1 overexpression increases whole cell cation currents in HEK-293 cells, the ion channel activity of APOL1 has not been assessed in glomerular podocytes, the major site of APOL1-associated kidney diseases. We characterize APOL1-associated whole cell and on-cell cation currents in HEK-293 T-Rex cells and demonstrate partial inhibition of currents by anti-APOL antibodies. We detect in primary human podocytes a similar cation current inducible by interferon-γ (IFNγ) and sensitive to inhibition by anti-APOL antibody as well as by a fragment of T. brucei Serum Resistance-Associated protein (SRA). CRISPR knockout of APOL1 in human primary podocytes abrogates the IFNγ-induced, antibody-sensitive current. Our novel characterization in HEK-293 cells of heterologous APOL1-associated cation conductance inhibited by anti-APOL antibody and our documentation in primary human glomerular podocytes of endogenous IFNγ-stimulated, APOL1-mediated, SRA and anti-APOL-sensitive ion channel activity together support APOL1-mediated channel activity as a therapeutic target for treatment of APOL1-associated kidney diseases.

Early intervention with compression garments prevents progression in mild breast cancer-related arm lymphedema: a randomized controlled trial.

BACKGROUND: Early diagnosis and compression treatment are important to prevent progression in breast cancer-related arm lymphedema (BCRAL). However, some mild BCRAL can be reversible, and therefore, compression treatment may not be needed. The aim of this study was to investigate the proportion of women with mild BCRAL showing progression/no progression of lymphedema after treatment with or without compression garments, differences in changes of lymphedema relative volume (LRV), local tissue water and subjective symptoms during 6 months. Also, adherence to self-care was examined. MATERIAL AND METHODS: Seventy-five women diagnosed with mild BCRAL were randomized to a compression group (CG) or noncompression group (NCG). Both groups received self-care instructions, and the CG were treated with a standard compression garment (ccl 1). Women in the NCG who progressed in LRV ≥2%, or exceeded 10% dropped out, and received appropriate treatment. The proportion showing progression/no progression of LRV, and changes in LRV was measured by Water Displacement Method. Changes in local tissue water were measured by Tissue Dielectric Constant (TDC), subjective symptoms by Visual Analogue Scale, and self-care by a questionnaire. RESULTS: A smaller proportion of LRV progression was found in the CG compared to the NCG at 1, 2 and 6 months follow-up (p ≤ 0.013). At 6 months, 16% had progression of LRV in the CG, compared to 57% in the NCG, (p = 0.001). Thus, 43% in the NCG showed no progression and could manage without compression. Also, CG had a larger reduction in LRV, at all time-points (p ≤ 0.005), and in the highest TDC ratio, when same site followed, at 6 months (p = 0.025). Subjective symptoms did not differ between the groups, except at 1 month, where the CG experienced more reduced tension (p = 0.008). There were no differences in adherence to self-care. CONCLUSION: Early treatment with compression garment can prevent progression in mild BCRAL. Trial registration: ISRCT nr ISRCTN51918431.

Sterile water injections for management of renal colic pain: a systematic review.

BACKGROUND: Since the 1950s a small number of centres have used sterile water injections (SWI) to treat renal colic pain. We undertook this review to determine the efficacy of SWI to manage the pain of renal colic. METHODS: We searched the electronic databases PubMed, Cochrane Central Register, CINAHL, and Scopus from database inception to 7 November 2021 for randomized controlled trials that met the inclusion criteria. RESULTS: Six trials were included in the review (n = 894 patients). Two placebo controlled trials were included in the meta-analysis. Other trials compared SWI to Diclofenac, Morphine, or oral Paracetamol. The overall quality of the trial was low. Compared to a placebo SWI demonstrated a significant reduction in self-reported pain at 30 min (Mean difference [MD] = -4.68, 95% Confidence Interval [CI] = -5.21, -4.15. p < 0.001, I2 = 0%) and at or beyond 60 min post-injection (MD = -5.34 95% CI = -5.85, -4.82, p ≤ 0.001, I2 = 0%). Pain relief provided by SWI was significantly better than oral paracetamol and equivalent to Diclofenac and Morphine. No significant side-effects were attributed to SWI use in any trials. DISCUSSION/CONCLUSION: SWI could be a suitable alternative for management of renal colic pain where alternatives such as non-steroidal anti-inflammatory and opioid drugs are either unavailable or contraindicated. However, further research is required to establish the role of SWI in renal colic pain management.

