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There is a need for real-time non-invasive, continuous monitoring of cerebral blood flow (CBF) during surgery, in intensive care units and clinical research. We investigated a new non-invasive hybrid technology employing ultrasound tagged near infrared spectroscopy (UT-NIRS) that may estimate changes in CBF using a cerebral blood flow index (CFI). Changes over time for UT-NIRS CFI and 133Xenon single photon emission computer tomography (133Xe-SPECT) CBF data were assessed in 10 healthy volunteers after an intravenous bolus of acetazolamide. UT-NIRS CFI was measured continuously and SPECT CBF was measured at baseline, 15 and 60 min after acetazolamide. We found significant changes over time in CFI by UT-NIRS and CBF by SPECT after acetazolamide (P ≤ 0.001). Post hoc tests showed a significant increase in CFI (P = 0.011) and SPECT CBF (P < 0.001) at 15 min after acetazolamide injection. There was a significant correlation between CFI and SPECT CBF values (r = 0.67 and P ≤ 0.033) at 15 min, but not at 60 min (P ≥ 0.777). UT-NIRS detected an increase in CFI following an acetazolamide bolus, which correlated with CBF measured with 133Xe-SPECT. This study demonstrates that UT-NIRS technology may be a promising new technique for non-invasive and real-time bedside CBF monitoring. [ABSTRACT FROM AUTHOR]

There is a striking similarity between the migraine-provoking effect of the nitric oxide (NO) donor glyceryl trinitrate (GTN) and that of calcitonin gene-related peptide (CGRP). We tested the hypothesis that NO releases CGRP to cause the delayed migraine attack after GTN.Methods: In a double-blind-cross-over study, 13 migraine without aura (MO) patients were administered GTN 0.5 µg/kg/ minute for 20 minutes and subsequently BIBN4096BS (olcegepant) 10 mg or placebo. Headache scores and development of MO were followed for 24 hours.Results: MO developed in seven of 13 with olcegepant and in nine of 13 with placebo (p = 0.68). The headache scores were similar after the two treatments (p = 0.58). Thus CGRP receptor blockade did not prevent GTN-induced migraine. Conclusions: The present study indicates that NO does not induce migraine by liberating CGRP. The most likely explanation for our findings is that CGRP has its effect higher than NO in the cascade of events leading to MO attacks. [ABSTRACT FROM PUBLISHER]

Three-dimensional echocardiography (3DE) is currently the preferred method for monitoring left ventricular ejection fraction (LVEF) in cancer patients receiving potentially cardiotoxic anti-neoplastic therapy. In Denmark, however, the traditional standard for LVEF monitoring has been rooted in nuclear medicine departments utilizing equilibrium radionuclide angiography (ERNA). Although ERNA remains a principal modality, there is an emerging trend towards the adoption of echocardiography for this purpose. Given this context, assessing the reproducibility of 3DE among non-specialized medical personnel is crucial for its clinical adoption in such departments. To assess the feasibility of 3DE for LVEF measurements by technologists, we evaluated the repeatability and reproducibility of two moderately experienced technologists. They performed 3DE on 12 volunteers over two sessions, with a collaborative review of the results from the first session before the second session. Two-way intraclass correlation values increased from 0.03 to 0.77 across the sessions. This increase in agreement was mainly due to the recognition of false low measurements. Our findings underscore the importance of incorporating reproducibility exercises in the context of 3DE, especially when operated by technologists. Additionally, routine control of the acquisitions by physicians is deemed necessary. Ensuring these hurdles are adequately managed enables the adoption of 3DE for LVEF measurements by technologists.

