Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro).

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS: The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION: If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

Delta tocotrienol as a supplement to FOLFOXIRI in first-line treatment of metastatic colorectal cancer. A randomized, double-blind, placebo-controlled phase II study.

PURPOSE: Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). MATERIAL AND METHODS: Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either δ-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18-75 years and ECOG performance status 0-1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo × 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy. RESULTS: Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36-1.36). Grade 3-4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the δ-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p = 0.047). CONCLUSION: The addition of δ-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.

OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.

Total trapeziometacarpal joint arthroplasty using wide awake local anaesthetic no tourniquet.

We conducted a descriptive study of 50 consecutive cases of total trapeziometacarpal joint arthroplasty by one surgeon using wide awake local anaesthetic no tourniquet to assess the usefulness and reliability of the anaesthesia, any adverse effects and patient acceptance. No difference was found when comparing the duration of surgery with 50 cases of total trapeziometacarpal joint arthroplasty inserted in a bloodless field under general or regional anaesthesia by the same surgeon. Wide awake local anaesthetic no tourniquet was found to be useful in providing adequate anaesthesia and haemostasis, and to be reliable and safe with no adverse effects. Patient satisfaction was high with 100% willing to repeat. Overall, wide awake local anaesthetic no tourniquet was a satisfactory method of anaesthesia for trapeziometacarpal joint arthroplasty with the potential for significant benefits to both patient and surgeon compared with traditional general anaesthesia and regional block.Level of evidence: II.

Interprofessional versus uniprofessional dyad learning for medical students in a clinical setting.

OBJECTIVES: The aim of the present study was to explore and compare medical students' perceived learning outcomes when treating patients under supervision in two different learning settings: a uniprofessional or an interprofessional dyad. METHODS: The design of the study is a qualitative interview study. Data were collected from October 2016 to June 2017 via semi-structured group interviews performed at the end of the clinical placement in an orthopaedic outpatient clinic for medical students in the last semester of the curriculum. In the placement, the students worked by turns in either a uniprofessional dyad with two medical students or an interprofessional dyad with a nursing student. The data from the interviews were analysed using Systematic Text Analysis. RESULTS: Overall, 21 students were interviewed. The students appreciated the authenticity of dealing with real patient problems. Both dyads provided the possibility of working as a professional, but the interprofessional dyad had a more authentic setting. In both dyads, the students' interdependence and mutual support promoted the acquisition of knowledge and skills. Working in the interprofessional dyad facilitated relationships between the professions, and the medical students became aware of some of their own profession's strengths and weaknesses. The interprofessional collaboration contributed to different perspectives on the patients' course of treatment and led to a more holistic understanding of the treatment. CONCLUSIONS: Interprofessional dyads have the potential to improve learning outcomes in the clinical training of medical students. Further studies are needed to explore the benefits across medical specialities and settings.

The Polygenic and Monogenic Basis of Blood Traits and Diseases.

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Dynamic LED light versus static LED light for depressed inpatients: results from a randomized feasibility trial.

BACKGROUND: Retrospective studies conducted in psychiatric wards have indicated a shorter duration of stay for depressed inpatients in bright compared to dim daylight-exposed rooms, pointing to a possible antidepressant effect of daylight conditions. Dynamic LED lighting, aiming to mimic daylight conditions, are currently been installed in several hospitals, but their feasibility is poorly investigated. METHODS: To investigate the feasibility of these systems, we developed and installed a LED-lighting system in four rooms in a psychiatric inpatient ward. The system could function statically or dynamically regarding light intensity and colour temperature. The system consisted of (A) a large LED luminaire built into the window jamb mimicking sunlight reflections, (B) two LED light luminaires in the ceiling and (C) a LED reading luminaire. In the static mode, the systems provided constant light from A and B. In the dynamic mode, the system changed light intensity and colour temperature using A, B and C. Patients with unipolar or bipolar depression were randomised to dynamic or static LED lighting for 4 weeks, in addition to standard treatment. Primary outcome was the rate of patients discontinuing the trial due to discomfort from the lighting condition. Secondary outcomes were recruitment and dropout rates, visual comfort, depressive symptoms and suicidal ideation. RESULTS: No participants discontinued due to discomfort from the LED lighting. Recruitment rate was 39.8%, dropout from treatment rates were 56.3% in the dynamic group and 33.3% in the static group. 78.1% in the dynamic group were satisfied with the lighting compared with 71.8% in the static group. Discomfort from the light (glare) was reported by 11.5% in the dynamic group compared to 5.1% in the static group. Endpoint suicidal scores were 16.8 (10.4) in the dynamic and 16.3 (14.9) in the static group. The lighting system was 100% functional. The light sensor system proved unstable. CONCLUSION: Dropout from treatment was high primarily due to early discharge and with a lack of endpoint assessments. The feasibility study has influenced an upcoming large-scale dynamic lighting efficacy trial where we will use a shorter study period of 3 weeks and with more emphasis on endpoint assessments. The lighting was well tolerated in both groups, but some found intensity too low in the evening. Thus, we will use higher intensity blue-enriched light in the morning and higher intensity amber (blue-depleted) light in the evening in the upcoming study. The light sensor system needs to be improved. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03363529.