A comparison of two versus four sterile water injections for the relief of back pain in labour: A multicentre randomised equivalence trial.

BACKGROUND: Recent trials demonstrated the safety and efficacy of sterile water injections to provide relief from labour back pain. While four injections is the most common approach variations in technique, such as employing two injections, are also used. AIM: To determine if the analgesic effect of two sterile water injections is clinically equivalent to four. METHODS: 238 women in labour with a Visual Analogue Scale pain score (VAS) of 70 millimetres (mm) (0 = no pain; 100 = worst pain imaginable) were randomised to two or four sterile water injections. The primary outcome was pain measured on a VAS at 30 min post treatment. A priori margin of equivalence was set at ±10 mm. Secondary outcomes included the likelihood of achieving an at least 30% and 50% reduction in pain, birth and neonatal outcomes. RESULTS: At 30 min post-injection the difference in VAS scores between the techniques was -5.97 (95% Confidence Interval [CI] -13.18-1.22). As the lower end of the CI exceeds the margin of -10 mm equivalence was not demonstrated. Both techniques achieved an at least 30% reduction in pain in over 75% of participants though duration of effect was longer in the four injection group. There was no difference in other birth related secondary outcomes. CONCLUSION: Four injections provided a margin of benefit over two injections in level and duration of analgesia. DISCUSSION: Four injections remains the technique of choice though two injections still provided significant pain relief and would be suitable where it was not possible or desirable to provide four.

Effect of topical local anaesthesia on injection pain associated with administration of sterile water injections - a randomized controlled trial.

BACKGROUND: Sterile water injections can provide effective pain relief during childbirth, particularly for low back pain related to childbirth. However, the pain associated administering the injections can negatively impact women's impressions of the procedure. It may discourage women from considering repeat doses despite the quality of analgesia experienced. Determining strategies to reduce the pain related to the administration of sterile water injections would improve the acceptability of the technique. Therefore, the aim of this study was to evaluate the effect of topical local anesthesia on the pain associated with administration of sterile water injections. METHODS: The study was designed as a multi-arm single-blind, randomized, controlled trial and 120 female healthy students were randomly divided according to one of four groups. The Intervention group received sterile water injections with topical local anesthesia. Control group 1 received sterile water injections without topical local anesthesia, control group 2 received injections of isotonic saline 0.9% with topical local anesthesia and control group 3 received injections of isotonic saline 0.9% without topical local anesthesia. Pain Immediately after the injections and subsidence in pain were recorded using a visual analogue scale. Sensations in the injection area were reported 15 min and the day after the injections. RESULTS: The main finding of this study was that local anesthesia with EMLA® reduces the pain associated with the administration of intracutaneous sterile water injections. There was a significant difference in the self-assessed pain score immediately following the injections between the control (73.3 mm) and intervention groups (50.0 mm), p = 0.001. No adverse side effects were reported. CONCLUSION: Local anesthesia with EMLA® reduces the pain associated with intracutaneous administration of sterile water injections. TRIAL REGISTRATION: The study was registered 08/07/2014 at ClinicalTrials.gov Identifier: NCT02213185 .

Sterile water injections for relief of labour pain (the SATURN trial): study protocol for a randomised controlled trial.