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF., Methods: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m 2 ) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up., Discussion: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition., Trial Registration: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome., Competing Interests: Conflict of interest C.F.A. reports grants from the Danish Heart Foundation, Toyota-Fonden, Arvid Nilsson's Foundation, Aase & Ejnar Danielsen's Foundation, Fru Asta Florida Bolding's Memorial Grant, KV Foundation and The Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Herlev, Denmark, during the conduct of the submitted work; personal fees from AstraZeneca and has acted as an unpaid sub-investigator in two trials from Novo Nordisk, outside the submitted work. J.H.L. reports grants from Danish Heart Foundation, Odense University Hospital Ph.D. Foundation, Steno Diabetes Center Odense Ph.D. Foundation, Eva and Henry Frænkel's Memorial Grant, Kurt and Grethe Bønnelykke's Foundation, Guldsmed A.L. Rasmussen's Memorial Grant. Funding organizations had no role in the trial program design, data collection, writing of the article or decision to submit the paper. J.J. reports grants from the Danish Heart Foundation, The CARDIOHGH at the Department of Cardiology, Herlev and Gentofte University Hospital, and The Capital Region of Denmark; personal fees from AstraZeneca (advisory board) and Boehringer Ingelheim (advisory board and contribution to the KARDINAL study), all outside the submitted work. M.A.O reports grants from the Danish Heart Foundation; Steno Diabetes Center Odense, Denmark; and the A.P. Møller Foundation, outside the submitted work. N.N. reports speaker fees from AstraZeneca and Bayer, all outside the submitted work. C.K. has received speaker fees or served on advisory boards for AstraZeneca, Boehringer Ingelheim, Novartis Genzyme, Amicus and Chiesi. C.T. reports speaker fees from Orion Pharma, personal fees for advisory board participation from Boehringer Ingelheim and Bayer A/S, all outside the submitted work. F.G. reports speaker fees from Orion Pharma, Vifor Pharma and Novartis, and personal fees for advisory board participation from Abbott, Pfizer, AstraZeneca, Ionis, Alnylam and Bayer, all outside the submitted work. F.K.K. has served on scientific advisory panels and/or been part of speaker's bureaus for, served as a consultant to and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, Lupin, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Pharmacosmos, Sanofi, ShouTi, Zealand Pharma and Zucara; and is a minority shareholder in Antag Therapeutics and co-owner of the weight loss clinic Medicinsk Vægttabsbehandling ApS. F.S.D. reports grants from The CARDIOHGH at the Department of Cardiology, Herlev and Gentofte University Hospital, the Novo Nordisk Foundation and speaker fees from Bayer, all outside the submitted work. K.H. reports grants from the Novo Nordisk Foundation, the Independent Research Fund Denmark, the Region of Southern Denmark, Odense University Hospital, Lilly and Herbert Hansen's Foundation, Jascha Fonden, the Ministry of Higher Education and Science, and the Danish Diabetes Academy all outside submitted work. L.K. reports speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis and Bayer. L.A. reports speaker fees from Novartis. M.S. reports grants from the Danish Heart Foundation, during the conduct of the study; personal fees and non-financial support from AstraZeneca, personal fees from Novo Nordisk and Boehringer Ingelheim, outside the submitted work. J.E.M. reports speaker fees from Novartis, Boehringer Ingelheim, Abiomed, Orion and Abbott, advisory board from Orion and Boehringer Ingelheim, and research grant Abiomed and Roche, all outside submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Soft tissue defects after total knee arthroplasties (TKA) represent a major orthopedic challenge with amputation as a feared outcome. Microvascular free flap coverage (FFC) can increase limb salvage rates, but complications related to the procedure are yet to be explored further. We aimed to review a single-center experience with FFC for soft tissue defects related to revision total knee arthroplasty., Methods: Through a retrospective chart review from 2006 to 2021, we identified all patients who had FFC of a knee with an existing TKA. Typically, patients underwent 2-stage revision arthroplasty. To identify areas of intervention, we divided the entire regimen into 2 phases divided by the free flap surgery (pre- and post-free flap)., Results: We identified 18 patients with a median age at free flap surgery of 69 years (range 39-85), who were followed for a median of 5.1 years (range 2 months to 10.6 years). The median duration from primary TKA to their final operation was 17.5 months (range 19 days to 7 years). Patients underwent a mean of 7.6 surgical procedures on their knee with 3.6 orthopedic revisions prior to the FFC and 0.6 after. Soft tissue coverage was achieved in all patients and no patients underwent amputation. One-third of patients experienced early complications at recipient site after free flap surgery. There were no donor site complications., Conclusion: Microvascular FFC of complex soft tissue defects after revision total knee arthroplasty proved achievable in all patients with successful limb salvage in all patients.

Background Information: The precise etiology of breast cancer is not completely understood, although women with BRCA1 gene mutations have a significantly increased risk of developing the disease. In addition, sporadic breast cancer is frequently associated with decreased BRCA1 gene expression. Growing evidence of Human papillomaviruses (HPVs) infections in breast tumors has raised the possibility of the involvement of HPVs in the pathogenesis of breast cancer. We investigated whether the effects of HPV oncoproteins E6 and E7 were influenced by the expression levels of BRCA1. HPV16E6E7 (prototype or E6D25E/E7N29S Asian variant type) were stably expressed in MDA-MB231 breast cancer cells, wild type for BRCA1, or with BRCA1 knocked down., Results: Expression of HPV16E6E7 oncogenes did not affect BRCA1 levels and the abundance of HPV16E6E7 was not altered by BRCA1 knockdown. BRCA1 levels did not alter HPV16E6E7-dependent degradation of G1-S cell cycle proteins p53 and pRb. However, we found that the expression of G2-M cell cycle protein cyclin B1 enhanced by HPV16E6E7 was impacted by BRCA1 levels. Especially, we found the correlation between BRCA1 and cyclin B1 expression and this was also confirmed in breast cancer samples from a Thai cohort. We further demonstrated that the combination of HPV oncoproteins and low levels of BRCA1 protein appears to enhance proliferation and invasion. Transactivation activities of HPV16E6E7 on genes regulating cell proliferation and invasion (TGF-β and vimentin) were significantly increased in BRCA1-deficient cells., Conclusions: Our results indicate that a deficiency of BRCA1 promotes the transactivation activity of HPV16E6E7 leading to increase of cell proliferation and invasion., Significance: HPV infection appears to have the potential to enhance the aggressiveness of breast cancers, especially those deficient in BRCA1., (© 2024 The Authors. Biology of the Cell published by Wiley‐VCH GmbH on behalf of Société Française des Microscopies and Société Biologie Cellulaire de France.)

