Publications by authors named "Anders Andersen"

196 Publications

Behavioral and Hemodynamic Changes Following Dichotic Training in Patients with Neurological Deficits of the Auditory Nervous System: A Case Series.

J Am Acad Audiol 2021 Mar 4. Epub 2021 Mar 4.

Department of Otolaryngology - Head and Neck Surgery, University of Kentucky, Lexington, Kentucky.

Background:  Dichotic listening occurs when one attends to different acoustical messages presented simultaneously to both ears. This is important for understanding speech in compromised listening situations, such as background noise. Deficits in dichotic listening can be remediated by participating in auditory training. We present two patients with binaural integration deficits who underwent dichotic interaural intensity difference (DIID) training.

Purpose:  The purpose of this investigation is to demonstrate improvement of dichotic listening deficits following DIID training in neurological patients seen clinically for hearing issues.

Research Design:  This was a case series utilizing a pre- and posttreatment design.

Study Sample:  This case series utilized two female participants who demonstrated binaural integration deficits during an auditory processing evaluation.

Intervention:  The participants underwent a pretraining auditory processing evaluation and functional magnetic resonance imaging (fMRI). Participants then underwent 12, 30-minute DIID training sessions followed by posttreatment auditory processing evaluations and fMRI.

Data Collection And Analysis:  Data was collected at the pretreatment appointment and then immediately following the completion of the training.

Results:  Each patient demonstrated varying degrees of improvement on the posttreatment assessment. Case 1 showed significant improvement on the Speech-in-Noise-Revised (SPIN-R) test. fMRI showed changes in activation patterns following training. Case 2 demonstrated improved scores on the Dichotic Digits Test and SPIN-R and increased activation of the calcarine sulcus following training.

Conclusion:  Dichotic training can be an efficacious treatment for binaural integration deficits and may show evidence of improving speech understanding in noise. This case series demonstrates a promising therapy to help patients improve auditory function by improving dichotic listening skills.
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http://dx.doi.org/10.1055/s-0040-1719095DOI Listing
March 2021

Correction to: Intraperitoneal mitomycin C improves survival compared to cytoreductive surgery alone in an experimental model of highgrade pseudomyxoma peritonei.

Clin Exp Metastasis 2021 Apr;38(2):253

Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310, Oslo, Norway.

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http://dx.doi.org/10.1007/s10585-021-10084-0DOI Listing
April 2021

The effect of external flow on the feeding currents of sessile microorganisms.

J R Soc Interface 2021 02 24;18(175):20200953. Epub 2021 Feb 24.

Centre for Ocean Life, National Institute of Aquatic Resources, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.

Microscopic sessile suspension feeders live attached to surfaces and, by consuming bacteria-sized prey and by being consumed, they form an important part of aquatic ecosystems. Their environmental impact is mediated by their feeding rate, which depends on a self-generated feeding current. The feeding rate has been hypothesized to be limited by recirculating eddies that cause the organisms to feed from water that is depleted of food particles. However, those results considered organisms in still water, while ambient flow is often present in their natural habitats. We show, using a point-force model, that even very slow ambient flow, with speed several orders of magnitude less than that of the self-generated feeding current, is sufficient to disrupt the eddies around perpendicular suspension feeders, providing a constant supply of food-rich water. However, the feeding rate decreases in external flow at a range of non-perpendicular orientations due to the formation of recirculation structures not seen in still water. We quantify the feeding flow and observe such recirculation experimentally for the suspension feeder in external flows typical of streams and rivers.
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http://dx.doi.org/10.1098/rsif.2020.0953DOI Listing
February 2021

Immediate versus postponed frozen embryo transfer after IVF/ICSI: a systematic review and meta-analysis.

Hum Reprod Update 2021 Feb 16. Epub 2021 Feb 16.

Fertility Department 4071, Copenhagen University Hospital, Copenhagen Ø DK-2100, Denmark.

Background: In Europe, the number of frozen embryo transfer (FET) cycles is steadily increasing, now accounting for more than 190 000 cycles per year. It is standard clinical practice to postpone FET for at least one menstrual cycle following a failed fresh transfer or after a freeze-all cycle. The purpose of this practice is to minimise the possible residual negative effect of ovarian stimulation on the resumption of a normal ovulatory cycle and receptivity of the endometrium. Although elective deferral of FET may unnecessarily delay time to pregnancy, immediate FET may be inefficient in a clinical setting, following an increased risk of irregular ovulatory cycles and the presence of functional cysts, increasing the risk of cycle cancellation.

Objective And Rationale: This review explores the impact of timing of FET in the first cycle (immediate FET) versus the second or subsequent cycle (postponed FET) following a failed fresh transfer or a freeze-all cycle on live birth rate (LBR). Secondary endpoints were implantation, pregnancy and clinical pregnancy rates (CPR) as well as miscarriage rate (MR).

Search Methods: We searched PubMed (MEDLINE) and EMBASE databases for MeSH and Emtree terms, as well as text words related to timing of FET, up to March 2020, in English language. There were no limitations regarding year of publication or duration of follow-up. Inclusion criteria were subfertile women aged 18-46 years with any indication for treatment with IVF/ICSI. Studies on oocyte donation were excluded. All original studies were included, except for case reports, study protocols and abstracts only. Covidence, a Cochrane-tool, was used for sorting and screening of literature. Risk of bias was assessed using the Robins-I tool and the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation framework.

Outcomes: Out of 4124 search results, 15 studies were included in the review. Studies reporting adjusted odds ratios (aOR) for LBR, CPR and MR were included in meta-analyses. All studies (n = 15) were retrospective cohort studies involving a total of 6,304 immediate FET cycles and 13,851 postponed FET cycles including 8,019 matched controls. Twelve studies of very low to moderate quality reported no difference in LBR with immediate versus postponed FET. Two studies of moderate quality reported a statistically significant increase in LBR with immediate FET and one small study of very low quality reported better LBR with postponed FET. Trends in rates of secondary outcomes followed trends in LBR regarding timing of FET. The meta-analyses showed a significant advantage of immediate FET (n =2,076) compared to postponed FET (n =3,833), with a pooled aOR of 1.20 (95% CI 1.01-1.44) for LBR and a pooled aOR of 1.22 (95% CI 1.07-1.39) for CPR.

