Glycocalyx shedding patterns identifies antipsychotic-naïve patients with first-episode psychosis.

Psychotic disorders have been linked to immune-system abnormalities, increased inflammatory markers, and subtle neuroinflammation. Studies further suggest a dysfunctional blood brain barrier (BBB). The endothelial Glycocalyx (GLX) functions as a protective layer in the BBB, and GLX shedding leads to BBB dysfunction. This study aimed to investigate whether a panel of 11 GLX molecules derived from peripheral blood could differentiate antipsychotic-naïve first-episode psychosis patients (n47) from healthy controls (HC, n49) and whether GLX shedding correlated with symptom severity. Blood samples were collected at baseline and serum was isolated for GLX marker detection. Machine learning models were applied to test whether patterns in GLX markers could classify patient groups. Associations between GLX markers and symptom severity were explored. Patients showed significantly increased levels of three GLX markers compared to HC. Based on the panel of 11 GLX markers, machine learning models achieved a significant mean classification accuracy of 81%. Post hoc analysis revealed associations between increased GLX markers and symptom severity. This study demonstrates the potential of GLX molecules as immuno-neuropsychiatric biomarkers for early diagnosis of psychosis, as well as indicate a compromised BBB. Further research is warranted to explore the role of GLX in the early detection of psychotic disorders.

Evaluating Danish Breast Cancer Group locoregional radiotherapy guideline adherence in clinical treatment data 2008-2016: The DBCG RT Nation study.

BACKGROUND AND PURPOSE: Guideline adherence in radiotherapy is crucial for maintaining treatment quality and consistency, particularly in non-trial patient settings where most treatments occur. The study aimed to assess the impact of guideline changes on treatment planning practices and compare manual registry data accuracy with treatment planning data. MATERIALS AND METHODS: This study utilised the DBCG RT Nation cohort, a collection of breast cancer radiotherapy data in Denmark, to evaluate adherence to guidelines from 2008 to 2016. The cohort included 7448 high-risk breast cancer patients. National guideline changes included, fractionation, introduction of respiratory gating, irradiation of the internal mammary lymph nodes, use of the simultaneous integrated boost technique and inclusion of the Left Anterior Descending coronary artery in delineation practice. Methods for structure name mapping, laterality detection, detection of temporal changes in population mean lung volume, and dose evaluation were presented and applied. Manually registered treatment characteristic data was obtained from the Danish Breast Cancer Database for comparison. RESULTS: The study found immediate and consistent adherence to guideline changes across Danish radiotherapy centres. Treatment practices before guideline implementation were documented and showed a variation among centres. Discrepancies between manual registry data and actual treatment planning data were as high as 10% for some measures. CONCLUSION: National guideline changes could be detected in the routine treatment data, with a high degree of compliance and short implementation time. Data extracted from treatment planning data files provides a more accurate and detailed characterisation of treatments and guideline adherence than medical register data.

Clinical considerations and pitfalls in the use of depot antipsychotics.

Long-acting injectable antipsychotics (LAI) is a frequently used treatment modality which has advantages over oral antipsychotics regarding hospitalization or relapse prevention. However, the pharmacokinetic properties of LAI greatly differ from oral antipsychotics. This necessitates an increased knowledge about LAI among clinicians, especially when commencing treatment, changing doses and discontinuing treatment. In this review, we summarize an array of clinically important characteristics of LAI and give a conceptual framework for understanding the pharmacokinetics of LAI.

End-of-life care for cancer patients with pre-existing severe mental disorders-a systematic review.

BACKGROUND: Cancer patients with pre-existing severe mental disorders (SMDs) less frequently receive guideline recommended cancer treatment and have a higher cancer mortality. However, knowledge is needed concerning end-of-life care in this patient group. The aim of this systematic review was to provide an overview of the literature concerning end-of-life care in cancer patients with pre-existing SMD. METHODS: A systematic search was conducted in the following databases: PubMed, Embase and Science Direct and all results were downloaded to Endnote on 1st of September 2023. The review was registered on International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42023468571). The quality of the studies was assessed according to the Newcastle-Ottawa Scale. RESULTS: Ten studies fulfilling the inclusion criteria were included. There was a recurring pattern indicating a difference between the end-of-life care received by cancer patients with SMD, compared to those without. Cancer patients with pre-existing SMD received more palliative end-of-life care but less high-intensive-end-of-life (HIEOL) care, e.g., less hospitalisations and chemotherapy at the end of life, and died less frequently at hospital. CONCLUSIONS: The study indicates that patients with pre-existing SMD and cancer more often received palliative end-of-life care and less HIEOL care compared to controls. Further research regarding the difference in end-of-life care is lacking, including the consequences of less intense HIEOL care for this patient group. Thus, further studies are needed to identify reasons for less intense HIEOL among cancer patients with pre-existing SMD.