Background: Elderly surgical patients have a high risk of postoperative complications. However, patients exhibit considerable diversity in health and functional status; thus, identifying the fragile may be necessary when selecting surgical candidates. We aimed to compare the prevalence of frailty in patients ≥90 years with patients aged 80-89. Second, we assessed the association between frailty and all-cause 30-day mortality., Methods: We performed a planned secondary analysis of the peri-interventional outcome study in the elderly (POSE), including 9497 patients (≥80 years) undergoing any surgical and nonsurgical procedures in 177 European centres from October 2017 to December 2018. The primary outcome assessment included frailty as a binary variable, and data were analysed using Fisher's exact test/Chi-squared test. The association between frailty and all-cause 30-day mortality was analysed using a multivariate logistic regression model adjusted for age, sex, surgical urgency, orthopaedic urgency, and surgical severity., Results: In total, 999 of 9497 (10.5%) patients were 90 years or above. Among patients ≥90 years, 274 (27.4%) were frail compared to 1062 (12.5%) of patients aged 80-89 (odds ratio (OR): 2.6; 95% CI 2.3-3.1). Frailty was associated with increased 30-day mortality in both the unadjusted (crude OR 6.3; 5.1-7.7) and adjusted analysis (OR 4.5; 3.6-5.7). In the adjusted analysis, age ≥90 was not associated with 30-day mortality., Conclusion: We found a high frequency of frailty in patients aged 90 years or above compared with patients aged 80-89. In addition, frailty was associated with an increased risk of 30-day mortality. Surprisingly, age was not a significant risk factor in the adjusted mortality analysis., (© 2023 Acta Anaesthesiologica Scandinavica Foundation.)

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated 1 . Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age 2 , along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment., (© 2024. The Author(s).)

JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed., Competing Interests: Declaration of interests L.F. and K.E.A. have an unrestricted grant from Bristol Myers Squibb. L.T.J. and M.F. declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Lymphedema (LE) is a common complication after breast cancer treatment, which negatively affects the quality of life (QOL). Hyperbaric Oxygen Treatment (HBOT) is an established treatment for radiation-induced tissue injury, but evidence of effect on breast cancer-related LE is inconclusive. We aimed to explore effects of HBOT on early breast cancer-related LE and the implications for QOL., Methods: We invited women with breast cancer treated with surgery, axillary dissection and radiotherapy, who had participated in a randomized controlled trial and who presented with LE 1 year after surgery. In a prospective observational study design, change in LE was assessed with perometry, dual-energy X-ray absorptiometry (DXA) and lymphoscintigraphy, and QOL by validated self-report scales. Participants were offered 40 sessions of HBOT on every weekday for 8 weeks and were followed for 6 months., Results: Out of 50 eligible participants, 20 women accepted participation. Nineteen women initiated and completed treatment and follow-up. None of the objective measures of LE severity showed consistent changes during the study period, but participants reported significant improvements in QOL (physical functioning, fatigue, insomnia and breast and arm symptoms), with improvements peaking at 6-month follow-up., Conclusion: Participants receiving HBOT experienced improved QOL without consistently significant changes in arm mass, volume or lymphatic drainage. These results call for studies into differential effect in patient sub-groups, and a large-scale, randomized placebo-controlled trial with long-term follow-up to assess the effect of HBOT in patients with soft tissue radiation injuries after breast cancer seems warranted., Trial Registration: Danish Health and Medicines Authority, EUDRACT no. 2015-000,604-25 Ethical committee of the Capitol Region, No. R96-A6604-14-S22., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Multiple mitochondrial enzymes employ lipoic acid as a coenzyme. Pathogenic variants in LIAS, encoding lipoic acid synthase (LIAS), are associated with autosomal recessive LIAS-related disorder (OMIM# 614462). This disorder is characterized by infantile-onset hypotonia, profound psychomotor delay, epileptic encephalopathy, nonketotic hyperglycinemia, and lactic acidosis. We present the case of a 20-year-old female who experienced developmental deficits at the age of 6 months and began to have seizures at 3 years of age. Exome sequencing revealed compound heterozygous novel variants in LIAS, designated c.277delC (p.Leu93Ter) and c.542A > T (p.Asp181Val). The p.Leu93Ter variant is predicted to cause loss of function due to the severe truncation of the encoded protein. To examine the p.Asp181Val variant, functional analysis was performed using Baker's yeast (Saccharomyces cerevisiae) lacking LIP5, the homologue of human LIAS. Wild-type LIAS promoted oxidative growth of the lip5∆ yeast strain. In contrast, lip5∆ yeast expressing p.Asp181Val exhibited poor growth, similar to known pathogenic variants, p.Asp215Glu and p.Met310Thr. Our work has expanded the phenotypic and genotypic spectrum of LIAS-related disorder and established the use of the yeast model as a system for functional study of novel missense variants in LIAS., Competing Interests: Declaration of Competing Interest Parith Wongkittichote, Chanseyha Chhay, Gazelle Zerafati-Jahromi, Judith L. Weisenberg, Ali Mian, Laran T. Jensen, and Dorothy K. Grange declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In patients with primary calcaneal malignancies, such as Ewing's sarcoma, radical treatment with amputation of the foot can result in serious functional impairment and chronic pain. Total calcanectomy followed by the reconstruction of the calcaneal defect offers an alternative treatment to amputation. Capanna et al. described a technique for successfully reconstructing long limb segmental bone defects using a free fibula flap placed within the intramedullary canal of an allograft. We present both a review of the literature on calcaneal reconstruction and describe how the principles of Capanna can be adapted to reconstruct the calcaneus. Total calcanectomy due to Ewing's sarcoma and the subsequent application of this novel reconstructive technique was performed in two young patients aged 5 and 16 years. The reconstruction was achieved by inserting a distally pedicled osteocutaneous fibula flap within the reamed canal of an allograft and placing the composite in the calcaneal defect. Reconstruction was successful with complete bone union between the allograft and the adjacent bone. There were no fractures or infections and both flaps survived. Functional outcome was assessed with a physiotherapist at a follow-up period of 2 years postoperatively, showing near-normal ambulance. This novel technique proved excellent as a limb salvage procedure, avoiding amputation, and offering a satisfactory oncological and functional outcome., Competing Interests: Conflict of Interest The authors have nothing to disclose., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Our incomplete understanding of the causes and pathways involved in the onset and progression of multiple sclerosis (MS) limits our ability to effectively treat this complex neurological disease. Recent studies explore the role of immune cells at different stages of MS and how they interact with cells of the central nervous system (CNS). The findings presented here begin to question the exclusivity of an antigen-specific cause and highlight how seemingly distinct immune cell types can share common functions that drive disease. Innovative techniques further expose new disease-associated immune cell populations and reinforce how environmental context is critical to their phenotype and subsequent role in disease. Importantly, the differentiation of immune cells into a pathogenic state is potentially reversible through therapeutic manipulation. As such, understanding the mechanisms that provide plasticity to causal cell types is likely key to uncoupling these disease processes and may identify novel therapeutic targets that replace the need for cell ablation., (© 2022. Springer Nature Limited.)