Wider Implications: The results of this review indicate a slightly higher LBR and CPR in immediate versus postponed FET. Thus, the standard clinical practice of postponing FET for at least one menstrual cycle following a failed fresh transfer or a freeze-all cycle may not be best clinical practice. However, as only retrospective cohort studies were assessed, the presence of selection bias is apparent, and the quality of evidence thus seems low. Randomised controlled trials including data on cancellation rates and reasons for cancellation are highly needed to provide high-grade evidence regarding clinical practice and patient counselling.
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http://dx.doi.org/10.1093/humupd/dmab002DOI Listing
February 2021

Annual incidence of severe ovarian hyperstimulation syndrome.

Dan Med J 2021 Jan 26;68(2). Epub 2021 Jan 26.

Introduction: Ovarian hyperstimulation syndrome (OHSS) is one of the major complications of assisted reproductive technology treatment. We assumed that it had declined in recent years owing to the options of new preventive strategies. The aim of the present study was to investigate the annual incidence of OHSS in Denmark in the course of a 17-year period.

Methods: This was a national register-based historical cohort study including all women with an OHSS diagnosis admitted to Danish hospitals between 2001 and 2017. Data included information on all OHSS diagnoses, duration of hospital stay, early pregnancy complications and other complications like thromboembolism and ovarian torsion. The annual number of initiated stimulated in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles was based on the annual reporting by the Danish Fertility Society.

Results: From 2001 to 2017, a total of 2,261 (1.2%) women with an OHSS admission were identified among 186,168 stimulated IVF/ICSI cycles. The annual incidence of OHSS varied from 0.9% to 1.2-1.4% with no overall change over time (p = 0.24. Early OHSS (defined as OHSS without a pregnancy in the cycle) was seen in 48.5% of the events, late OHSS (defined as OHSS with a pregnancy in the cycle) in 51.2% of cycles. Among all women with OHSS, 75% were hospitalised for more than 24 hours, with mean 4.3 and 6.2 days in hospital for early and late OHSS, respectively.

Conclusions: The annual incidence of severe OHSS leading to a hospital admission remained stable for 17 years, which suggests that OHSS preventive actions like use of antagonist cycles, agonist triggering and freeze all should be better implemented in Denmark.

Funding: none.

Trial Registration: not relevant.
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January 2021

Agreement between dermatologists' selection of the lesional area and characteristics best representing atopic dermatitis severity: Online survey.

J Am Acad Dermatol 2021 Jan 5. Epub 2021 Jan 5.

Department of Dermato-Venereology and Wound Healing Centre, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1016/j.jaad.2020.12.042DOI Listing
January 2021

The effect of tethering on the clearance rate of suspension-feeding plankton.

Proc Natl Acad Sci U S A 2020 12 16;117(48):30101-30103. Epub 2020 Nov 16.

Centre for Ocean Life, National Institute of Aquatic Resources, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.

Many planktonic suspension feeders are attached to particles or tethered by gravity when feeding. It is commonly accepted that the feeding flows of tethered suspension feeders are stronger than those of their freely swimming counterparts. However, recent flow simulations indicate the opposite, and the cause of the opposing conclusions is not clear. To explore the effect of tethering on suspension feeding, we use a low-Reynolds-number flow model. We find that it is favorable to be freely swimming instead of tethered since the resulting feeding flow past the cell body is stronger, leading to a higher clearance rate. Our result underscores the significance of the near-field flow in shaping planktonic feeding modes, and it suggests that organisms tether for reasons that are not directly fluid dynamical (e.g., to stay near surfaces where the concentration of bacterial prey is high).
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http://dx.doi.org/10.1073/pnas.2017441117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720100PMC
December 2020

Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients.

Ther Drug Monit 2021 04;43(2):247-255

Departments of Pharmacology and.

Background: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase.

Methods: This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry.

Results: In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold.

Conclusions: The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.
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http://dx.doi.org/10.1097/FTD.0000000000000835DOI Listing
April 2021

Online Patient Recruitment in Clinical Trials: Systematic Review and Meta-Analysis.

J Med Internet Res 2020 11 4;22(11):e22179. Epub 2020 Nov 4.

Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.

Background: Recruitment for clinical trials continues to be a challenge, as patient recruitment is the single biggest cause of trial delays. Around 80% of trials fail to meet the initial enrollment target and timeline, and these delays can result in lost revenue of as much as US $8 million per day for drug developing companies.

Objective: This study aimed to conduct a systematic review and meta-analysis examining the effectiveness of online recruitment of participants for clinical trials compared with traditional in-clinic/offline recruitment methods.

Methods: Data on recruitment rates (the average number of patients enrolled in the study per month and per day of active recruitment) and conversion rates (the percentage of participants screened who proceed to enroll into the clinical trial), as well as study characteristics and patient demographics were collected from the included studies. Differences in online and offline recruitment rates and conversion rates were examined using random effects models. Further, a nonparametric paired Wilcoxon test was used for additional analysis on the cost-effectiveness of online patient recruitment. All data analyses were conducted in R language, and P<.05 was considered significant.

Results: In total, 3861 articles were screened for inclusion. Of these, 61 studies were included in the review, and 23 of these were further included in the meta-analysis. We found online recruitment to be significantly more effective with respect to the recruitment rate for active days of recruitment, where 100% (7/7) of the studies included had a better online recruitment rate compared with offline recruitment (incidence rate ratio [IRR] 4.17, P=.04). When examining the entire recruitment period in months we found that 52% (12/23) of the studies had a better online recruitment rate compared with the offline recruitment rate (IRR 1.11, P=.71). For cost-effectiveness, we found that online recruitment had a significantly lower cost per enrollee compared with offline recruitment (US $72 vs US $199, P=.04). Finally, we found that 69% (9/13) of studies had significantly better offline conversion rates compared with online conversion rates (risk ratio 0.8, P=.02).