Endocrine, cardiac and neuropsychological aspects of adult congenital adrenal hyperplasia.

OBJECTIVE: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome. DESIGN, PARTICIPANTS, MEASUREMENTS: Thirty-seven individuals with CAH and 33 age- and sex-matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24-h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires. RESULTS: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m2, p = 0.006), reduced insulin sensitivity (HOMA-IR): 2.7 vs. 1.9, p = 0.018), prolonged E-wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self-reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems. CONCLUSION: A sex-specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self-reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits.

Through Clinicians Eyes: Use of an In-consultation Patient Decision Aid in Radiation Treatment for Early Breast Cancer. A Qualitative Study.

INTRODUCTION: Shared decision making (SDM) has become a crucial element on the political agenda and represents a vital aspect of modern healthcare. However, successful implementation of SDM highly depends on the attitude of clinicians towards SDM. The overall aim of our study was to explore the experience of oncologists and nurses with SDM using the Decision Helper, an in-consultation decision aid, at four Danish radiotherapy departments. METHODS: Semi-structured interviews were conducted with 20 clinicians. The participants were selected using purposive sampling to include nurses and oncologists, male and female, with different levels of experience with SDM and clinical work. The analysis was a data-driven, iterative process with inductive coding of all interviews and meaning condensation. RESULTS: Two main themes emerged: "Using the Decision Helper changes the consultation" and "Change of attitude among Danish oncologists." Each of the two themes included four elaborative subthemes, which are reported with supporting citations in this paper. In brief, the use of SDM and the Decision Helper should ideally be adjusted to the individual patient and depends highly on the oncologist. The participants described ambitions towards "making the right decision for this patient at this time." The healthcare system, however, has pitfalls that may hinder SDM, e.g., rigid interpretation of guideline-based recommendations. CONCLUSION: Using an in-consultation Decision Helper has the potential for individualized, structured patient engagement in decision making. There is a need for patient decision aids in clinical guidelines to ensure patient engagement in decision making.

Benefit of respiratory gating in the Danish Breast Cancer Group partial breast irradiation trial.

BACKGROUND AND PURPOSE: Partial breast irradiation (PBI)has beenthe Danish Breast Cancer Group(DBCG) standard for selected breast cancer patients since 2016 based onearlyresults from the DBCG PBI trial.During trial accrual, respiratory-gated radiotherapy was introduced in Denmark. This study aims to investigate the effect of respiratory-gating on mean heart dose (MHD). PATIENTS AND METHODS: From 2009 to 2016 the DBCG PBI trial included 230 patientswith left-sided breast cancer receiving external beam PBI, 40 Gy/15 fractions/3 weeks.Localization of the tumor bed on the planning CT scan, the use of respiratory-gating, coverage of the clinical target volume (CTV), and doses to organs at risk were collected. RESULTS: Respiratory-gating was used in 123 patients (53 %). In 176 patients (77 %) the tumor bed was in the upper and in 54 patients (23 %) in the lower breast quadrants. The median MHD was 0.37 Gy (interquartile range 0.26-0.57 Gy), 0.33 Gy (0.23-0.49 Gy) for respiratory-gating, and 0.49 Gy (0.31-0.70 Gy) for free breathing, p < 0.0001. MHD was < 1 Gy in 206 patients (90 %) and < 2 Gy in 221 patients (96 %). Respiratory-gating led to significantly lower MHD for upper-located, but not for lower-located tumor beds, however, all MHD were low irrespective of respiratory-gating. Respiratory-gating did not improve CTV coverage or lower lung doses. CONCLUSIONS: PBI ensured a low MHD for most patients. Adding respiratory-gating further reduced MHD for upper-located but not for lower-located tumor beds but did not influence target coverage or lung doses. Respiratory-gating is no longer DBCG standard for left-sided PBI.