Dynamic LED-light versus static LED-light for depressed inpatients: study protocol for a randomised clinical study.

INTRODUCTION: Retrospective studies conducted in psychiatric inpatient wards have shown a relation between the intensity of daylight in patient rooms and the length of stay, pointing to an antidepressant effect of ambient lighting conditions. Light therapy has shown a promising antidepressant effect when administered from a light box. The emergence of light-emitting diode (LED) technology has made it possible to build luminaires into rooms and to dynamically mimic the spectral and temporal distribution of daylight. The objective of this study is to investigate the antidepressant efficacy of a newly developed dynamic LED-lighting system installed in an inpatient ward. METHODS AND ANALYSIS: In all, 150 inpatients with a major depressive episode, as part of either a major depressive disorder or as part of a bipolar disorder, will be included. The design is a two-arm 1:1 randomised study with a dynamic LED-lighting arm and a static LED-lighting arm, both as add-on to usual treatment in an inpatient psychiatric ward. The primary outcome is the baseline adjusted score on the 6-item Hamilton Depression Rating Scale at week 3. The secondary outcomes are the mean score on the Suicidal Ideation Attributes Scale at week 3, the mean score on the 17-item Hamilton Depression Rating Scale at week 3 and the mean score on the World Health Organisation Quality of Life-BREF (WHOQOL-BREF) at week 3. The spectral distribution of daylight and LED-light, with a specific focus on light mediated through the intrinsically photosensitive retinal ganglion cells, will be measured. Use of light luminaires will be logged. Assessors of Hamilton Depression Rating Scale scores and data analysts will be blinded for treatment allocation. The study was initiated in May 2019 and will end in December 2021. ETHICS AND DISSEMINATION: No ethical issues are expected. Results will be published in peer-reviewed journals, disseminated electronically and in print and presented at symposia. TRIAL REGISTRATION NUMBER: NCT03821506; Pre-results.

FADS and PPARG2 Single Nucleotide Polymorphisms are Associated with Plasma Lipids in 9-Mo-Old Infants.