Conclusions: Targeting potential participants using online remedies is an effective approach for patient recruitment for clinical research. Online recruitment was both superior in regard to time efficiency and cost-effectiveness compared with offline recruitment. In contrast, offline recruitment outperformed online recruitment with respect to conversion rate.
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http://dx.doi.org/10.2196/22179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673977PMC
November 2020

Structural characterization and magnetic properties of chromium jarosite KCr(OD)(SO).

Phys Chem Chem Phys 2020 Nov 28;22(43):25001-25010. Epub 2020 Oct 28.

Niels Bohr Institute, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark.

Potassium chromium jarosite, KCr(OH)(SO) (Cr-jarosite), is considered a promising candidate to display spin liquid behavior due to the strong magnetic frustration imposed by the crystal structure. However, the ground state magnetic properties have been debated, since Cr-jarosite is notoriously non-stoichiometric. Our study reports the magnetic properties for deuterated KCr(OD)(SO) on chemically well-defined samples, which have been characteried by a combination of powder X-ray diffraction, neutron diffraction, solid state NMR spectroscopy, and scanning electron microscopy with energy dispersive spectroscopy. Eight polycrystalline samples, which all contained only 1-3% Cr vacancies were obtained. However, significant substitution (2-27%) of potassium with HO and/or HO was observed and resulted in pronounced stacking disorder along the c-axis. A clear second-order transition to an antiferromagnetically ordered phase at T = 3.8(1) K with a small net moment of 0.03 μ per Cr-ion was obtained from vibrating sample magnetometry and temperature dependent neutron diffraction. The moment is attributed to spin canting caused by the Dzyaloshinskii-Moriya interaction. Thus, our experimental results imply that even ideal potassium chromium jarosite will exhibit magnetic order below 4 K and therefore it does not qualify as a true spin liquid material.
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http://dx.doi.org/10.1039/d0cp04978fDOI Listing
November 2020

Neuroplasticity in Corticolimbic Brain Regions in Patients after Anterior Cruciate Ligament Reconstruction.

J Athl Train 2020 Oct 16. Epub 2020 Oct 16.

Johanna is an Assistant Professor in the Department of Athletic Training and Clinical Nutrition at the University of Kentucky in Lexington, Kentucky. Email:

Context: Fear has been cited as the primary barrier for return to sport (RTS) after anterior cruciate ligament reconstruction (ACLR). Understanding the neural factors contributing to fear after ACLR may help identify interventions for this population.

Objective: The objective of this study was to characterize the underlying neural substrate of injury-related fear in patients after ACLR versus healthy matched controls during a picture imagination task (PIT) consisting of sports-specific images and activities of daily living images.

Design: Case-Control Study Setting: Research Laboratory Patients or Other Participants: A total of 24 right-hand dominant participants (12 left-sided ACLR and 12 controls) were enrolled. Participants underwent full brain functional magnetic resonance imaging (fMRI).

Main Outcome Measure(s): Functional data were acquired with Blood Oxygen Level Dependent (BOLD) echoplanar imaging. Independent t-tests were used to identify significant between group differences in BOLD signal changes during all images of the PIT. Paired t-tests were used to examined differences in BOLD signal change between sports-specific images and activities of daily living (ADLs) in the ACLR group.

Results: Increased activation in the inferior parietal lobule (IPL) and the mediodorsal thalamus (MDT) were observed during PIT in the ACLR group. Inability to suppress the default mode network (DMN) in the ACLR group was observed. The ACLR group exhibited increased activation in the cerebellum and inferior occipital regions during the sports-specific task when compared to ADLs, but no other regions of interest demonstrated statistically significant differences.

Conclusion: These findings suggest that ACLR patients may be more disposed to processing fear, anxiety, and/or pain for sports-specific activities and activities of daily living. Psychosocial interventions may be warranted after ACLR to reduce injury-related fear and mitigate potentially maladaptive neuroplasticity after ACLR.
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http://dx.doi.org/10.4085/JAT0042-20DOI Listing
October 2020

Serum ferritin level is inversely related to number of previous pregnancy losses in women with recurrent pregnancy loss.

Fertil Steril 2021 Feb 25;115(2):389-396. Epub 2020 Sep 25.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Objective: To study whether low serum ferritin (s-ferritin) levels are associated with recurrent pregnancy loss (RPL), and whether low s-ferritin predicts the risk of another pregnancy loss or the ability to conceive.

Design: Cohort study.

Setting: Fertility clinic at a university hospital.

Patient(s): Eighty-four women referred to the RPL Unit and 153 women of reproductive age with no known fertility problem. s-Ferritin levels were measured in serum samples taken before pregnancy attempt.

Intervention: None.

Main Outcome Measure(s): s-Ferritin levels were correlated to pregnancy history, ability to conceive, and time to conception during the first 2 years after sampling. Furthermore, s-ferritin levels were correlated to outcome of the first pregnancy after referral for RPL.

Result(s): Women with RPL had lower s-ferritin than the comparison group, 39.9 μg/L versus 62.2 μg/L, and had a higher prevalence of low iron stores (s-ferritin <30 μg/L), 35.7% versus 13.7%. We found an inverse relationship between s-ferritin level and number of pregnancy losses before referral. We did not find s-ferritin level to be associated with ability to conceive or time to pregnancy in either group. Nor did s-ferritin level predict the risk of losing the first pregnancy after referral for RPL.

Conclusion(s): The inverse relationship between s-ferritin levels and previous pregnancy losses suggests that low s-ferritin is associated with a more severe reproductive disturbance in women with RPL. Whether low s-ferritin is causally related to RPL and if such women could benefit from iron supplementation to achieve a live birth warrants further investigation.
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http://dx.doi.org/10.1016/j.fertnstert.2020.08.1410DOI Listing
February 2021

Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

BMJ 2020 08 5;370:m2519. Epub 2020 Aug 5.

Fertility Clinic, Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Hvidovre, Kettegaard Allé 30, Copenhagen DK-2650, Denmark.

Objective: To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment.

Design: Multicentre, randomised controlled superiority trial.

Setting: Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain.

Participants: 460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection.

Interventions: Women were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure.

Main Outcome Measures: The primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle.

Results: Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group.

Conclusions: In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present.