Clinical experiences of guided tapering of antipsychotics for patients with schizophrenia- a case series.

BACKGROUND: 80% of patients value information on treatment options as an important part of recovery, further patients with a history of psychotic episodes feel excluded from decision making about their antipsychotic treatment, and on top of that, mental health staff is prone to be reluctant to support shared decision making and medication tapering for patients with schizophrenia. This case series aims to demonstrate the tapering of antipsychotic medication and how guided tapering affects the patient's feeling of autonomy and psychiatric rehabilitation. CASE PRESENTATION: We present six patients diagnosed with schizophrenia (International Classification of Mental and Behavioral Disorders- 10th Edition codes F20.0-5, F20.7-9) who underwent professionally guided tapering in our clinic. The clinic aims to guide the patients to identify the lowest possible dose of antipsychotic medication in a safe setting to minimise the risk of severe relapse. Two patients completely discontinued their antipsychotic medication, two suffered a relapse during tapering, one chose to stop the tapering at a low dose, and one patient with treatment resistant schizophrenia, which is still tapering down. CONCLUSIONS: Reducing the antipsychotic dose increased emotional awareness in some patients (n = 4) helping them to develop better strategies to handle stress and increased feelings of recovery. Patients felt a greater sense of autonomy and empowerment during the tapering process, even when discontinuation was not possible. Increased awareness in patients and early intervention during relapse may prevent severe relapse. IMPACT AND IMPLICATIONS: Some patients with schizophrenia might be over medicated, leading to unwanted side effects and the wish to reduce their medication. The patients in our study illustrate how guided tapering of antipsychotic medication done jointly with the patient can lead to improved emotional awareness and the development of effective symptom management strategies. This may in turn lead to a greater sense of empowerment and identity and give life more meaning, supporting the experience of personal recovery.

Functional Connectivity Between Auditory and Medial Temporal Lobe Networks in Antipsychotic-Naïve Patients With First-Episode Schizophrenia Predicts the Effects of Dopamine Antagonism on Auditory Verbal Hallucinations.

Background: Understanding how antipsychotic medication ameliorates auditory verbal hallucinations (AVHs) through modulation of brain circuitry is pivotal for understanding the pathophysiology of psychosis and for predicting treatment response. Methods: This case-control study included examinations at baseline and at follow-up after 6 weeks. Initially, antipsychotic-naïve patients with first-episode schizophrenia who were experiencing AVHs were recruited together with healthy control participants. Antipsychotic treatment with the relatively selective D2 receptor antagonist amisulpride was administered as monotherapy. Functional connectivity measured by resting-state functional magnetic resonance imaging between networks of interest was used to study the effects of D2 blockade on brain circuitry and predict clinical treatment response. Hallucinations were rated with the Positive and Negative Syndrome Scale. Results: Thirty-two patients experiencing AVHs and 34 healthy control participants were scanned at baseline. Twenty-two patients and 34 healthy control participants were rescanned at follow-up. Connectivity between the auditory network and the medial temporal lobe network was increased in patients at baseline (p = .002) and normalized within 6 weeks of D2 blockade (p = .018). At baseline, the connectivity between these networks was positively correlated with ratings of hallucinations (t = 2.67, p = .013). Moreover, baseline connectivity between the auditory network and the medial temporal lobe network predicted reduction in hallucinations (t = 2.34, p = .032). Conclusions: Functional connectivity between the auditory network and the medial temporal lobe predicted response to initial antipsychotic treatment. These findings demonstrate that connectivity between networks involved in auditory processing, internal monitoring, and memory is associated with the clinical effect of dopamine antagonism.

Shared decision making with breast cancer patients - does it work? Results of the cluster-randomized, multicenter DBCG RT SDM trial.