BACKGROUND: Up to 80% of women use some form of pharmacological analgesia during labour and birth. The side effects of pharmacological agents are often incompatible with the concurrent use of non-pharmacological pain-relieving strategies, such as water immersion, ambulation and upright positioning, or may have negative effects on both the mother and foetus. Sterile water injections given into the skin of the lumbar region have been demonstrated to reduce back pain during labour. However, the injections given for back pain have no effect on abdominal contraction pain. The analgesic efficacy of sterile water injections for abdominal pain during childbirth is unknown. The injections cause an immediate, brief but significant pain that deters some women from using the procedure. This study aims to investigate the use of water injections given intradermally into the abdomen to relieve labour contraction pain. A vapocoolant spray will be applied to the skin immediately prior to the injections to reduce the injection pain. METHODS: In this pragmatic, placebo-controlled trial, 154 low-risk women in labour at term with a labour pain score ≥ 60 on a 100-ml visual analogue scale (VAS) will be randomly allocated to receive either six injections of sterile water or a sodium chloride 0.9% solution as a placebo (0.1-0.3 ml per injection). Three injections are given along the midline from the fundus to the supra-pubis and three laterally across the supra-pubis. The primary outcome will be the difference in VAS score 30 min post-injection between the groups. Secondary outcomes include VAS score of the injection pain on administration, VAS score of labour pain at 60 and 90 min and maternal and neonatal birth outcomes. DISCUSSION: Access to effective pain relief during labour is fundamental to respectful and safe maternity care. Pharmacological analgesics should support rather than limit other non-pharmacological strategies. Sterile water injections have the potential to provide an alternative form of labour pain relief that is easy to administer in any labour and birth setting and is compatible with other non-pharmacological choices. TRIAL REGISTRATION: ANZCTR ACTRN12621001036808 . Registered on 05 August 2021.

Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease.

People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding sequence variants in the APOL1 gene. Inheriting two copies of these APOL1 risk variants, known as G1 and G2, causes high rates of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-associated end-stage kidney disease. Disease risk follows a recessive mode of inheritance, which is puzzling given the considerable data that G1 and G2 are toxic gain-of-function variants. We developed coisogenic bacterial artificial chromosome (BAC) transgenic mice harboring either the wild-type (G0), G1 or G2 forms of human APOL1. Expression of interferon gamma (IFN-γ) via plasmid tail vein injection results in upregulation of APOL1 protein levels together with robust induction of heavy proteinuria and glomerulosclerosis in G1/G1 and G2/G2 but not G0/G0 mice. The disease phenotype was greater in G2/G2 mice. Neither heterozygous (G1/G0 or G2/G0) risk variant mice nor hemizygous (G1/-, G2/-) mice had significant kidney injury in response to IFN-γ, although the heterozygous mice had a greater proteinuric response than the hemizygous mice, suggesting that the lack of significant disease in humans heterozygous for G1 or G2 is not due to G0 rescue of G1 or G2 toxicity. Studies using additional mice (multicopy G2 and a non-isogenic G0 mouse) supported the notion that disease is largely a function of the level of risk variant APOL1 expression. Together, these findings shed light on the recessive nature of APOL1-nephropathy and present an important model for future studies.

Association of Circulating Extracellular Matrix Components with Central Hemodynamics and Arterial Distensibility of Peripheral Arteries.

BACKGROUND: In addition to neuronal and endothelial regulators of vascular tone, the passive mechanical properties of arteries, determined by the molecular structure of extracellular matrices, are the principle modulators of vascular distensibility. Specifically, the association between collagen type IV (Col IV), a constituent of basement membrane, and arterial compliance remains unclear. METHODS: In 31 healthy adult men, radial applanation tonometry and pulse wave analysis were used to assess aortic augmentation index (AIx), aortic-to-radial pulse pressure amplification (PPAmpl), and time to reflection wave. RESULTS: Plasma Col IV and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) concentrations were correlated with AIx (r = 0.51, p = 0.021 and r = -0.45, p = 0.042, respectively) after adjustment for age and heart rate (HR). Greater matrix metalloproteinase-9 (MMP-9) and TIMP-1 levels were associated with high PPAmpl (r = 0.45 and r = 0.64, respectively) and hence with compliant arteries. Multiple regression analyses revealed that 99% of the variation in PPAmpl was attributable to age, HR, Col IV, TIMP-1, and Col × TIMP-1 interaction (p < 0.001). No relations between tonometric variables and levels of MMP-1, -2, and -3; TIMP-2 and -4; fibronectin; glycosaminoglycans; and hydroxyproline were found. CONCLUSION: High circulating Col IV level indexes were associated with stiffer peripheral arteries whereas increased MMP-9 and TIMP-1 concentrations were associated with more compliant ones.