Toxicity resulting from off-target effects, beyond acetylcholine esterase inhibition, for the commonly used organophosphate (OP) insecticides chlorpyrifos (CPS) and malathion (MA) was investigated using Saccharomyces cerevisiae and Caenorhabditis elegans model systems. Mitochondrial damage and dysfunction were observed in yeast following exposure to CPS and MA, suggesting this organelle is a major target. In the C. elegans model, the mitochondrial unfolded protein response pathway showed the most robust induction from CPS and MA treatment among stress responses examined. GABAergic neurodegeneration was observed with CPS and MA exposure. Impaired movement observed in C. elegans exposed to CPS and MA may be the result of motor neuron damage. Our analysis suggests that stress from CPS and MA results in mitochondrial dysfunction, with GABAergic neurons sensitized to these effects. These findings may aid in the understanding of toxicity from CPS and MA from high concentration exposure leading to insecticide poisoning., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laran T. Jensen reports financial support was provided by Thailand Science Research and Innovation. Amornrat Naranuntarat Jensen reports financial support was provided by Thailand Science Research and Innovation. Conflicts of interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Anti-resorptive osteoporosis treatment might be more effective in patients with high bone turnover. In this registry study including clinical data, high pre-treatment bone turnover measured with biochemical markers was correlated with higher bone mineral density increases. Bone turnover markers may be useful tools to identify patients benefitting most from anti-resorptive treatment., Introduction: In randomized, controlled trials of bisphosphonates, high pre-treatment levels of bone turnover markers (BTM) were associated with a larger increase in bone mineral density (BMD). The purpose of this study was to examine this correlation in a real-world setting., Methods: In this registry-based cohort study of osteoporosis patients (n = 158) receiving antiresorptive therapy, the association between pre-treatment levels of plasma C-telopeptide of type I Collagen (CTX) and/or N-terminal propeptide of type I procollagen (PINP) and change in bone mineral density (BMD) at lumbar spine, total hip, and femoral neck upon treatment was examined. Patients were grouped according to their pre-treatment BTM levels, defined as values above and below the geometric mean for premenopausal women., Results: Pre-treatment CTX correlated with annual increase in total hip BMD, where patients with CTX above the geometric mean experienced a larger annual increase in BMD (p = 0.008) than patients with CTX below the geometric mean. The numerical pre-treatment level of CTX showed a similar correlation at all three skeletal sites (total hip (p = 0.03), femoral neck (p = 0.04), and lumbar spine (p = 0.0003)). A similar association was found for PINP where pre-treatment levels of PINP above the geometric mean correlated with a larger annual increase in BMD for total hip (p = 0.02) and lumbar spine (p = 0.006)., Conclusion: Measurement of pre-treatment BTM levels predicts osteoporosis patients' response to antiresorptive treatment. Patients with high pre-treatment levels of CTX and/or PINP benefit more from antiresorptive treatment with larger increases in BMD than patients with lower pre-treatment levels., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Introduction: Periprosthetic infection is one of the most severe complications following implant-based breast reconstruction affecting 5%-10% of the women. Currently, many surgeons apply antibiotics locally on the breast implant to reduce the risk of postoperative infection, but no randomised, placebo-controlled trials have tested the treatment's efficacy., Methods and Analysis: The BREAST-AB trial (BREAST-AntiBiotics) is an investigator-initiated, multicentre, randomised, placebo-controlled, double-blind trial of local treatment with gentamicin, vancomycin and cefazolin on breast implants in women undergoing implant-based breast reconstruction. The trial drug consists of 80 mg gentamicin, 1 g vancomycin and 1 g cefazolin dissolved in 500 mL of isotonic saline. The placebo solution consists of 500 mL isotonic saline. The trial drug is used to wash the dissected tissue pocket and the breast implant prior to insertion. The primary outcome is all-cause explantation of the breast implant within 180 days after the breast reconstruction surgery. This excludes cases where the implant is replaced with a new permanent implant, for example, for cosmetic reasons. Key long-term outcomes include capsular contracture and quality of life. The trial started on 26 January 2021 and is currently recruiting., Ethics and Dissemination: The trial was approved by the Regional Ethics Committee of the Capital Region (H-20056592) on 1 January 2021 and the Danish Medicines Agency (2020070016) on 2 August 2020. The main paper will include the primary and secondary outcomes and will be submitted to an international peer-reviewed journal., Trial Registration Number: NCT04731025., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Preoperative location of hyperfunctioning parathyroid glands (HPGs) is vital when planning minimally invasive surgery in patients with primary hyperparathyroidism (PHPT). Dual-isotope subtraction scintigraphy with 99m Tc-MIBI/ 123 Iodide using SPECT/CT and planar pinhole imaging (Di-SPECT) has shown high sensitivity, but is challenged by high radiation dose, time consumption and cost. 11 C-Choline PET/CT (faster with a lower radiation dose) is non-inferior to Di-SPECT. We aim to clarify to what extent the two are interchangeable and how often there are discrepancies., Design: This is a prospective, GCP-controlled cohort study., Patients and Measurements: One hundred patients diagnosed with PHPT were included and underwent both imaging modalities before parathyroidectomy. Clinical implications of differences between imaging findings and negative imaging results were assessed. Surgical findings confirmed by biochemistry and pathology served as reference standard., Results: Among the 90 patients cured by parathyroidectomy, sensitivity was 82% (95% confidence interval [CI]: 74%-88%) and 87% (95% CI: 79%-92%) for Choline PET and Di-SPECT, respectively, p = .88. In seven cases at least one imaging modality found no HPG. Of these, neither modality found any true HPGs and only two were cured by surgery. When a positive finding in one modality was incorrect, the alternative modality was correct in approximately half of the cases., Conclusion: Choline PET and Di-SPECT performed equally well and are both appropriate as first-line imaging modalities for preoperative imaging of PHPT. When the first-line modality fails to locate an HPG, additional preoperative imaging with the alternate modality offers no benefit. However, if parathyroidectomy is unsuccessful, additional imaging with the alternate modality has merit before repeat surgery., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objectives: Patients undergoing microvascular reconstruction after head and neck cancer typically have several comorbidities, and the procedures are often followed by complications and prolonged hospitalization. Consequently, the application of enhanced recovery after surgery (ERAS) for these patients undergoing microvascular reconstruction has gained attention in recent years. ERAS is a peri- and postoperative care concept that has repeatedly shown beneficial results for a wide variety of surgical procedures, including microvascular reconstruction. This study presents the results after the introduction of our ERAS protocol for head and neck cancer reconstruction., Methods: We prospectively treated 30 consecutive patients according to our ERAS protocol from June 2019 to December 2020 and compared the results of the treated patients with those of patients treated with our traditional recovery after surgery (TRAS) protocol. We are based on our ERAS protocol on the following core elements of recovery: improved patient information, goal-directed fluid therapy, minimally invasive surgery, opioid-sparing multimodal analgesia, early ambulation, and pre-defined functional discharge criteria., Results: The baseline characteristics of the groups were comparable. The ERAS group had a significantly shorter length of stay (13.1 vs. 20.3 days, p < 0.001), significantly shorter time to ambulation (3.0 days vs. 6.4 days, p < 0.001), shorter time to removal of nasogastric tube (13.3 days vs. 22.7 days, p = 0.05), and fewer tracheostomies performed (10% vs. 90%, p < 0.001). There were no differences in complications, flap survival, or 30-day re-admissions between the two groups., Conclusion: The introduction of ERAS in patients with head and neck cancer undergoing microvascular reconstruction seems safe and results in improved recovery., Level of Evidence: 3., Competing Interests: Nothing to disclose, (© 2022 The Author(s).)