BACKGROUND AND PURPOSE: Shared decision making (SDM) is a patient engaging process advocated especially for preference-sensitive decisions, such as adjuvant treatment after breast cancer. An increasing call for patient engagement in decision making highlights the need for a systematic SDM approach. The objective of this trial was to investigate whether the Decision Helper (DH), an in-consultation patient decision aid, increases patient engagement in decisions regarding adjuvant whole breast irradiation. MATERIAL AND METHODS: Oncologists at four radiotherapy units were randomized to practice SDM using the DH versus usual practice. Patient candidates for adjuvant whole breast irradiation after breast conserving surgery for node-negative breast cancer were eligible. The primary endpoint was patient-reported engagement in the decision process assessed with the Shared Decision Making Questionnaire (SDM-Q-9) (range 0-100, 4 points difference considered clinical relevant). Other endpoints included oncologist-reported patient engagement, decisional conflict, fear of cancer recurrence, and decision regret after 6 months. RESULTS: Of the 674 included patients, 635 (94.2%) completed the SDM-Q-9. Patients in the intervention group reported higher level of engagement (median 80; IQR 68.9 to 94.4) than the control group (71.1; IQR 55.6 to 82.2; p < 0.0001). Oncologist-reported patient engagement was higher in the invention group (93.3; IQR 82.2 to 100) compared to control group (73.3; IQR 60.0 to 84.4) (p < 0.0001). CONCLUSION: Patient engagement in medical decision making was significantly improved with the use of an in-consultation patient decision aid compared to standard. The DH on adjuvant whole breast irradiation is now recommended as standard of care in the Danish guideline.

Recurrence and Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Synchronous and Metachronous Peritoneal Metastases of Colorectal Origin.

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved the 5-year survival for colorectal cancer (CRC) patients with peritoneal metastases (PM). Little is known about recurrence patterns and recurrence rates between synchronous (S) and metachronous (M) PM following CRS+HIPEC. We aimed to describe the recurrence patterns, overall survival (OS) and disease-free survival (DFS) in S-PM and M-PM patients after complete CRS+HIPEC. From June 2006 to December 2020, a prospective cohort study included 310 CRC patients, where 181 patients had S-PM (58.4%) and 129 patients had M-PM (41.6%). After a median 10.3-month follow-up, 247/310 (79.7%) patients experienced recurrence, and recurrence sites included isolated peritoneal (32.4%), multifocal (peritoneal and liver and/or lung(s)) (22.7%), isolated liver (17.8%), isolated lung (10.5%) and other (16.6%) sites. Recurrence patterns did not differ between S-PM and M-PM. M-PM patients had an impaired DFS compared to S-PM patients (9.4 months (95% CI: 7.3-12.1) vs. 12.5 months (95% CI: 11.2-13.9), p = 0.01). The median OS was similar for S-PM and M-PM (38.4 months (95% CI: 31.2-46.8) vs. 40.8 months (95% CI: 28.8-46.8), p = 0.86). Despite frequent recurrence at extraperitoneal locations, long-term survival was achievable after CRS+HIPEC in CRC patients with PM. The recurrence patterns and OS did not differ between groups, yet M-PM patients had a shorter DFS.

Negative symptoms and social cognition as mediators of the relationship between neurocognition and functional outcome in schizophrenia.

Introduction: In this study we assessed the contribution of psychopathology, including the two domains of negative symptoms (motivational deficit and expressive deficit), processing speed as an index of neurocognition, and emotion recognition, as an index of social cognition, to poor functional outcomes in people with schizophrenia. Methods: The Positive and Negative Syndrome Scale was used to evaluate positive symptoms and disorganization and the Brief Negative Symptom Scale to assess negative symptoms. The Symbol Coding and the Trail Making Test A and B were used to rate processing speed and the Facial Emotion Identification Test to assess emotion recognition. Functional outcome was assessed with the Personal and Social Performance Scale (PSP). Regression analyses were performed to identify predictors of functional outcome. Mediation analyses was used to investigate whether social cognition and negative symptom domains fully or partially mediated the impact of processing speed on functional outcome. Results: One hundred and fifty subjects from 8 different European centers were recruited. Our data showed that the expressive deficit predicted global functioning and together with motivational deficit fully mediated the effects of neurocognition on it. Motivational deficit was a predictor of personal and social functioning and fully mediated neurocognitive impairment effects on the same outcome. Both motivational deficit and neurocognitive impairment predicted socially useful activities, and the emotion recognition domain of social cognition partially mediated the impact of neurocognitive deficits on this outcome. Conclusions: Our results indicate that pathways to functional outcomes are specific for different domains of real-life functioning and that negative symptoms and social cognition mediate the impact of neurocognitive deficits on different domains of functioning. Our results suggest that both negative symptoms and social cognition should be targeted by psychosocial interventions to enhance the functional impact of neurocognitive remediation.

