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To investigate whether dynamic pupillary responses differ between patients with age-related macular degeneration (AMD) and healthy controls (HC), and to evaluate their potential as functional biomarkers using high-frequency, VR-based video-oculography. A controlled clinical study included 17 AMD patients and 17 age-matched HCs; four AMD participants were excluded for low recording quality. Dynamic pupillary responses were recorded with the BulbiCam video-oculography system (400 Hz), which presented independent monocular light stimuli through multiple permutations of bright (300 cd/m²) and dark (5 cd/m²) conditions. Measured variables included pupil diameter, latency, peak velocity, and pupil diameter-time integral (PDTI). Each eye was tested separately, and repeated sessions were analysed for reliability (intraclass correlation coefficient, ICC), repeatability (agreement index, AI), and stability (stability index, SI). Group differences were assessed using analysis of variance (ANOVA) and receiver operating characteristic (ROC) analysis. AMD eyes showed larger steady-state pupil diameter and higher PDTI than controls (p < 0.05). First peak velocity was reduced in the worst eye only, while latencies were unchanged. PDTI and diameter demonstrated high reliability and stability across repetitions, and ROC analysis confirmed effective group discrimination. High-frequency VR pupillometry detected reproducible functional alterations in AMD, consistent with impaired macular photoreceptor input but preserved reflex transmission. PDTI and diameter serve as diagnostic (population-level) and monitoring (patient-level) biomarkers, offering a non-invasive and objective method for AMD detection and follow-up in clinical and research settings.

Nordic skiing, an energy-demanding endurance sport, may be particularly susceptible to low energy availability (LEA) and relative energy deficiency in sport (REDs). The objective was to examine the nutritional practices and physical symptoms associated with (REDs among young elite Norwegian Nordic skiers during the off-season, with particular emphasis on energy and CHO intake, in the transition from the competitive season to preparation for the subsequent season. Thirty female and thirty male Nordic skiers participated in a 24-week controlled clinical trial. The daily dietary intake variables were carbohydrates (CHO), protein, and calcium (Ca) intake and weekly training hours. The blood variables were vitamin D, total osteocalcin (tOC), procollagen type 1 N-terminal propeptide/cross-linked C-telopeptide type 1-collagen (PINP1/CTX1) ratio, heart rate (HR), resting metabolic rate (RMR), bone mineral density (BMD), lean body mass (LM), visceral adipose tissue (VAT), and body fat percentage (BF%). Energy intake increased by 25%, and CHO increased by 14.5% for both sexes during the study, and training volume increased by 41% for female athletes and 83% for male athletes, respectively. There were positive correlations between higher BMD, bone markers, RMR, and LM and negative correlations between VAT and REDs symptoms. VAT was correlated with RMR and bone markers. LM emerged as a key predictor for health variables, explaining variability across multiple REDs markers. Nordic skiers seem unable to increase energy intake sufficiently during the preparation period, leading up to the competitive season, as demonstrated by a large discrepancy between changes in energy intake, especially CHO, and exercise volume. The correlations between energy intake and BMD, RMR, VAT, and HR underscore the clinical consequences of insufficient energy intake, which may arise if individuals focus on low body mass and body fat percentage without sufficient knowledge. VAT, tOC, and the P1NP/CTX-ratio are promising indicators for monitoring dietary interventions in individuals with REDs and should be considered in future research on REDs treatment strategies.