BACKGROUND: Dietary intake of polyunsaturated fatty acids (PUFAs), e.g., linoleic acid and n-3 (ω-3) long-chain PUFAs, has been shown in adults to affect plasma cholesterol and triglycerides (TGs), respectively. Little is known about the effects of PUFAs on plasma lipids in early life. OBJECTIVE: The aim of this study was to explore the associations between plasma concentrations of total, LDL, and HDL cholesterol and TGs in infants and 2 single nucleotide polymorphisms (SNPs) in the fatty acid desaturase genes (FADS) oppositely associated with docosahexaenoic acid (rs1535 and rs174448) and potential effect modification by a functional peroxisome proliferator-activated receptor-γ2 gene variant (PPARG2 Pro12Ala). METHODS: In 9-mo-old infants (n = 561) from 3 Danish cohorts, we analyzed associations between plasma lipids, erythrocyte PUFAs, and FADS SNPs, and interactions with PPARG2 Pro12Ala genotype, by multiple linear regression. We also examined potential effect modification by breastfeeding, as 46% of the infants were still being breastfed. RESULTS: Minor allele carriage of rs174448 was associated with lower total cholesterol (difference: -0.22 mmol/L; 95% CI: -0.37, -0.06 mmol/L; P = 0.006) and LDL cholesterol (difference: -0.15 mmol/L; 95% CI: -0.29, -0.01 mmol/L; P = 0.035), but no associations were observed with TGs or for rs1535. Minor allele carriage of both FADS SNPs was associated with 1 SD lower HDL cholesterol, but only in currently breastfed infants (rs174448 × breastfeeding, P = 0.080; rs1535 × breastfeeding, P = 0.030) and PPARG2 minor allele carriers (rs174448 × PPARG2, P = 0.001; rs1535 × PPARG2, P = 0.004). Erythrocyte arachidonic acid and eicosapentaenoic acid were inversely associated with LDL cholesterol [estimated effect (ß): -0.3 mmol/L; 95% CI: -0.06, -0.00 mmol/L per percentage of fatty acids (FA%); P = 0.035] and TGs (ß: -0.23 mmol/L; 95% CI: -0.41, -0.05 mmol/L per FA%; P = 0.015), respectively. CONCLUSIONS: The observed associations with FADS variants indicate that PUFAs are involved in plasma lipid regulation in 9-mo-old infants. Observed FADS SNP differences and interactions with breastfeeding and PPARG2 warrant additional studies to explore the effects of individual FADS SNPs on PUFA status and potential genetic modification of dietary PUFA effects.

Selection in Europeans on Fatty Acid Desaturases Associated with Dietary Changes.

FADS genes encode fatty acid desaturases that are important for the conversion of short chain polyunsaturated fatty acids (PUFAs) to long chain fatty acids. Prior studies indicate that the FADS genes have been subjected to strong positive selection in Africa, South Asia, Greenland, and Europe. By comparing FADS sequencing data from present-day and Bronze Age (5-3k years ago) Europeans, we identify possible targets of selection in the European population, which suggest that selection has targeted different alleles in the FADS genes in Europe than it has in South Asia or Greenland. The alleles showing the strongest changes in allele frequency since the Bronze Age show associations with expression changes and multiple lipid-related phenotypes. Furthermore, the selected alleles are associated with a decrease in linoleic acid and an increase in arachidonic and eicosapentaenoic acids among Europeans; this is an opposite effect of that observed for selected alleles in Inuit from Greenland. We show that multiple SNPs in the region affect expression levels and PUFA synthesis. Additionally, we find evidence for a gene-environment interaction influencing low-density lipoprotein (LDL) levels between alleles affecting PUFA synthesis and PUFA dietary intake: carriers of the derived allele display lower LDL cholesterol levels with a higher intake of PUFAs. We hypothesize that the selective patterns observed in Europeans were driven by a change in dietary composition of fatty acids following the transition to agriculture, resulting in a lower intake of arachidonic acid and eicosapentaenoic acid, but a higher intake of linoleic acid and α-linolenic acid.

Urinary metabolomics reveals glycemic and coffee associated signatures of thyroid function in two population-based cohorts.

BACKGROUND: Triiodothyronine (T3) and thyroxine (T4) as the main secretion products of the thyroid affect nearly every human tissue and are involved in a broad range of processes ranging from energy expenditure and lipid metabolism to glucose homeostasis. Metabolomics studies outside the focus of clinical manifest thyroid diseases are rare. The aim of the present investigation was to analyze the cross-sectional and longitudinal associations of urinary metabolites with serum free T4 (FT4) and thyroid-stimulating hormone (TSH). METHODS: Urine Metabolites of participants of the population-based studies Inter99 (n = 5620) and Health2006/Health2008 (n = 3788) were analyzed by 1H-NMR spectroscopy. Linear or mixed linear models were used to detect associations between urine metabolites and thyroid function. RESULTS: Cross-sectional analyses revealed positive relations of alanine, trigonelline and lactic acid with FT4 and negative relations of dimethylamine, glucose, glycine and lactic acid with log(TSH). In longitudinal analyses, lower levels of alanine, dimethylamine, glycine, lactic acid and N,N-dimethylglycine were linked to a higher decline in FT4 levels over time, whereas higher trigonelline levels were related to a higher FT4 decline. Moreover, the risk of hypothyroidism was higher in subjects with high baseline trigonelline or low lactic acid, alanine or glycine values. CONCLUSION: The detected associations mainly emphasize the important role of thyroid hormones in glucose homeostasis. In addition, the predictive character of these metabolites might argue for a potential feedback of the metabolic state on thyroid function. Besides known metabolic consequences of TH, the link to the urine excretion of trigonelline, a marker of coffee consumption, represents a novel finding of this study and given the ubiquitous consumption of coffee requires further research.