Fetal growth restriction (FGR) affects 5-10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment., (© 2022. The Author(s).)

Background: Disturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects., Methods: We included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18 F-fluorodopa ( 18 F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion., Results: Individual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% ( p  = .003) and included dopamine synthesis capacity (K i 4p ) in the nucleus accumbens ( p  = .664), GABA levels in the ACC ( p  = .019), glutamate plus glutamine levels in the thalamus ( p  = .678), and the interaction term K i 4p  × GABA ( p  = .016)., Conclusions: Our multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between K i 4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information., (© 2022 The Authors.)

Ingested nutrients are proposed to control mammalian behavior by modulating the activity of hypothalamic orexin/hypocretin neurons (HONs). Previous in vitro studies showed that nutrients ubiquitous in mammalian diets, such as non-essential amino acids (AAs) and glucose, modulate HONs in distinct ways. Glucose inhibits HONs, whereas non-essential (but not essential) AAs activate HONs. The latter effect is of particular interest because its purpose is unknown. Here, we show that ingestion of a dietary-relevant mix of non-essential AAs activates HONs and shifts behavior from eating to exploration. These effects persisted despite ablation of a key neural gut → brain communication pathway, the cholecystokinin-sensitive vagal afferents. The behavioral shift induced by the ingested non-essential AAs was recapitulated by targeted HON optostimulation and abolished in mice lacking HONs. Furthermore, lick microstructure analysis indicated that intragastric non-essential AAs and HON optostimulation each reduce the size, but not the frequency, of consumption bouts, thus implicating food palatability modulation as a mechanism for the eating suppression. Collectively, these results suggest that a key purpose of HON activation by ingested, non-essential AAs is to suppress eating and re-initiate food seeking. We propose and discuss possible evolutionary advantages of this, such as optimizing the limited stomach capacity for ingestion of essential nutrients., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The extent of symptoms due to primary hyperparathyroidism (PHPT) depends on the population being studied. PHPT is mainly discovered incidentally through routine laboratory findings. Less is known about patient-experienced improvement following successful parathyroidectomy. The aim of our study was to assess the changes in the quality of life (QoL) after successful surgery using an SF-36 questionnaire., Design: This is a prospective cohort study based on questionnaires., Methods: Forty consecutive patients diagnosed with PHPT were prospectively administered an SF-36 questionnaire before and 6 months after successful parathyroidectomy. A subgroup of 18 patients answered the questionnaire at 1 and 3 months after surgery. Successful surgery was based on biochemistry and pathology reports as confirmed by an endocrinologist. Results of each SF-36 subcategory were compared to the results at baseline in order to detect changes in patient-reported QoL after successful surgery., Results: There were significant improvements in six of eight SF-36 subcategories: vitality (P = 0.0001), physical functioning (P = 0.04), general health perception (P = 0.004), physical role functioning (P = 0.04), social role functioning (P = 0.004), and mental health perception (P = 0.0001). Changes appeared within a month after surgery with no further significant changes at later time points., Conclusions: Parathyroidectomy significantly improves QoL as measured by a decrease in SF-36 scores as early as 1 month after successful parathyroidectomy. The SF-36 QoL questionnaire is suitable for monitoring changes in patient well-being after successful parathyroidectomy.