ABSTRACT Background and objective Nordic skiers represent a low-impact, weight-sensitive sport and may be inclined to engage in weight-controlling behavior, hence increasing their risk for low energy availability and impairment in health and performance. Jarlsberg cheese (J) is rich in vitamin K₂ from fermentation by Propionibacterium freudenreichii subsp. shermanii LMGT 2951 (Pf) and lactic acid bacteria and increases the osteocalcin (OC) level. Vitamin K is essential for activating OC, which is described to be associated positively with muscle strength, whereas propionic acid bacteria are found to enhance endurance. Except for Pf and its by-products, J and Norvegia (N) cheeses have almost identical nutrient content. The objective of this study was to compare the effects of Jarlsberg and N as potential supplements to training on muscle strength (MS), lean body mass (LBM) and VO2 max. Methods Thirty female and 30 male Nordic skiers were block randomized 1:1 to either J or N and studied during a 24-week offseason training schedule. The Norvegia group served as a control group. Females and males were treated with 75 and 90 grams/day, respectively. MS by seated pulldown and half-squat, LBM by DXA, and VO2 max were measured at baseline and after the 24 weeks off-season period. Dietary intake and training hours were registered and monitored at baseline and every eight weeks during the study. Results MS significantly increased in both groups after 24 weeks (p < 0.01). The mean increase difference in MS-upper body favored Jarlsberg by 0.95 kg (95% CI: −0.02–1.46), approaching significance (p = 0.06). No significant difference was found between groups in MS-lower body. LBM and VO2-max both increased significantly in each group (p ≤ 0.05), with no notable differences between groups. Correlation analysis identified LBM as the dominant outcome variable at both baseline and 24 weeks. Endurance training was the dominant input variable and correlated significantly positively both multiply and partially to LBM, (p = 0.04, p = 0.02), respectively. At baseline and 24-weeks sex, endurance training along with OC-level explained 65% and 68% of the LBM variations, respectively. Conclusion Both Jarlsberg cheese, characterized by its unique Propionibacterium freudenreichii content, and Norvegia cheese, when combined with off-season training, led to increases in LBM, VO₂ max, and MS, with no significant differences observed between groups. However, there was a trend toward greater improvements in MS in the Jarlsberg group. Overall, increases in LBM through structured training appear to be a key driver of gains in both muscle strength and aerobic capacity. Protocol number XCS-Jarlsberg/IIA ClinicalTrial.gov NCT06688032

Background Blunt implementation of Western trauma system models is not feasible in low-resource communities with long prehospital transit times. The aims of the study were to evaluate to which extent a low-cost prehospital trauma system reduces trauma deaths where prehospital transit times are long, and to identify specific life support interventions that contributed to survival. Methods In the study period from 1997 to 2006, 2,788 patients injured by land mines, war, and traffic accidents were managed by a chain-of-survival trauma system where non-graduate paramedics were the key care providers. The study was conducted with a time-period cohort design. Results 37% of the study patients had serious injuries with Injury Severity Score ≥ 9. The mean prehospital transport time was 2.5 hours (95% CI 1.9 - 3.2). During the ten-year study period trauma mortality was reduced from 17% (95% CI 15 -19) to 4% (95% CI 3.5 - 5), survival especially improving in major trauma victims. In most patients with airway problems, in chest injured, and in patients with external hemorrhage, simple life support measures were sufficient to improve physiological severity indicators. Conclusion In case of long prehospital transit times simple life support measures by paramedics and lay first responders reduce trauma mortality in major injuries. Delegating life-saving skills to paramedics and lay people is a key factor for efficient prehospital trauma systems in low-resource communities.

Some cases of breast cancer are composed of clones of hormonal-independent growing cells, which do not respond to therapy. In the present study, the effect of Benzene-Poly-Carboxylic Acid Complex (BP-C1) on growth of human breast-cancer cells was tested. BP-C1 is a novel anti-cancer complex of benzene-poly-carboxylic acids with a very low concentration of cis-diammineplatinum (II) dichloride. Human breast cancer cells, MCF-7 and T47D, were used. Cell viability was detected by XTT assay and apoptosis was detected by Flow Cytometry and by annexin V/FITC/PI assay. Caspases were detected by western blot analysis and gene expression was measured by using the Applied Biosystems® TaqMan® Array Plates. The results showed that exposure of the cells to BP-C1 for 48 h, significantly (P<0.001) reduced cell viability, induced apoptosis and activated caspase 8 and caspace 9. Moreover, gene expression experiments indicated that BP-C1 increased the expression of pro-apoptotic genes (CASP8AP1, TNFRSF21, NFkB2, FADD, BCL10 and CASP8) and lowered the level of mRNA transcripts of inhibitory apoptotic genes (BCL2L11, BCL2L2 and XIAP. These findings may lead to the development of new therapeutic strategies for treatment of human cancer using BP-C1 analog.