Trial Registration: Clinicaltrials.gov NCT02746562.
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http://dx.doi.org/10.1136/bmj.m2519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399608PMC
August 2020

Improved patient satisfaction and diagnostic accuracy in skin diseases with a Visual Clinical Decision Support System-A feasibility study with general practitioners.

PLoS One 2020 29;15(7):e0235410. Epub 2020 Jul 29.

LEO Innovation Lab, Copenhagen, Denmark.

Patient satisfaction is an important indicator of health care quality, and it remains an important goal for optimal treatment outcomes to reduce the level of misdiagnoses and inappropriate or absent therapeutic actions. Digital support tools for differential diagnosis to assist clinicians in reaching the correct diagnosis may be helpful, but how the use of these affect patients is not clear. The primary objective of this feasibility study was to investigate patient experience and satisfaction in a primary care setting where general practitioners (GPs) used a visual clinical decision support system (CDSS) compared with standard consultations. Secondary objectives were diagnostic accuracy and length of consultation. Thirty-one patients with a dermatologist-confirmed skin diagnosis were allocated to consult GPs that had been randomized to conduct either standard consultations (SDR, n = 21) or CDSS (n = 16) on two separate study days one week apart. All patients were diagnosed independently by multiple GPs (n = 3-8) in both the SDR and CDSS study arms. Using the CDSS, more patients felt involved in the decision making (P = 0.05). In addition, more patients were exposed to images during the consultations (P = 6.8e-27), and 83% of those that were shown images replied they felt better supported in the consultation. The use of CDSS significantly improved the diagnostic accuracy (34%, P = 0.007), and did not increase the duration of the consultation (median 10 minutes in both arms). This study shows for the first time that compared with standard GP consultations, CDSS assist the GP on skin related diagnoses and improve patient satisfaction and diagnostic accuracy without impacting the duration of the consultations. This is likely to increase correct treatment choices, patient adherence, and overall result in better healthcare outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235410PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390264PMC
September 2020

High adherence and low dropout rate in a virtual clinical study of atopic dermatitis through weekly reward-based personalized genetic lifestyle reports.

PLoS One 2020 2;15(7):e0235500. Epub 2020 Jul 2.

LEO Innovation Lab, Copenhagen, Denmark.

Introduction: Clinical trials often suffer from significant recruitment barriers, poor adherence, and dropouts, which increase costs and negatively affect trial outcomes. The aim of this study was to examine whether making it virtual and reward-based would enable nationwide recruitment, identify patients with variable disease severity, achieve high adherence, and reduce dropouts.

Methods: In a siteless, virtual feasibility study, individuals with atopic dermatitis (AD) were recruited online. During the 8-week study, subjects used their smartphones weekly to photograph target AD lesions, and completed patient-oriented eczema measure (POEM) and treatment use questionnaires. In return, subjects were rewarded every week with personalized lifestyle reports based on their DNA.

Results: Over the course of the 11 day recruitment period, 164 (82% women and 18% men) filled in the form to participate, of which 65 fulfilled the inclusion criteria and signed the informed consent. Ten were excluded as they did not complete the mandatory study task of returning the DNA sample. 55 (91% women, 9% men) subjects returned the DNA sample and were enrolled throughout Denmark, the majority outside the Copenhagen capital region in rural areas with relatively low physician coverage. The mean age was 28.5 (SD ±9.5 years, range 18-52 years). The baseline POEM score was 14.5±5.6 (range 6-28). Based on the POEM, 7 individuals had mild, 28 had moderate, 17 had severe, and 3 had very severe eczema. The retention rate was 96% as 53 out of 55 enrolled completed the study. The adherence was very high, and more than 90% of all study tasks were completed. Follow up of 41 subjects showed that 90% would take part again or continue if the study had been longer.

Conclusion: A virtual trial design enables recruitment with broad geographic reach and throughout the full spectrum of disease severity. Providing personalized genetic reports as a reward seems to contribute to high adherence and retention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235500PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332076PMC
September 2020

Brain structure changes over time in normal and mildly impaired aged persons.

AIMS Neurosci 2020 20;7(2):120-135. Epub 2020 May 20.

Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky, Lexington, Kentucky, USA.

Structural brain changes in aging are known to occur even in the absence of dementia, but the magnitudes and regions involved vary between studies. To further characterize these changes, we analyzed paired MRI images acquired with identical protocols and scanner over a median 5.8-year interval. The normal study group comprised 78 elders (25M 53F, baseline age range 70-78 years) who underwent an annual standardized expert assessment of cognition and health and who maintained normal cognition for the duration of the study. We found a longitudinal grey matter (GM) loss rate of 2.56 ± 0.07 ml/year (0.20 ± 0.04%/year) and a cerebrospinal fluid (CSF) expansion rate of 2.97 ± 0.07 ml/year (0.22 ± 0.04%/year). Hippocampal volume loss rate was higher than the GM and CSF global rates, 0.0114 ± 0.0004 ml/year (0.49 ± 0.04%/year). Regions of greatest GM loss were posterior inferior frontal lobe, medial parietal lobe and dorsal cerebellum. Rates of GM loss and CSF expansion were on the low end of the range of other published values, perhaps due to the relatively good health of the elder volunteers in this study. An additional smaller group of 6 subjects diagnosed with MCI at baseline were followed as well, and comparisons were made with the normal group in terms of both global and regional GM loss and CSF expansion rates. An increased rate of GM loss was found in the hippocampus bilaterally for the MCI group.
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http://dx.doi.org/10.3934/Neuroscience.2020009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321765PMC
May 2020

Hippo signaling, actin polymerization, and follicle activation in fragmented human ovarian cortex.

Mol Reprod Dev 2020 06 7;87(6):711-719. Epub 2020 Jun 7.