Case of primary low-grade neuroendocrine carcinoma of the skin.

A man presents a 4 mm skin tumour at his general practitioner. The tumour is removed on the suspicion of a dermatofibroma. Important differential diagnoses are sebaceous neoplasms, melanomas, Merkel cell carcinomas and large cell neuroendocrine carcinoma, and metastases of neuroendocrine neoplasms from the gut or lung. Immunohistochemical staining excluded sebaceous neoplasm, melanoma and Merkel cell carcinoma, however, was positive for multiple neuroendocrine markers. Relevant scans showed no signs of a primary tumour anywhere else. The final diagnosis was a primary low-grade neuroendocrine carcinoma of the skin. At 30 months follow-up, there was no sign of recurrence.

Influence of psychopathology and metabolic parameters on quality of life in patients with first-episode psychosis before and after initial antipsychotic treatment.

The impact of psychological and physical health on quality of life (QoL) in patients with early psychosis remain relatively unexplored. We evaluated the predictive value of psychopathological and metabolic parameters on QoL in antipsychotic-naïve patients with first-episode psychosis before and after initial antipsychotic treatment. At baseline, 125 patients underwent assessments of psychopathology, prevalence of metabolic syndrome (MetS), and QoL. After 6 weeks of antipsychotic monotherapy, 89 patients were re-investigated. At baseline, the prevalence of MetS was 19.3% (n = 22). After 6 weeks, body weight (1.3 kg, p < 0.001) and body mass index (0.4 kg/m2, p < 0.001) increased, and four additional patients developed MetS. Multivariate linear regression revealed that positive and negative symptoms, and to some degree waist circumference, were predictors of QoL at both time points. Our findings suggest that in the earliest stages of antipsychotic treatment, metabolic side-effects may be less influential on QoL than psychopathological severity.

Dose- and substrate-dependent reduction of enteric methane and ammonia by natural additives in vitro.

Ruminants contribute to global warming by emitting greenhouse gasses, particularly methane (CH4) which is a product of rumen fermentation. The use of feed additives able to modulate rumen fermentation is a promising strategy to reduce enteric CH4 and ammonia (NH3) emissions. Among the various strategies investigated, plant secondary metabolites (PSMs) have attracted attention due to their apparent potential to reduce enteric CH4 and NH3 emissions, and it would be possible to use such compounds as feed additives in organic production systems. In an in vitro system simulating rumen fermentation, we have tested the impact of different classes of naturally occurring PSMs; catechin and quercetin (flavonoids), salicylic acid (phenolic acid) and tannic acid (hydrolysable tannin). The PSMs were added to two different basal feeds (maize and grass silages) at three inclusion doses 1.5, 3 and 6% of the feed dry matter (DM). CH4 production was significantly lowered upon addition of quercetin to two basal feeds at doses of 3 and 6%, and this without changes in concentrations of total volatile fatty acid (VFA) produced during fermentation. Quercetin, as the only tested additive, reduced CH4 production, and when added to maize silage and grass silage, the reduction increased linearly with increasing dose, ie., by 51 and 43%, respectively, at a dose of 3% of feed DM and by 86 and 58%, respectively, at a dose of 6% of feed DM. Moreover, quercetin significantly reduced NH3 concentration by >12% at doses of 3 and 6% in feed DM irrespective of the basal feed used as compared to when the basal feeds were incubated alone. Although none of the other additives affected CH4 formation, several additives had significant impacts on concentrations of NH3 and VFAs in the incubated fluid after fermentation. This study demonstrated a dose-dependent ability of quercetin to reduce CH4 emission from rumen fermentation, however, the magnitude of the suppression of CH4 depended on the basal feed. Furthermore, quercetin reduced NH3 concentration irrespective of the basal feed type. These findings encourage to in vivo studies to verify whether quercetin can reduce CH4 emission also in cows.

The Risk of Growth Disturbance Is Low After Pediatric Anterior Cruciate Ligament Reconstruction With a Femoral Growth Plate Sparing Technique.