Background Convulsing patients are one of the most common reasons for dispatch in the prehospital system. Determining the underlying cause of symptoms is paramount for both patient safety and determining the correct patient course. This study aims to describe the population of patients presenting with convulsions at first contact with an anesthesiologist-staffed mobile emergency care unit, to uncover the underlying reason for the convulsions, and to establish the outcome of the patient and correlate this to patient age. Methods This retrospective cohort study was conducted through a manual review of prehospital records paired with data from the Danish Civil Person Register. It investigates all patients presenting with convulsions in Odense, Denmark, from January 1, 2011, through December 31, 2020. Patients were stratified into seven age groups and had their diagnoses categorized into eight diagnostic groups. (Endocrine, Febrile convulsions, Cerebrovascular, Cardiopulmonary, Miscellaneous, Neurological, Psychiatric, and Non-specific). Patient mortality was recorded at 7, 30, and 90 days. Results In total 3,388 patients were analyzed. The distribution of patients across age groups only stood out for patients aged 0–4 years, who accounted for 33% ( n  = 1,130) of the population. The underlying cause for convulsions varied greatly depending on patient age. The most common diagnoses were Unspecific diagnoses (38%, n  = 1,289), Febrile convulsions (25%, n  = 837), and Neurological diseases (20%, n  = 689). The highest rate of conveyance with MECU physician escort was in patients within the age group (80 + years) with a conveyance rate of 44.1%. The lowest rate of anesthesiologist-escorted conveyance was found in patients within the age group (20–39 years) with a conveyance rate of 22.3%. Ninety-three patients died within 7 days of contact with the mobile emergency care unit. At thirty days, 147 (4.3%) had died, and the total number of deaths within 90 days was 203 (6.0%). Conclusion Patient trajectories vary greatly across age groups. Patient mortality rates following an episode of convulsions increased considerably with age. Insight in underlying causes of convulsions and their severity may help the prehospital physician determine the correct course of action for the patient, benefiting both the provider and the patient.

The aim of this study was to compare the efficacy and tolerability of BP-C1 vs equal-looking placebo in metastatic breast cancer. A randomized, double-blind, placebo-controlled multi-center study with a semicross-over design was performed. Sixteen patients received daily intramuscular injection of 0.035 mg/kg bodyweight of BP-C1 and 15 patients received equal-looking placebo for 32 days. After 32 days, the placebo patients crossed to BP-C1 with the last observation in the placebo period as baseline. The status of receptors including estrogen receptor (ER), progesterone receptor (PtR), and human EGF receptor 2 (HER2) was analyzed prior to inclusion in the study. Thoracoabdominal CT scan was blindly analyzed by the same independent radiologist in accordance with the RECIST criteria 1.1. Toxicity was assessed according to the NCI Bethesda Version 2.0 (CTC-NCI), and the quality of life (QOL) was assessed according to European Organization for the Research and Treatment of Cancer QOL-C30 and QOL-BR23. The sum of target lesion diameters (sum lesions) after 32 days of treatment increased by 8.9% ( =0.08) in the BP-C1 arm compared to 37.6% ( <0.001) in placebo patients. Twelve of the 15 placebo patients subsequently had BP-C1 treatment. The increase in sum lesions was 3.5% in these patients. The sum of CTC-NCI was increased 18.7% in the BP-C1 arm ( =0.38) compared to 50.9% ( =0.04) in placebo patients. Four mild/moderate adverse events (AEs) present in BP-C1. Two mild/moderate AEs and one severe AE present in placebo. The QOL benchmarks \"breast cancer problems last week\", \"sexual interest and activity last 4 weeks\", and \"breast cancer-related pain and discomfort last week\" were stable in the BP-C1 arm but deteriorated in placebo patients. The sum lesions increased significantly in ER+ ( =0.02) and PtR+ ( =0.03) but not in HER2+. The increase in sum lesions significantly decreased ( =0.02) with an increasing number of negative receptors. A total of 32 days of BP-C1 treatment inhibited cancer growth and was well tolerated with few and mainly mild AEs. The efficacy of BP-C1 was superior in receptor-negative patients. NCT03603197.

IntroductionDaily intake of vitamin K2-rich Jarlsberg cheese is shown to positively affect bone turnover markers (BTMs) in fertile women. How do postmenopausal women and adult men respond to a cheese intervention?PurposeTo estimate the optimal daily efficacy dose (OED) of Jarlsberg cheese to increase serum osteocalcin level in postmenopausal females and males past 55 years of age and estimate the effect on BTMs.MethodsTen expected healthy postmenopausal females and 10 healthy males past 55 years voluntarily participated in a two-dimensional response surface pathway designed dose-response study with three design levels. The duration of each design level was 4 weeks. Blood samples were taken at baseline and the end of each design level for measurements of osteocalcin (OC), vitamin K2, the BTMs procollagen type 1 N-terminal propeptide (P1NP) and serum cross-linked C-telopeptide type I collagen (CTX-1) and other biochemical parameters.ResultsIn the female group, the OC level increased significantly (p<0.01) during the first design level but decreased slightly during the second and third design levels. Among males, the OC level increased monotonously during the study and significantly in the second and third design levels (p<0.01). There was no significant change in P1NP, but CTX decreased significantly (p≤0.05) in both sex groups. The ratio P1NP/CTX increased significantly (p≤0.05) in the female group. S-phosphate and s-urea increased significantly (p≤0.02) while s-calcium and s-magnesium were unchanged. After the study, four of the participating women received a diagnosis of osteoporosis.ConclusionEstimated OED of Jarlsberg cheese was 47 and 67 g/day for postmenopausal females and adult males, respectively. The development in OC and BTMs suggests an anabolic effect of Jarlsberg cheese on bone tissue.