Laboratory of Reproductive Biology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

The Hippo pathway has been associated with regulation of early follicle growth. Studies of murine ovaries suggest that changes in the actin cytoskeleton, caused by fragmentation, result in inhibition of the Hippo pathway, and in turn, may activate follicle growth. In humans, the connections between fragmentation, the actin cytoskeleton, and follicle activation are yet to be confirmed. In this study, we investigated the impact in vitro fragmentation of a human ovarian cortex on (a) actin polymerization, (b) components of the Hippo pathway, and (c) follicle growth in vivo. The results showed that the ratio between globular and filamentous actin remained unchanged at all timepoints (0, 10, 30, 60, 120, and 240 min) following tissue fragmentation. Neither was the Hippo pathway effector protein YES-associated protein upregulated nor was gene expression of the downstream growth factors CCN2, CCN3, or CCN5 increased at any timepoint in the fragmented cortex. Furthermore, the number of growing follicles was similar in fragmented and intact cortex pieces after 6 weeks' xenotransplantation. However, the total number of surviving follicles was considerably lower in the fragmented cortex compared with intact tissue, suggesting detrimental effects of fragmentation on tissue grafting. These results indicate that fragmentation is likely to be ineffective to activate follicle growth in the human ovarian cortex.
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http://dx.doi.org/10.1002/mrd.23353DOI Listing
June 2020

Remarkable reversal of C-NMR assignment in d, d compared to d, d acetylacetonate complexes: analysis and explanation based on solid-state MAS NMR and computations.

Phys Chem Chem Phys 2020 Apr;22(15):8048-8059

Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense, Denmark.

13C solid-state MAS NMR spectra of a series of paramagnetic metal acetylacetonate complexes; [VO(acac)2] (d1, S = ½), [V(acac)3] (d2, S = 1), [Ni(acac)2(H2O)2] (d8, S = 1), and [Cu(acac)2] (d9, S = ½), were assigned using modern NMR shielding calculations. This provided a reliable assignment of the chemical shifts and a qualitative insight into the hyperfine couplings. Our results show a reversal of the isotropic 13C shifts, δiso(13C), for CH3 and CO between the d1 and d2versus the d8 and d9 acetylacetonate complexes. The CH3 shifts change from about -150 ppm (d1,2) to roughly 1000 ppm (d8,9), whereas the CO shifts decrease from 800 ppm to about 150 ppm for d1,2 and d8,9, respectively. This was rationalized by comparison of total spin-density plots and computed contact couplings to those corresponding to singly occupied molecular orbitals (SOMOs). This revealed the interplay between spin delocalization of the SOMOs and spin polarization of the lower-energy MOs, influenced by both the molecular symmetry and the d-electron configuration. A large positive chemical shift results from spin delocalization and spin polarization acting in the same direction, whereas their cancellation corresponds to a small shift. The SOMO(s) for the d8 and d9 complexes are σ-like, implying spin-delocalization on the CH3 and CO groups of the acac ligand, cancelled only for CO by spin polarization. In contrast, the SOMOs of the d1 and d2 systems are π-like and a large CO-shift results from spin polarization, which accounts for the reversed assignment of δiso(13C) for CH3 and CO.
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http://dx.doi.org/10.1039/d0cp00980fDOI Listing
April 2020

Pharmacodynamic assessment of mycophenolic acid in resting and activated target cell population during the first year after renal transplantation.

Br J Clin Pharmacol 2020 06 16;86(6):1100-1112. Epub 2020 Feb 16.

Department of Pharmacology, Oslo University Hospital, Oslo, Norway.

Aims: To explore the pharmacodynamics of mycophenolic acid (MPA) through inosine monophosphate dehydrogenase (IMPDH) capacity measurement and purine levels in peripheral blood mononuclear cells (PBMC) longitudinally during the first year after renal transplantation (TX).

Methods: PBMC were isolated from renal recipients 0-4 days prior to and 6-9 days, 5-7 weeks and 1 year after TX (before and 1.5 hours after dose). IMPDH capacity and purine (guanine and adenine) levels were measured in stimulated and nonstimulated PBMC.

Results: Twenty-nine patients completed the follow-up period, of whom 24 received MPA. In stimulated PBMC, the IMPDH capacity (pmol 10 cells min ) was median (interquartile range) 127 (95.8-147) before TX and thereafter 44.9 (19.2-93.2) predose and 12.1 (4.64-23.6) 1.5 hours postdose across study days after TX. The corresponding IMPDH capacity in nonstimulated PBMC was 5.71 (3.79-6.93), 3.35 (2.31-5.62) and 2.71 (1.38-4.08), respectively. Predose IMPDH capacity in nonstimulated PBMC increased with time, reaching pre-TX values at 1 year. In stimulated PBMC, both purines were reduced before (median 39% reduction across days after TX) and after (69% reduction) dose compared to before TX. No alteration in the purine levels was observed in nonstimulated PBMC. Patients needing dose reductions during the first year had lower pre-dose IMPDH capacity in nonstimulated PBMC (1.87 vs 3.00 pmol 10 cells min , P = .049) at 6-9 days.

Conclusion: The inhibitory effect of MPA was stronger in stimulated PBMC. Nonstimulated PBMC became less sensitive to MPA during the first year after TX. Early IMPDH capacity appeared to be predictive of dose reductions.
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http://dx.doi.org/10.1111/bcp.14218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256122PMC
June 2020

Preparation of the endometrium and timing of blastocyst transfer in modified natural cycle frozen-thawed embryo transfers (mNC-FET): a study protocol for a randomised controlled multicentre trial.

BMJ Open 2019 12 15;9(12):e031811. Epub 2019 Dec 15.

The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Introduction: Despite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome.

Methods And Analysis: Multicentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18-41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed.

Ethics And Dissemination: The study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated.

Trial Registration Number: The study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-031811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924851PMC
December 2019

Ovarian cortical follicle density in infertile women with low anti-Müllerian hormone.

J Assist Reprod Genet 2020 Jan 22;37(1):109-117. Epub 2019 Nov 22.

The Fertility Clinic, Section 4071, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Purpose: To evaluate the association between anti-Müllerian hormone (AMH) and follicle density in infertile women with diminished ovarian reserve (DOR) versus women with normal ovarian reserve?

Methods: Case-control study comparing follicle densities in ovarian cortex from 20 infertile women with DOR (AMH ≤ 5 pmol/L) and 100 controls with presumed normal ovarian reserve.