Purpose: To evaluate radiological tibial and femoral length and axis growth disturbances, as well as clinical outcome in skeletal immature anterior cruciate ligament reconstruction (ACLR) patients treated with a femoral growth plate-sparing ACLR technique. Methods: Skeletally immature patients who underwent operation between 2013 to 2019 with ALCR using the femoral growth plate-sparing technique were investigated with follow-up after growth plate closure. The inclusion criteria were isolated ACL rupture in patients with open physis in the distal femur and proximal tibia seen at plain radiography. The minimum follow-up time was 29 months. Patients were evaluated with full extremity radiographs measuring limb length discrepancy and coronal knee alignment compared to contralateral leg, as well as clinical evaluation with Rolimeter measurements and the Knee Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee subjective knee form (IKDC), and Tegner Activity Scale scores. Results: Sixty-five patients were examined with radiography, and 52 patients were assessed with clinical examination. The mean follow-up time was 68 (range, 29-148) months. No limb-length discrepancy (-0.65 mm [confidence interval {CI}, -2.21 to 0.92]) or angular deformity at tibia (-0.25° [CI, -0.78° to 0.28°]) was found. There was a small but statistically significant different angular deformity at the distal femur compared to the contralateral leg (-1.51° [CI, -2.31 to -0.72]) at follow-up. The side-to-side difference in knee laxity at follow-up was 2.4 mm. At follow-up the KOOS Sport, KOOS Quality of Life (QoL), IKDC, and Tegner scores were 80, 75, 86, and 5, respectively. Sixty-seven percent of the patients met the Patient Acceptable Symptom State, and 52% reported results exceeding the KOOS Sport MCID Level and 69% the KOOS QoL level. Conclusions: Femoral physis-sparing ALCR is associated with a low risk of alignment and length disturbances. The technique provides otherwise good subjective clinical outcome and knee stability. Level of Evidence: Level IV, therapeutic case series.

Carbon-fiber alternative to the commercial gating surrogate for the Varian Truebeam™.

BACKGROUND: In this study we present the Tracking Accessory 3 (TA3) as an alternative to the commercial gating block (GB) surrogate for the Varian Truebeam™ gating system (TGS). The TGS requires three visible reflectors to track the surrogate, presenting an opportunity for a surrogate to be made with less material and thus smaller dosimetric footprint than the commercial four reflector model. MATERIALS AND METHODS: Relative dose and depth dose profiles below the TA3 and the GB were measured with radiosensitive film. Accuracy and reproducibility of the detected motion amplitude for three TA3s and one GB were determined using a respiratory phantom with surrogate to determine the camera's tracking volume. Clinical performance was evaluated prospectively in 10 breast cancer patients treated with deep inspiration breath hold monitored with TA3 and compared to previously published results. Non-parametric statistics were applied to test for significance. RESULTS AND CONCLUSIONS: Surface doses were increased up to 94% and 187% for the TA3 and GB, respectively, compared to no surrogate. The surface area influenced by at least 25% increase in dose was 12 cm2 and 105 cm2 for the TA3 and GB, respectively. The water equivalent thickness of the surrogates was found to be 1 mm for the TA3 and 3 mm for GB. The difference in measured amplitude were <0.2 mm for TA3 compared to the GB. The TA3s and GB were detected at all extremes of the clinically relevant tracking volume of the TGS. Clinical performance showed no significant differences. The TA3 caused less surface dose increase compared to the commercial GB. In the tested range all surrogates measured motion amplitude within 0.2 mm of reference value, which is not a clinically relevant difference. The TA3 showed no significant differences in clinical performance to similarly positioned surrogates.

Impact of letrozole co-treatment during ovarian stimulation on oocyte yield, embryo development, and live birth rate in women with normal ovarian reserve: secondary outcomes from the RIOT trial.