BackgroundDaily intake of 57 g Jarlsberg cheese has been shown to increase the total serum osteocalcin (tOC). Is this a general cheese effect or specific for Jarlsberg containing vitamin K2 and 1,4-dihydroxy-2naphtoic acid (DHNA)?Methods66 healthy female volunteers (HV) were recruited. By skewed randomisation (3:2), 41 HV were allocated to daily intake of 57 g Jarlsberg (J-group) and 25–50 g Camembert (C-group) in 6 weeks. After 6 weeks the C-group was switched to Jarlsberg. The study duration was 12 weeks with clinical investigations every 6 weeks. The main variables were procollagen type 1 N-terminal propeptide (PINP), tOC, carboxylated osteocalcin (cOC) and the osteocalcin ratio (RO) defined as the ratio between cOC and undercarboxylated osteocalcin (ucOC). Serum cross-linked C-telopeptide type I collagen (CTX), vitamin K2, lipids and clinical chemistry were used as secondary variables.ResultsPINP, tOC, cOC, RO and vitamin K2 increased significantly (p<0.01) after 6 weeks in the J-group. PINP remained unchanged in the C-group. The other variables decreased slightly in the C-group but increased significantly (p≤0.05) after switching to Jarlsberg. No CTX-changes detected in neither of the groups.Serum lipids increased slightly in both groups. Switching to Jarlsberg, total cholesterol and low-density lipoprotein-cholesterol were significantly reduced (p≤0.05). Glycated haemoglobin (HbA1c), Ca++ and Mg++ were significantly reduced in the J-group, but unchanged in the C-group. Switching to Jarlsberg, HbA1c and Ca++ decreased significantly.ConclusionThe effect of daily Jarlsberg intake on increased s-osteocalcin level is not a general cheese effect. Jarlsberg contain vitamin K2 and DHNA which increases PINP, tOC, cOC and RO and decreases Ca++, Mg++ and HbA1c. These effects reflect increased bone anabolism and a possible reduced risk of adverse metabolic outcomes.Trial registration number NCT04189796.

Background: Response surface pathway (RSP) design has been recently developed and described for dose-finding studies. The aim of this paper was to introduce and demonstrate additional procedures to strengthen and generalize the design and combine RSP with classical study design. Materials and methods: Nine bull calves and six heifer calves were included in an unbalanced 2 X 2 Latin Square (LSQ) designed study with large and small aperture bottle teats. The two LSQ sequences were performed with independent randomized three-level between-patient RSP design with an odd number of response classifications. The milk temperature window was 8[degrees]C-38[degrees]C with a mid temperature of 23[degrees]C. X-rays of the abdominal cavity were taken before, during, and immediately after intake of milk and recorded as \"milk\", \"trace\", or \"no milk\". Based on the results of the first design level, the milk temperatures for five calves in the second design level were obtained by a randomization procedure. A similar procedure was performed for seven calves in the third design level. Adjustment of the dose from one design level to the next was based on a k-adjustment factor estimated to ensure coverage of the entire predefined dose window. Results: Starting with a low number of subjects and increasing this number with increasing design levels reduces the sample size without reducing the power. The suggested randomization procedure worked as expected. No milk in Rumen was recorded and minimum milk temperature (MMT) was estimated to be <8[degrees]C for both teats. The odd number of response categories increases the flexibility of RSP, enabling category redefinition in hindsight from \"trace\" to \"uncertain\". After category redefinition, MMT for large bottle teat was estimated to be 14.3[degrees]C (95% confidence interval: 8.3-20.3[degrees]C), but 8[degrees]C for small. Conclusion: The suggested changes and additional procedures increase the strength and flexibility of the RSP design. Keywords: k-adjustment factor, Latin Square design, patient reduction in clinical trials, randomized response surface pathway design