Results: For all women > 25 years, the follicle densities correlated positively with AMH levels. For each single picomole per liter increase in AMH the follicle density increased by 6% (95% CI 3.3-8.5%) when adjusted for age. This was similar for women with DOR and controls. The follicle density was 1.8 follicles/mm cortical tissue in women with DOR versus 7.0 in age-paired controls (p = 0.04). The women with DOR had a median AMH of 1.8 pmol/L versus 14.4 pmol/L in the age-paired control group (p < 0.001). The ratio of AMH/follicle density was 1:1 (1.8/1.8) in women with DOR and 2:1 (14.4/7.0) in the age-paired controls. Analyses for gonadotropin receptor polymorphisms could not explain the characteristics of women with DOR. The proportion of secondary follicles was higher in women with DOR compared with controls (4.6% versus 1.4%, p = 0.0003). Pooling all patients, the follicle density decreased significantly by 7.7% for every year added (p < 0.0001). The women with DOR had lower follicle densities than the controls, but the slopes were equal in the two cohorts.

Conclusions: Follicle density and AMH concentrations correlate also when AMH is low. However, AMH is only a reliable marker for the true ovarian reserve when age is included in the estimation and women with DOR may have more follicles than their AMH levels imply.
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http://dx.doi.org/10.1007/s10815-019-01633-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000582PMC
January 2020

Sex-specific Estrogen Levels and Reference Intervals from Infancy to Late Adulthood Determined by LC-MS/MS.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Context: The lack of sensitive and robust analytical methods has hindered the reliable quantification of estrogen metabolites in subjects with low concentrations.

Objective: To establish sex-specific reference ranges for estrone (E1) and estradiol (E2) throughout life and to evaluate sex-differences using the state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of E1, E2, and estriol (E3).

Design: LC-MS/MS method development and construction of estrogen reference ranges.

Settings: Population-based cross-sectional cohorts from the greater Copenhagen and Aarhus areas.

Participants: Healthy participants aged 3 months to 61 years (n = 1838).

Results: An isotope diluted LC-MS/MS method was developed and validated for measurements of serum E1, E2, and E3. Limits of detections (LODs) were 3 pmol/L (E1), 4 pmol/L (E2), and 12 pmol/L (E3), respectively. This sensitive method made it possible to differentiate between male and female concentration levels of E1 and E2 in children. In girls, E2 levels ranged from
Conclusion: Reference ranges of simultaneous quantification of E1 and E2 by this novel specific and highly sensitive LC-MS/MS method provide an invaluable tool in clinical practice and in future research studies.
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http://dx.doi.org/10.1210/clinem/dgz196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007877PMC
March 2020

Strategic room type allocation for nursing wards through Markov chain modeling.

Artif Intell Med 2019 08 19;99:101705. Epub 2019 Aug 19.

KU Leuven, Department of Computer Science, CODeS & imec, Belgium.

Providing patients with the best possible care is the most essential function of any hospital. In an increasing number of countries, hospitals are governed by the number of patients they are able to attract and the corresponding services they provide for patients. One such service, which is often of significant importance for patients, is the option to choose their room type. Hospital decision makers would benefit from a strategic method for optimizing the configuration of room types among nursing wards by distinguishing between patients who prefer private rooms and those who have no preference concerning whether they are assigned to a private or shared room. Such a decision support method is currently non-existent, therefore the goal of this study is to provide a methodology for hospital management. Specifically, a mixed modeling approach is proposed which evaluates the patient flow behavior by applying a Continuous-Time Markov Chain within a heuristic search procedure. This procedure recursively improves a configuration of rooms among the wards by sampling from a gradually improved interpolation of an objective function. Based on patient data obtained from both a Danish and Belgian hospital, the performance and robustness of the proposed approach is validated through various numerical experiments, demonstrating that solutions within a relative gap of 1% from the optimum are attained in most cases.
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http://dx.doi.org/10.1016/j.artmed.2019.101705DOI Listing
August 2019

Biopsying, fragmentation and autotransplantation of fresh ovarian cortical tissue in infertile women with diminished ovarian reserve.

Hum Reprod 2019 10;34(10):1924-1936

The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Study Question: Can ovarian biopsying per se and/or autotransplantation of fragmented ovarian cortical tissue activate dormant follicles and increase the number of recruitable follicles for IVF/ICSI in women with diminished ovarian reserve (DOR)?

Summary Answer: Ovarian biopsying followed by immediate autotransplantation of fragmented cortical tissue failed to increase the number of recruitable follicles for IVF/ICSI 10 weeks after the procedure either at the graft site or in the biopsied ovary, but 12 of the 20 women subsequently had a clinical pregnancy during the 1-year follow-up.

What Is Known Already: Infertile women with DOR constitute a group of patients with poor reproductive outcome mainly due to the low number of mature oocytes available for IVF/ICSI. Recent studies have shown that in vitro activation of residual dormant follicles by both chemical treatment and tissue fragmentation has resulted in return of menstrual cycles and pregnancies in a fraction of amenorrhoeic women with premature ovarian insufficiency.

Study Design, Size, Duration: This is a prospective clinical cohort study including 20 women with DOR treated at the fertility clinic, Rigshospitalet, Denmark, during April 2016-December 2017. Non-pregnant patients were on average followed for 280 days (range 118-408), while women who conceived were followed until delivery. Study follow-up of non-pregnant patients ended in September 2018.

Participants, Materials, Setting, Methods: The study included infertile women aged 30-39 years with preserved menstrual cycles, indication for IVF/ICSI and repeated serum measurements of anti-Müllerian hormone (AMH) ≤ 5 pmol/L. Patients were randomized to have four biopsies taken from either the left or the right ovary by laparoscopy followed by fragmentation of the cortical tissue to an approximate size of 1 mm3 and autotransplanted to a peritoneal pocket. The other ovary served as a control. Patients were followed weekly for 10 weeks with recording of hormone profile, antral follicle count (AFC), ovarian volume and assessment for ectopic follicle growth. After 10 weeks, an IVF/ICSI-cycle with maximal ovarian stimulation was initiated.