Intake of macro- and micronutrients in Danish vegans.

BACKGROUND: Since information about macro- and micronutrient intake among vegans is limited we aimed to determine and evaluate their dietary and supplementary intake. METHODS: Seventy 18-61 years old Danish vegans completed a four-day weighed food record from which their daily intake of macro- and micronutrients was assessed and subsequently compared to an age-range-matched group of 1,257 omnivorous individuals from the general Danish population. Moreover, the vegan dietary and supplementary intake was compared to the 2012 Nordic Nutrition Recommendations (NNR). RESULTS: Dietary intake differed significantly between vegans and the general Danish population in all measured macro- and micronutrients (p < 0.05), except for energy intake among women and intake of carbohydrates among men. For vegans the intake of macro- and micronutrients (including supplements) did not reach the NNR for protein, vitamin D, iodine and selenium. Among vegan women vitamin A intake also failed to reach the recommendations. With reference to the NNR, the dietary content of added sugar, sodium and fatty acids, including the ratio of PUFA to SFA, was more favorable among vegans. CONCLUSIONS: At the macronutrient level, the diet of Danish vegans is in better accordance with the NNR than the diet of the general Danish population. At the micronutrient level, considering both diet and supplements, the vegan diet falls short in certain nutrients, suggesting a need for greater attention toward ensuring recommended daily intake of specific vitamins and minerals.

Greenlandic Inuit show genetic signatures of diet and climate adaptation.

The indigenous people of Greenland, the Inuit, have lived for a long time in the extreme conditions of the Arctic, including low annual temperatures, and with a specialized diet rich in protein and fatty acids, particularly omega-3 polyunsaturated fatty acids (PUFAs). A scan of Inuit genomes for signatures of adaptation revealed signals at several loci, with the strongest signal located in a cluster of fatty acid desaturases that determine PUFA levels. The selected alleles are associated with multiple metabolic and anthropometric phenotypes and have large effect sizes for weight and height, with the effect on height replicated in Europeans. By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs.

Endoscopic carpal tunnel release.

ECTR is an elegant minimally invasive operative treatment of CTS, providing a rapid rehabilitation without increasing the risk of complications. However, there is a significant learning curve and the cost of the operation is significantly higher than with conventional open technique. However, the faster rehabilitation and the probability of reducing sick leave may lead to ECTR being overall more cost-effective than open CTR.

Combination of zoledronic Acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma.

PURPOSE: To investigate the efficacy and safety of zoledronic acid (ZA) combined with targeted therapy (TT). MATERIALS AND METHODS: A retrospective study was performed in patients with metastatic renal cell carcinoma treated with ZA and TT. RESULTS: Twenty-one patients received ZA and TT to prevent skeletal-related events and no pretherapy oral and maxillofacial (OM) examination (cohort A). Six patients (29%) developed osteonecrosis of the jaw (ONJ), which was observed only in patients receiving sunitinib and ZA. Sixteen patients received TT and ZA for hypercalcemia and no pretherapy OM examination (cohort B). In these patients, no ONJ was observed. Nine patients received ZA and TT and pretherapy OM examination (cohort C). One patient (11%) developed ONJ during sunitinib and ZA treatment. Mean skeletal morbidity rates were 0.8 for cohort A and 1.2 for cohort C. In the combined cohort (A plus C; n = 30), 47% developed skeletal-related events, 7% pathologic fracture, 7% medullary compression, and 37% progression of bone metastases. Patients who developed ONJ had a significantly improved median survival of 31.6 months compared with 14.5 months in patients without ONJ (P = .039). CONCLUSION: The combination of ZA and TT resulted in high, clinically meaningful activity. ONJ may be exacerbated by concomitant ZA and sunitinib. Regular OM examinations before and during treatment are recommended.