STUDY QUESTION: Does letrozole (LZ) co-treatment during ovarian stimulation with gonadotropins for in IVF impact follicle recruitment, oocyte number and quality, embryo quality, or live birth rate (LBR)? SUMMARY ANSWER: No impact of LZ was found in follicle recruitment, number of oocytes, quality of embryos, or LBR. WHAT IS KNOWN ALREADY: Multi-follicle stimulation for IVF produces supra-physiological oestradiol levels. LZ is an aromatase inhibitor that lowers serum oestradiol thus reducing negative feedback and increasing the endogenous gonadotropins in both the follicular and the luteal phases, effectively normalizing the endocrine milieu during IVF treatment. STUDY DESIGN, SIZE, DURATION: Secondary outcomes from a randomized, double-blind placebo-controlled trial (RCT) investigating once-daily 5 mg LZ or placebo during stimulation for IVF with FSH. The RCT was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018 and pregnancy outcomes of frozen-thawed embryo transfers (FET) registered until May 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred fifty-nine women with expected normal ovarian reserve (anti-Müllerian hormone 8-32 nmol/l) were randomized to either co-treatment with LZ (n = 80) or placebo (n = 79). In total 1268 oocytes were aspirated developing into 386 embryos, and morphology and morphokinetics were assessed. One hundred twenty-nine embryos were transferred in the fresh cycle and 158 embryos in a subsequent FET cycle. The effect of LZ on cumulative clinical pregnancy rate (CPR), LBR, endometrial thickness in the fresh cycle, and total FSH consumption was reported. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of usable embryos of retrieved oocytes was similar in the LZ group and the placebo group with 0.31 vs 0.36 (mean difference (MD) -0.05, 95% CI (-0.12; 0.03), P = 0.65). The size and number of aspirated follicles at oocyte retrieval were similar with 11.8 vs 10.3 follicles per patient (MD 1.5, 95% CI (-0.5; 3.1), P = 0.50), as well as the number of retrieved oocytes with 8.0 vs 7.9 oocytes (MD 0.1, 95% CI (-1.4; 1.6), P = 0.39) in the LZ and placebo groups, respectively. The chance of retrieving an oocyte from the 13 to 16 mm follicles at trigger day was 66% higher (95% CI (24%; 108%), P = 0.002) in the placebo group than in the LZ group, whilst the chance of retrieving an oocyte from the ≥17 mm follicles at trigger day was 50% higher (95% CI (2%; 98%), P = 0.04) in the LZ group than in the placebo group. The proportion of fertilized oocytes with two-pronuclei per retrieved oocytes or per metaphase II oocytes (MII) (the 2PN rates) were similar regardless of fertilization with IVF or ICSI with 0.48 vs 0.57 (MD -0.09, 95% CI (-0.24; 0.04), P = 0.51), and 0.62 vs 0.64 (MD -0.02, 95% CI (-0.13; 0.07), P = 0.78) in the LZ and placebo groups, respectively. However, the MII rate in the ICSI group was significantly lower with 0.75 vs 0.88 in the LZ vs the placebo group (MD -0.14, 95% CI (-0.22; -0.06), P = 0.03). Blastocysts on Day 5 per patient were similar with 1.5 vs 2.0, P = 0.52, as well as vitrified blastocysts per patient Day 5 with 0.8 vs 1.2 in (MD -0.4, 95% CI (-1.0; 0.2), P = 0.52) and vitrified blastocysts per patient Day 6 with 0.6 vs 0.6 (MD 0, 95% CI (-0.3; 0.3), P = 1.00) in the LZ vs placebo group, respectively. Morphologic evaluation of all usable embryos showed a similar distribution in 'Good', 'Fair', and 'Poor', in the LZ vs placebo group, with an odds ratio (OR) of 0.8 95% CI (0.5; 1.3), P = 0.68 of developing a better class embryo. Two hundred and ninety-five of the 386 embryos were cultured in an embryoscope. Morphokinetic annotations showed that the odds of having a high KIDscore™ D3 Day 3 were 1.2 times higher (CI (0.8; 1.9), P = 0.68) in the LZ group vs the placebo group. The CPR per transfer was comparable with 31% vs 39% (risk-difference of 8%, 95% CI (-25%; 11%), P = 0.65) in the LZ and placebo group, respectively, as well as CPR per transfer adjusted for day of transfer, oestradiol and progesterone levels at trigger, progesterone levels mid-luteal, and number of oocytes retrieved (adjusted OR) of 0.8 (95% CI (0.4; 1.6), P = 0.72). Comparable LBR were found per transfer 28% vs 37% (MD -9%, 95% CI (-26%; 9%), P = 0.60) and per randomized women 24% vs 30% (MD of -6%, CI (-22%; 8%), P = 0.60) in the LZ group and placebo group, respectively. Furthermore, 4.8 years since the last oocyte aspiration, a total of 287 of 386 embryos have been transferred in the fresh or a subsequently FET cycle, disclosing the cumulative CPR, which is similar with 38% vs 34% (MD 95% CI (8%; 16%), P = 0.70) in the LZ vs placebo group. LIMITATIONS, REASONS FOR CAUTION: Both cleavage stage and blastocyst transfer and vitrification were permitted in the protocol, making it necessary to categorize their quality and pool the results. The study was powered to detect hormonal variation but not embryo or pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The similar utilization rate and quality of the embryos support the use of LZ co-treatment for IVF with specific indication as fertility preservation, patients with previous cancer, or poor responders. The effect of LZ on mature oocytes from different follicle sizes and LBRs should be evaluated in a meta-analysis or a larger RCT. STUDY FUNDING/COMPETING INTEREST(S): Funding was received from EU Interreg for ReproUnion, Sjaelland University Hospital, Denmark, Ferring Pharmaceuticals, and Gedeon Ricther. Roche Diagnostics contributed with assays. A.P. has received grants from Ferring, Merck Serono, and Gedeon Richter, consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, speakers fees from Gedeon Richter, Ferring, Merck A/S, Theramex, & Organon, and travel support from Gedeon Richter. The remaining authors declare that they have no competing interests in the research or publication. TRIAL REGISTRATION NUMBERS: NCT02939898 and NCT02946684.