Background and Aim: Primary Raynaud's phenomenon (pRP) is characterized by an exaggerated response to cold, resulting in the whitening typically of the fingers and toes. The patients are generally perceived as healthy individuals with a benign condition. However, the condition has been associated with increased cardiovascular mortality and changes in autonomic nervous system activity. This study aimed to investigate whether pRP is associated with pervasive changes in autonomic nervous activity. The hypothesis was that patients with pRP have increased sympathetic nervous activity., Methods: The autonomic nervous activity of 22 patients with pRP was investigated by means of heart rate variability (HRV) and the plasma catecholamine response to head-up tilt and compared with 22 age- and gender-matched controls. In addition, the patients were examined with a [ 123 I]metaiodobenzylguanidine heart scintigraphy and compared with an external control group., Results: The plasma norepinephrine response to head-up tilt was significantly lower in the patient group than in the control group. Similarly, the heart scintigraphy revealed a lower heart-to-mediastinum ratio in the patient group than in the control group. HRV analysis did not reveal significant differences between the groups., Conclusion: The findings of the study showed that the autonomic nervous activity of patients with pRP was altered compared with the activity of healthy individuals. This was observed both during rest and after positional stress, but the findings did not uniformly concur with our initial hypothesis., (© 2021 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Background: In 2015, we published one of the first reports using an enhanced recovery protocol (ERP) in microsurgery 1 , and in 2016, our final ERP setup in autologous breast reconstruction (ABR) using free abdominal flaps 2 . We showed that by adhering to a few simple, easy to measure, functional discharge criteria, it was possible to safely discharge the patients by the third postoperative day (POD). However, one of the challenges of interpreting studies using ERP in ABR is the often heterogenous patient populations and the need to clearly distinguish between primary and secondary and unilateral and bilateral reconstructions., Materials and Methods: In the 5-year period from 2016-2020, the same surgical team, performed 147 unilateral, delayed breast reconstructions (135 DIEP, 9 MS-TRAM-2, and 3 SIEA flaps) according to our previous analgesic protocol and surgical strategy. Data were collected prospectively., Results: Three flaps were lost (2%) and 82% of the patients(n=128) were discharged to home by POD 2 (n=8%) or 3 (74%). The remaining 18% (n=26) were discharged by POD 4 (12.5%) or 5 (5.5%). Ten patients (7%) were reoperated, and 17 patients (12%) had minor complications within POD 30 (infection, seroma, etc.) that did not necessitate hospital admission., Conclusion: Using our ERP, unproblematic discharge directly to home is possible on POD 3 in more than 80% of patients after ABR. ERP is no longer a research tool but considered standard of care in microsurgical breast reconstruction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Dopamine activity has been associated with the response to antipsychotic treatment. Our study used a four-parameter model to test the association between the striatal decarboxylation rate of 18 F-DOPA to 18 F-dopamine (k 3 ) and the effect of treatment on psychotic symptoms in antipsychotic-naïve patients with first-episode psychosis. We further explored the effect of treatment with a partial dopamine D 2 receptor agonist (aripiprazole) on k 3 and dopamine synthesis capacity (DSC) determined by the four-parameter model and by the conventional tissue reference method., Methods: Sixty-two individuals (31 patients and 31 control subjects) underwent 18 F-DOPA positron emission tomography at baseline, and 15 patients were re-examined after 6 weeks. Clinical re-examinations were completed after 6 weeks (n = 28) and 6 months (n = 15). Symptoms were evaluated with the Positive and Negative Syndrome Scale., Results: High baseline decarboxylation rates (k 3 ) were associated with more positive symptoms at baseline (p < .001) and with symptom improvement after 6 weeks (p = .006). Subregion analyses showed that baseline k 3 for the putamen (p = .003) and nucleus accumbens (p = .013) and DSC values for the nucleus accumbens (p = .003) were associated with psychotic symptoms. The tissue reference method yielded no associations between DSC and symptoms or symptom improvement. Neither method revealed any effects of group or treatment on average magnitudes of k 3 or DSC, whereas changes in dopamine synthesis were correlated with higher baseline values, implying a potential effect of treatment., Conclusions: Striatal decarboxylation rate at baseline was associated with psychotic symptoms and treatment response. The strong association between k 3 and treatment effect potentially implicate on new treatment strategies., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted ( N  = 29). The remaining 85% were offered denosumab ( N  = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm 2 ) and total hip (0.019 g/cm 2 ) in the denosumab group but no change at the femoral neck(-0.011g/cm 2 ). In the ZA group, we observed no significant change at the spine (0.015 g/cm 2 ) and total hip (-0.001g/cm 2 ) and a small significant decrease at the femoral neck (-0.037 g/cm 2 ). However, when we compared BMD change between the treatment groups, we found no significant difference. Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA. Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis.We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years.We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice.