Midwives' Experiences of Providing the "Inspirational Lecture" as a Care Intervention for Expectant Parents-A Qualitative Study.

Background: In most Western countries, ordinary parental classes exist and have become a well-established form of professional support within midwifery care, even though some of these classes lack evidence of benefits for the parents. A Swedish randomized controlled trial including an intervention as a pilot study, revealed that a type of parental preparatory professional support provided for expectant parents, the "inspirational lecture," showed a tendency to be beneficial for parents' birth experience, and their perceived quality of parental couple relationship. However, there is no previous research on the midwives' experiences from providing the inspirational lecture. Carrying out research on midwives' experiences from providing the lecture, could bring future opportunities to provide a work-integrated learning (WIL) related to professionals' skills, and the pedagogic used. Aim: To elucidate midwives' experiences about providing the inspirational lecture as a care intervention for expectant parents. Methods: Midwives were interviewed and data were analyzed using qualitative content analysis. Results: The midwives strived to put childbirth into a comprehensive and manageable context for the expectant parents, during the inspirational lecture. For this, different approaches were used to make expectant parents understand how the parents themselves can be engaged participants in their own birth. Conclusion and Clinical Implications: The midwives used the inspirational lecture to provide the expectant parents with knowledge about how they, as a parental couple, could cooperate and feel safe in relation to the upcoming birth. This could be understood as if the midwives were striving to facilitate the integrative power of the parental couple, which is the couples' ability to gather their joint power. These results can assist midwives and serve as a reference for providing parental classes for expectant parents with a focus on promoting both the parents' individual as well as mutual skills.

Caesarean delivery rates and analgesia effectiveness following injections of sterile water for back pain in labour: A multicentre, randomised placebo controlled trial.

BACKGROUND: About a third of women experience severe back pain during labour. Injecting small volumes of intracutaneous sterile water into the lumbar region can be used to relieve this pain, however the procedure is controversial and previous reviews call for high quality trials to establish efficacy. We evaluated the impact on birth outcomes and analgesic effects of sterile water injections. METHODS: A multicentre, double-blind trial undertaken between December 2012 and December 2017 in one British and 15 Australian maternity units. Women experiencing severe back-pain in labour were assigned (1:1) by an independently generated randomisation schedule stratified by site to injections of either sterile water or saline placebo. Participants and caregivers were blinded to group allocation. The primary outcome was caesarean delivery rate. Main secondary outcomes included at least 30% or 50% reduction in self-reported pain scores at 30, 60 and 90 minutes after treatment. Intention to treat analysis were used and the level of significance for the multiple clinical outcomes was set at p<0.001 with the Bonferroni correction applied. The study is registered with the ACTRN Registry number, ACTRN1261100022195. FINDINGS: Between December 9, 2012, and December 15, 2017, 1166 women were recruited and randomised: 587 women received sterile water injections (SWI) and 579 a saline placebo. Seven women in the SWI group and 12 in the placebo group were excluded as consent was not completed, leaving 580 and 567, respectively, included in the analysis. The proportions of caesarean delivery were 17·1% (82 of 580) in the SWI group and 14·8% (82 of 567) in the placebo (RR 1·16, 95% CI 0·88-1.51; p = 0·293). At 30 min post treatment 60·8% (330 of 543) of women in the SWI group reported a 30% reduction in self-reported pain compared to 31·4% (163 of 520) placebo (RR 1·94, 95% CI 1·68-2·24; p=<0·001) and 43·3% (235 of 534) SWI reported a 50% reduction versus 18·1% (94 of 520) placebo (RR 2·39, 95% CI 1·95-2·94; p=<0·001). The analgesic effect of SWI compared to placebo remained significant at 60 and 90 min post-treatment. There were no significant differences in other maternal or neonatal outcomes. INTERPRETATION: Compared to placebo, injections of sterile water did not reduce rates of caesarean delivery. For the main secondary outcome of pain relief the intervention did result in significantly more women reporting at least 30% and 50% reduction in pain for up to 90 min. Water injections have no effect on birth outcomes though can be an effective treatment for the relief of labour-related back pain.Funded by the National Health and Medical Research Council.