Main Results And The Role Of Chance: No difference in the number of mature follicles after ovarian stimulation 10 weeks after the procedure in the biopsied versus the control ovaries was observed (1.0 vs. 0.7 follicles, P = 0.35). In only three patients, growth of four follicles was detected at the graft site 24-268 days after the procedure. From one of these follicles, a metaphase II (MII) oocyte was retrieved and fertilized, but embryonic development failed. Overall AMH levels did not change significantly after the procedure (P = 0.2). The AFC increased by 0.14 (95% CI: 0.06;0.21) per week (P < 0.005), and the biopsied ovary had on average 0.6 (95% CI: 0.3;-0.88) follicles fewer than the control ovary (P = 0.01). Serum levels of androstenedione and testosterone increased significantly by 0.63 nmol/L (95% CI: 0.21;1.04) and 0.11 nmol/L (95% CI: 0.01;0.21) 1 week after the procedure, respectively, and testosterone increased consecutively over the 10 weeks by 0.0095 nmol/L (95% CI: 0.0002;0.0188) per week (P = 0.045). In 7 of the 20 patients, there was a serum AMH elevation 5 to 8 weeks after the procedure. In this group, mean AMH increased from 2.08 pmol/L (range 1.74-2.34) to 3.94 pmol/L (range 3.66-4.29) from Weeks 1-4 to Weeks 5-8. A clinical pregnancy was obtained in 12 of the 20 (60%) patients with and without medically assisted reproduction (MAR) treatments. We report a cumulated live birth rate per started IVF/ICSI cycle of 18.4%.

Limitations, Reason For Caution: Limitations of the study were the number of patients included and the lack of a non-operated control group. Moreover, 9 of the 20 women had no male partner at inclusion and were treated with donor sperm, but each of these women had an average of 6.8 (range 4-9) unsuccessful MAR treatments with donor sperm prior to inclusion.

Wider Implications Of The Findings: Although 12 out of 20 patients became pregnant during the follow-up period, the current study does not indicate that biopsying, fragmenting and autotransplanting of ovarian cortical tissue increase the number of recruitable follicles for IVF/ICSI after 10 weeks. However, a proportion of the patients may have a follicular response in Weeks 5-8 after the procedure. It could therefore be relevant to perform a future study on the possible effects of biopsying per se that includes stimulation for IVF/ICSI earlier than week 10.

Study Funding/competing Interest(s): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. The funders had no role in the study design, data collection and interpretation, or decision to submit the work for publication. None of the authors have a conflict of interest.

Trial Registration Number: NCT02792569.
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http://dx.doi.org/10.1093/humrep/dez152DOI Listing
October 2019

Tacrolimus Can Be Reliably Measured With Volumetric Absorptive Capillary Microsampling Throughout the Dose Interval in Renal Transplant Recipients.

Ther Drug Monit 2019 10;41(5):607-614

Departments of Pharmacology and.

Background: Therapeutic drug monitoring is standard practice for the immunosuppressant tacrolimus (Tac). Venous blood sampling at outpatient clinics is time-consuming and impractical with regard to obtaining trough concentrations on clinical visit days. Home-based blood sampling may be patient friendly and pave the way for limited sampling strategies for the prediction of total drug exposure. The aim was to establish a Tac assay for dried capillary microsamples, ensuring reliable measurements during the full dose interval in renal transplant recipients.

Methods: An assay based on volumetric absorptive microsampling and liquid chromatography tandem mass spectrometry was validated. The agreement between capillary microsamples and liquid venous samples was investigated in stable renal recipients on twice-daily Tac dosing. Sampling throughout the 12-hour dose interval was examined at 2 separate days, at least 1 week apart, for each participant. Two sets of samples were obtained at each time point, one delivered directly to the laboratory and one sent through mail.

Results: Twenty-seven renal transplant recipients were included, of whom 26 were investigated twice. Tac was efficiently extracted from the dried microsamples (mean recovery 94%-103%). The between-series mean accuracy was 88%-98% with coefficients of variation ≤5.0% (≤11% at the lower limit of quantification), measurement range 0.70-60 mcg/L. The mean difference between parallel microsamples was 5%-7%. Overall, the mean differences between dried microsamples and liquid samples were -3.1% when mailed (n = 679) and -4.2% when directly delivered (n = 682). Less than 8% were outside ±20%. The microsamples were stable for 1 month at ambient temperature.

Conclusions: The microsample method demonstrated acceptable performance. Tac concentrations can be reliably quantified throughout the dose interval by using volumetric absorptive microsampling in renal transplant recipients, and the results are not influenced by postal shipment.
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http://dx.doi.org/10.1097/FTD.0000000000000655DOI Listing
October 2019

Intraperitoneal mitomycin C improves survival compared to cytoreductive surgery alone in an experimental model of high-grade pseudomyxoma peritonei.

Clin Exp Metastasis 2019 12 20;36(6):511-518. Epub 2019 Sep 20.

Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310, Oslo, Norway.

Pseudomyxoma peritonei (PMP) is a rare cancer commonly originating from appendiceal neoplasms that presents with mucinous tumor spread in the peritoneal cavity. Patients with PMP are treated with curative intent by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The value of adding HIPEC to CRS has not been proven in randomized trials, and the objective of this study was to investigate the efficacy of intraperitoneal mitomycin C (MMC) and regional hyperthermia as components of this complex treatment. Xenograft tissue established from a patient with histologically high-grade PMP with signet ring cell differentiation was implanted intraperitoneally in 65 athymic nude male rats and the animals were stratified into three treatment groups; the cytoreductive surgery group (CRSG, CRS only), the normothermic group (NG, CRS and intraperitoneal chemotherapy perfusion (IPEC) with MMC at 35 ºC), and the hyperthermic group (HG, CRS and IPEC at 41 ºC). The main endpoints were survival and tumor weight at autopsy. Adequate imitation of the clinical setting and treatment approach was achieved. The median survival was 31 days in the CRSG, 60 days in NG and 67 days in HG. The median tumor weights at autopsy were 34 g in CRSG, 23 g NG and 20 g in HG. In conclusion, the addition of IPEC with MMC after CRS doubled the survival time and reduced tumor growth compared to CRS alone. Adding regional hyperthermia resulted in a modest improvement of treatment outcome.
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http://dx.doi.org/10.1007/s10585-019-09991-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834750PMC
December 2019

Perinatal outcomes in 521 gestations after fresh and frozen cycles: a secondary outcome of a randomized controlled trial comparing GnRH antagonist versus GnRH agonist protocols.