Background: Use of 11 C-Choline PET/CT is gaining ground in detecting hyperfunctioning parathyroid glands in primary hyperparathyroidism. The purpose of this study was to evaluate the robustness of 11 C-Choline PET/CT by assessing intra- and inter-observer agreement to determine whether the method was reader sensitive and therefore should only be performed at highly specialised sites with a high number of cases. PET/CT images of 40 patients diagnosed with primary hyperparathyroidism were anonymised and evaluated three times by three readers: an expert reader and two non-experts (non-experts were experienced in PET/CT imaging, but not in 11 C-Choline PET/CT in the setting of primary hyperparathyroidism). Number of hyperfunctioning parathyroid glands, location relative to the thyroid gland and confidence of each assessment (low, moderate or high) were noted, and intra- and inter-observer agreement calculated using Fleiss' kappa method. Sensitivities and specificities of the non-experts were calculated using the expert reader as gold standard., Results: Intra-observer agreement was 'good' to 'near perfect' for all readers. Inter-observer agreement was good between non-experts and the expert, with kappa values ≥ 0.74. Sensitivities between non-experts and the expert were high, > 81%, when assessing which side and 75% when assessing thyroid quadrant. All specificities were > 94%. Reader certainties were 'high' in > 80% of cases for the expert and > 70% and > 65%, respectively for the two non-experts., Conclusion: 11 C-Choline PET/CT is not reader sensitive for the localisation of hyperfunctioning parathyroid glands and may therefore be safely implemented at sites that have a moderate number of cases. Access to a cyclotron laboratory is, however, a necessity for the production of 11 C-Choline. The study was conducted in accordance with the Helsinki 2 declaration and The International Council for Harmonisation Guideline for Good Clinical Practice (ICH&#95;GCP) clinical trial, approved by the Research Ethics Committee of the Capital Region of Denmark (Journal-nr.:H-18012490, date of approval: 18 June 2018) and the Danish Medicines Agency (EudraCT no. 2018-000726-63, date of approval: 6 June 2018). The GCP unit in Eastern Denmark has carried out regular monitoring of the trial according to GCP (ID: 2018-1050).

Raynaud's phenomenon (RP) is characterized by the episodic whitening of the fingers upon exposure to cold. A recently described thermographic algorithm was proposed as a diagnostic replacement of the currently applied finger systolic pressure (FSP) test. The aim of the study was to evaluate the performance of the thermographic algorithm when applied in patients suspected of having RP. Forty-three patients were examined using thermographic imaging after local cooling of the hands in water of 10 °C for 1 min. The thermographic algorithm was applied to predict the probability of RP. The performance of the algorithm was evaluated with different cut-off levels. A new algorithm was proposed based on patients from the target population. The performance of the tested algorithm was noninferior to the FSP test, when a cut-off level of 0.05 was applied, yielding a sensitivity and specificity of 69% and 58%, respectively. The accuracy was 66%. The FSP test had a sensitivity and specificity of 77% and 37%, respectively, and the accuracy was 59%. The thermographic method proved useful for detecting RP and was able to replace the FSP test as a diagnostic test. The alternative algorithm revealed that other thermographic variables were more predictive of the target population, but this should be verified in future patients.

Purpose: To investigate whether patients with normal tension glaucoma (NTG) show an enhanced stress response to reduced oxygen supply compared to age-matched healthy controls, measured by serum adrenaline and endothelin-1 (ET-1) levels and changes in distal finger temperature., Methods: A thorough clinical characterization of patients with NTG and age-matched controls was performed prior to inclusion in the study. Twelve patients with NTG and eleven healthy controls met the inclusion criteria and were enrolled in the study. All subjects underwent a two-day investigation. Participants were randomly exposed to either hypoxia or normoxia during the first visit. Hypoxia or normoxia was induced for two hours through a tightly fitting face mask. In addition, the peripheral circulation was assessed with a thermographic camera. Blood samples were obtained before, during, and after hypoxia or normoxia to evaluate systemic stress molecules such as catecholamines and ET-1 levels., Results: In patients with NTG, reduced oxygen supply induced an increase in peripheral blood adrenaline ( p  < 0.05) and a decrease during recovery ( p  < 0.01). A difference in distal finger temperature was shown in patients with NTG under hypoxia compared to normoxia (exposure: p  < 0.05; recovery: p  < 0.05). Hypoxia induced an increase in peripheral blood ET-1 levels in both groups (NTG: p  < 0.01; controls: p  < 0.05)., Conclusion: Patients with NTG had an enhanced physiological stress response as a consequence of hypoxia compared with age-matched controls. Although more studies are needed, the present study supports the involvement of vascular risk factors in the pathophysiology of NTG., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Line Marie Dalgaard et al.)