Modern Challenges to Gastrointestinal Nutrition Physicians and the Nutrition Support Team: Cautionary Tales and Call to Action.

The current climate of healthcare economics in the United States has imposed unprecedented market stressors on health institutions traditionally providing tertiary care to those with the most challenging healthcare needs. In such a stressed financial atmosphere, administrators look to streamline costs and cut margins as tightly as possible. This often results in restructuring, consolidating, or closing service lines that are perceived as unprofitable or unsupportable. Nutrition support often falls into this category because of few sources of direct revenue-generating activities and poor reimbursement from third-party payers. This article discusses the challenges to modern nutrition support teams, particularly those with gastroenterologists as physician leaders, and delineates market forces that need shifting to continue to make this a viable part of the healthcare system.

Conventional versus ultrasound treat to target: no difference in magnetic resonance imaging inflammation or joint damage over 2 years in early rheumatoid arthritis.

OBJECTIVE: To investigate whether an ultrasound-guided treat-to-target strategy for early RA would lead to reduced MRI inflammation or less structural damage progression compared with a conventional treat-to-target strategy. METHODS: A total of 230 DMARD-naïve early RA patients were randomized to an ultrasound tight control strategy targeting DAS <1.6, no swollen joints and no power Doppler signal in any joint or a conventional strategy targeting DAS <1.6 and no swollen joints. Patients in both arms were treated according to the same DMARD escalation strategy. MRI of the dominant hand was performed at six time points over 2 years and scored according to the OMERACT RA MRI scoring system. A total of 218 patients had baseline and one or more follow-up MRIs and were included in the analysis. The mean MRI score change from baseline to each follow-up and the 2 year risk for erosive progression were compared between arms. RESULTS: MRI bone marrow oedema, synovitis and tenosynovitis improved over the first year and was sustained during the second year of follow-up, with no statistically significant differences between the ultrasound and the conventional arms at any time point. The 2 year risk for progression of MRI erosions was similar in both treatment arms: ultrasound arm 39%, conventional arm 33% [relative risk 1.16 (95% CI 0.81, 1.66), P = 0.40]. CONCLUSION: Incorporating ultrasound information in treatment decisions did not lead to reduced MRI inflammation or less structural damage compared with a conventional treatment strategy. The findings support that systematic use of ultrasound does not provide a benefit in the follow-up of patients with early RA. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, http://clinicaltrials.gov, NCT01205854.

Vitamin D status in preschool children and its relations to vitamin D sources and body mass index-Fish Intervention Studies-KIDS (FINS-KIDS).

OBJECTIVES: The aims of this study were to determine vitamin D status (serum 25-hydroxyvitamin D3 [s-25(OH)D3]) and examine possible associations between vitamin D status and vitamin D-rich dietary sources, sun exposure, and body mass index in preschool children ages 4 to 6 y. METHODS: This is a cross-sectional study based on baseline data (collected in January-February 2015) from the two-armed randomized controlled trial Fish Intervention Studies-KIDS (FINS-KIDS) conducted in Bergen, Norway. S-25(OH)D3 concentration was determined by liquid chromatography-tandem mass spectrometry. Information regarding habitual dietary intake, recent sun vacations, and body mass index were assessed with questionnaires answered by the children's caregivers. RESULTS: The children (n = 212) had a mean (standard deviation) s-25(OH)D3 of 60.7 (13.8) nmol/L; 18.9% had s-25(OH)D3 ≤50 nmol/L. In logistic regression models, non-overweight versus overweight status was inversely associated with s-25(OH)D3 ≤50 nmol/L (odds ratio: 0.41; 95% confidence interval, 0.18-0.95; P = 0.037). Non-sun versus sun vacations were associated with s-25(OH)D3 ≤75 nmol/L (odds ratio: 5.33; 95% confidence interval, 1.93-14.77; P = 0.001). CONCLUSIONS: The majority of the preschool children (81%) had s-25(OH)D3 >50 nmol/L. Children with overweight status had an increased risk of s-25(OH)D3 ≤50 nmol/L, and children who had not been on sun vacations were at a greater risk of s-25(OH)D3 ≤75 nmol/L.