Reprod Biomed Online 2019 Oct 17;39(4):659-664. Epub 2019 May 17.

The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Research Question: Are perinatal outcomes different after treatment with the gonadotrophin-releasing hormone (GnRH) antagonist versus the long GnRH agonist protocol for IVF?

Design: Perinatal outcomes were secondary outcomes in a large Phase IV, dual-centre, open-label, randomized controlled trial to compare GnRH antagonist and long GnRH agonist protocols in women <40 years undergoing their first assisted reproductive technology treatment. Women (n = 1050) were randomized in a ratio 1:1 from January 2009 to December 2013 and followed until December 2016. All fresh and frozen embryo transfer (FET) cycles from a single oocyte aspiration, resulting in a gestation (human chorionic gonadotrophin >10 IU/l) were included (n = 521). Data were analysed to compare preterm birth [PTB] (<37 weeks), very PTB (<32 weeks), low birthweight [LBW] (<2500 g) and very LBW (<1500 g) rates among singleton live births in GnRH antagonist versus agonist protocol.

Results: Similar perinatal outcomes were found after both protocols. In singletons after fresh embryo transfer, mean gestational age at delivery was 39.1 ± 2.49 versus 39.3 ± 1.90 (P = 0.67) and very PTB rates 1.9% versus 0% (P = 0.17). Mean birthweight was 3264 ± 662 g in the antagonist and 3341 ± 562 g in the agonist group (P = 0.37). LBW was found in 12.4% versus 7% (P = 0.19) and very LBW in 2.9% versus 1% (P = 0.34). In FET cycles, the perinatal outcomes were similar. Small for gestational age and large for gestational age rates were similar in both protocols for singleton live births after fresh and FET.

Conclusions: Perinatal outcomes are similar after the GnRH antagonist versus GnRH agonist protocols for IVF. The choice of the GnRH analogue in ovarian stimulation should be based solely on optimizing the chance of pregnancy and not on risks in perinatal outcomes.
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http://dx.doi.org/10.1016/j.rbmo.2019.05.010DOI Listing
October 2019

Contribution of recruitable follicles to circulating anti-Müllerian hormone levels following maximal gonadotrophin stimulation in patients with limited ovarian reserve.

Gynecol Endocrinol 2020 Mar 6;36(3):273-276. Epub 2019 Aug 6.

Fertility Clinic, Hvidovre Hospital, Copenhagen University, Hvidovre, Denmark.

In women, the majority of anti-Müllerian hormone (AMH) measured in serum originate from small antral follicles measuring 2-10 mm. In gonadotrophin-stimulated cycles prior to assisted reproductive technology (ART), most of the recruitable follicles develop beyond 10 mm in size and thus lose their AMH secretion capacity causing declining serum AMH levels. The aim of this study was to define the residual serum AMH level after elimination of the AMH producing recruitable follicles following maximal gonadotrophin stimulation. We measured serum AMH and number of follicles according to size at several time points during a cycle of maximal gonadotrophin stimulation (fixed dose of 300 IE HP-hMG) in 107 women with low AMH (median AMH 5 pmol/L, interquartile range (IQR) 3.3-8.3). We found that AMH decreased gradually and reached a minimum level of -55.4% (95% CI -59.6; -50.7) of the baseline value four days after ovulation trigger. Our findings suggest that the residual AMH production origins from pre-antral and small antral follicles not visible by sonography and that they account for up to 40% of the circulating AMH.
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http://dx.doi.org/10.1080/09513590.2019.1648414DOI Listing
March 2020

Planktonic encounter rates with non-spherical encounter zones.

J R Soc Interface 2019 07 31;16(156):20190398. Epub 2019 Jul 31.

Department of Physics and Centre for Ocean Life, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.

We present general formulae for planktonic predator-prey encounter rates with encounter zones of convex shape and randomly moving point-like prey with ballistic motion. When the predator is not moving, we show that the encounter rate is independent of the shape of the encounter zone around it and proportional to the product of the surface area of the encounter zone and the prey speed. By contrast, the shape of the encounter zone plays a role when both the predator and the prey are moving. Slow predator motion results in only a weak increase of the encounter rate relative to the non-motile predator situation, but it may lead to a significant shift in where prey impact the surface of the encounter zone. By analysing disc-like and rod-like encounter zones with lengthwise and sideways motion, respectively, we show that fast predator motion may significantly influence the encounter rate, depending on the shape and the direction of motion of the encounter zone.
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http://dx.doi.org/10.1098/rsif.2019.0398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685015PMC
July 2019

Dense Dwarfs versus Gelatinous Giants: The Trade-Offs and Physiological Limits Determining the Body Plan of Planktonic Filter Feeders.

Am Nat 2019 08 11;194(2):E30-E40. Epub 2019 Jun 11.

Most marine plankton have a high energy (carbon) density, but some are gelatinous with approximately 100 times more watery bodies. How do those distinctly different body plans emerge, and what are the trade-offs? We address this question by modeling the energy budget of planktonic filter feeders across life-forms, from micron-sized unicellular microbes such as choanoflagellates to centimeter-sized gelatinous tunicates such as salps. We find two equally successful strategies, one being small with high energy density (dense dwarf) and the other being large with low energy density (gelatinous giant). The constraint that forces large-but not small-filter feeders to be gelatinous is identified as a lower limit to the size-specific filter area, below which the energy costs lead to starvation. A further limit is found from the maximum size-specific motor force that restricts the access to optimum strategies. The quantified constraints are discussed in the context of other resource-acquisition strategies. We argue that interception feeding strategies can be accessed by large organisms only if they are gelatinous. On the other hand, organisms that use remote prey sensing do not need to be gelatinous, even if they are large.
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http://dx.doi.org/10.1086/703656DOI Listing
August 2019