Raynaud's phenomenon (RP) is characterized by the episodic whitening of the fingers upon exposure to cold. Verification of the condition is crucial in vibration-exposed patients. The current verification method is outdated, but thermographic imaging seems promising as a diagnostic replacement. By investigating patients diagnosed with RP, the study aimed at developing a simple thermographic procedure that could be applied to future patients where verification of the diagnosis is needed. Twenty-two patients with primary RP and 58 healthy controls were examined using thermographic imaging after local cooling of the hands for 1 min in water of 10°C. A logistic regression model was fitted with the temperature curve characteristics to convey a predicted probability of having RP. The characteristics time to end temperature and baseline temperature were the most appropriate predictors of RP among those examined ( p = 0.004 and p = 0.04, respectively). The area under the curve was 0.91. The cut-off level 0.46 yielded a sensitivity and specificity of 82% and 86%, respectively. The positive and negative predictive values were 69% and 93%, respectively. This newly developed thermographic method was able to distinguish between patients with RP and healthy controls and was easy to operate. Thus, the method showed great promise as a method for verification of RP in future patients. Trial registration: ClinicalTrials.gov NCT03094910.

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. Bacopa monnieri extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a Saccharomyces cerevisiae model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for B. monnieri extracts to limit proliferation and promote an apoptosis-like event in RAD1 deleted yeast was not elucidated. Our current analysis has revealed that B. monnieri extracts have the capacity to promote mutations in rad1 ∆ cells. In addition, the effects of B. monnieri extracts on rad1 ∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of RAD1 in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of B. monnieri extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from B. monnieri identified a chemical-genetic interaction between bacopasaponin C and rad1 ∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.

Background: SGLT2 inhibitors are a promising treatment option in patients with heart failure and reduced ejection fraction. We aimed to investigate the effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with heart failure and reduced ejection fraction., Methods: Empire HF Renal was a prespecified substudy of the investigator-initiated, double-blind, randomised, placebo-controlled Empire HF trial. The study was done at Herlev and Gentofte University Hospital (Herlev, Denmark), with patients recruited from four Danish heart failure outpatient clinics. Patients with New York Heart Association class I-III symptoms, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or matched placebo once daily for 12 weeks. The allocation sequence was computer-generated. Patients and study investigators were masked to treatment allocation. The coprimary prespecified renal outcomes were the between-group difference in the changes in estimated extracellular volume, estimated plasma volume, and measured GFR from baseline to 12 weeks. All analyses were done in the intention-to-treat population (apart from safety analyses, which were done in patients who received at least one dose of study drug), with no interim analyses done during the trial. The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585, and EudraCT, 2017-001341-27., Findings: Between June 29, 2017, and July 15, 2019, we assessed 391 patients for eligibility, of whom 120 (31%) were randomly assigned to empagliflozin or placebo, including 105 (88%) without diabetes. In intention-to-treat analyses, 60 (100%) patients in the empagliflozin group and 59 (98%) patients in the placebo group were included for estimated extracellular volume and estimated plasma volume, and 59 (98%) patients in the empagliflozin group and 58 (97%) patients in the placebo group were included for measured GFR. Empagliflozin treatment resulted in reductions in estimated extracellular volume (adjusted mean difference -0·12 L, 95% CI -0·18 to -0·05; p=0·00056), estimated plasma volume (-7·3%, -10·3 to -4·3; p<0·0001), and measured GFR (-7·5 mL/min, -11·2 to -3·8; p=0·00010) compared with placebo. Five (8%) of 60 patients in the empagliflozin group and three (5%) of 60 patients in the placebo group had one or more serious adverse events., Interpretation: In patients with heart failure and reduced ejection fraction, empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks. Fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2 inhibitors., Funding: Research Council at Herlev and Gentofte University Hospital, Research and Innovation Foundation of the Department of Cardiology at Herlev and Gentofte University Hospital, Capital Region of Denmark, Danish Heart Foundation, and AP Møller Foundation for the Advancement of Medical Science., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a recognized adverse effect of standard (neo)adjuvant chemotherapy in breast cancer (BC) treatment. However, there is no consensus on a validated method for assessing CIPN. Heart rate variability (HRV) and vibration perception threshold (VPT) could be used as objective measures to describe CIPN. The aim of this pilot study was to investigate whether subjectively reported CIPN was associated with altered HRV and VPT in BC patients., Methods: We performed a cross-sectional pilot study evaluating 30 BCE patients previously treated with chemotherapy, 26 BCE patients who did not receive chemotherapy, and 22 controls without breast cancer. Self-reported CIPN was registered for the BC patients. All participants were subjected to multi-frequency vibration analyses to determine VPT along with short ECG measurements to determine HRV measures., Results: Self-reported CIPN was registered in 14 (46.6%) BC patients treated with chemotherapy. The VPT at 64 Hz (P = 0.022) and mean HR (P = 0.022) were significantly higher and the HRV measures SDNN (P = 0.023), RMSSD (P = 0.007), LF (P = 0.050) and HF (P = 0.045) were significantly lower in BC patients reporting CIPN compared to controls when adjusted for age. VPT at 64 Hz and 125 Hz were significantly higher in BC patients not reporting CIPN compared to controls when adjusted for age., Conclusion: We found elevated VPT and mean HR along with decreased HRV parameters in 14 BCE patients reporting CIPN. These findings support the need for further investigation into whether HRV and vibration analysis could contribute to an objective assessment of CIPN., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)