Meal sugar-protein balance determines postprandial FGF21 response in humans.

Biological mechanisms to promote dietary balance remain unclear. Fibroblast growth factor 21 (FGF21) has been suggested to contribute to such potential regulation considering that FGF21 1) is genetically associated with carbohydrate/sugar and protein intake in opposite directions, 2) is secreted after sugar ingestion and protein restriction, and 3) pharmacologically reduces sugar and increases protein intake in rodents. To gain insight of the nature of this potential regulation, we aimed to study macronutrient interactions in the secretory regulation of FGF21 in healthy humans. We conducted a randomized, double-blinded, crossover meal study (NCT05061485), wherein healthy volunteers consumed a sucrose drink, a sucrose + protein drink, and a sucrose + fat drink (matched sucrose content), and compared postprandial FGF21 responses between the three macronutrient combinations. Protein suppressed the sucrose-induced FGF21 secretion [incremental area under the curve (iAUC) for sucrose 484 ± 127 vs. sucrose + protein -35 ± 49 pg/mL × h, P < 0.001]. The same could not be demonstrated for fat (iAUC 319 ± 102 pg/mL × h, P = 203 for sucrose + fat vs. sucrose). We found no indications that regulators of glycemic homeostasis could explain this effect. This indicates that FGF21 responds to disproportionate intake of sucrose relative to protein acutely within a meal, and that protein outweighs sucrose in FGF21 regulation. Together with previous findings, our results suggests that FGF21 might act to promote macronutrient balance and sufficient protein intake.NEW & NOTEWORTHY Here we test the interactions between sugar, protein, and fat in human FGF21 regulation and demonstrate that protein, but not fat, suppresses sugar-induced FGF21 secretion. This indicates that protein outweighs the effects of sugar in the secretory regulation of FGF21, and could suggest that the nutrient-specific appetite-regulatory actions of FGF21 might prioritize ensuring sufficient protein intake over limiting sugar intake.

Methane reduction by quercetin, tannic and salicylic acids: influence of molecular structures on methane formation and fermentation in vitro.

Plant secondary metabolites (PSMs) can potentially reduce ruminal methane formation. However, related to differences in their molecular structures, it is not yet clear what causes an anti-methanogenic effect. In an in vitro system simulating rumen fermentation, we investigated the impact of eight compounds with distinct chemical characteristics (gallic and salicylic acids, tannic acid, catechin, epicatechin, quercetin, rutin, and salicin) when added to a basal feed (maize silage) at a concentration of 12% of the feed dry matter. After 48 h of incubation in buffered rumen fluid, methane production was significantly lowered by quercetin (43%), tannic acid (39%) and salicylic acid (34%) compared to the control (maize silage alone) and without changes in total volatile fatty acid production during fermentation. No other PSM reduced methane formation as compared to control but induced significant differences on total volatile fatty acid production. The observed differences were related to lipophilicity, the presence of double bond and carbonyl group, sugar moieties, and polymerization of the compounds. Our results indicate the importance of distinct molecular structures of PSMs and chemical characteristics for methane lowering properties and volatile fatty acid formation. Further systematic screening studies to establish the structure-function relationship between PSMs and methane reduction are warranted.