Customized voluntary waiting period before first insemination in primiparous dairy cows. Effect on milk production, fertility and health.

Customized voluntary waiting period (VWP) before first insemination was tested in 18 commercial dairy herds in Sweden, to assess milk production, fertility and health in primiparous cows expected to be suited for extended VWP. Cow selection for extended VWP was based on 3 criteria in early lactation: 1) the 10% of cows with highest genomic persistency index, 2) cows with a difficult calving or disease during the first month of lactation, and 3) cows with higher yield during d 4-33 after calving than the herd average for primiparous cows. Cows meeting at least one of these criteria were randomly assigned to either the ExtExt treatment (extended VWP of at least 175 d, n = 174; calving interval (CInt) = 16.3 mo) or the ExtConv treatment (conventional VWP of maximum 100 d n = 173; CInt = 12.4 mo). Cows not meeting any of the criteria were assigned to the ConvConv treatment (conventional VWP, n = 183; CInt = 12.0 mo). There were no differences in milk yield per day in the CInt between treatments, although 305-d and whole-lactation (WL) milk yields were higher for ExtExt cows (10,371 and 13,803 kg) than ExtConv cows (9,812 and 10,257 kg). Milk yield at the last test milking before dry-off was lower in ExtExt compared with ExtConv cows (24.9 vs 28.3), however the results showed no difference in dry period length between the treatments. Regarding reproductive performance, the ExtExt cows had higher first service conception rate (FSCR; 60% vs. 45%) and lower number of inseminations per conception (NINS; 1.67 vs. 2.19), compared with the ExtConv cows. As expected, ConvConv cows had the lowest milk yield in 305-d, in WL, and per day in the CInt, however, FSCR and NINS did not differ between ConvConv cows and cows in the other 2 VWP treatments. Disease incidence was higher for cows in the ExtConv compared with the ConvConv treatment, but there was no difference between ExtExt and the 2 other VWP treatments. Further, no difference in proportion of cows with good udder health or culling rate was detected between any of the treatments, though due to low prevalence the study lacked power to draw major conclusions on these results. Thus prolonging VWP for suitable primiparous cows can produce benefits such as improved fertility in the form of higher FSCR and lower NINS, as well as lower dry-off yield, without compromising milk yield or prolonging dry period length.

A randomized study on the effect of extended voluntary waiting period in primiparous dairy cows on milk yield during first and second lactation.

Extending the voluntary waiting period (VWP) for primiparous cows can have a positive impact on fertility without a negative impact on milk production per day in the calving interval (CInt). We investigated the effect of extended VWP during first lactation on milk yield (MY) during 2 consecutive lactations in primiparous cows. The study involved 16 commercial herds in southern Sweden. A total of 533 Holstein and Red dairy cattle (Swedish Red, Danish Red, Ayrshire) dairy cows were randomly assigned to a conventional 25 to 95 d VWP (n = 252) or extended 145 to 215 d VWP (n = 281). Data on calvings, inseminations, and test-day yields were retrieved from the Swedish Milk Recording System. Cows with VWP according to plan and completing 1 or 2 CInt with a second or third calving were included in the data analysis. Whole lactation and 305-d energy-corrected milk (ECM) yield were higher for the extended VWP group than the conventional VWP group in both the first lactation (12,307 vs. 9,587 and 9,653 vs. 9,127 kg ECM) and second lactation (12,817 vs. 11,986 and 11,957 vs. 11,304 kg ECM). We found no difference between the VWP groups in MY per day during the first CInt or during the first and second CInt combined, although MY per day during the second CInt was around 1.5 kg higher for cows with extended VWP than for cows with conventional VWP. Thus extended VWP for primiparous cows can be used as a management tool without compromising MY.

A randomized study on the effect of an extended voluntary waiting period in primiparous dairy cows on fertility, health, and culling during first and second lactation.

When the voluntary waiting period (VWP), defined as the days between calving and when the cow is eligible to receive the first insemination, is extended, high-yielding dairy cows may have better opportunities to regain energy balance before first insemination. This study investigated the effect of an extended (145-215 days in milk [DIM], n = 280) or conventional (25-95 DIM, n = 251) VWP treatment on fertility, disease incidence, and culling rate in cows during their first lactation. The cows were also followed through a second lactation without intervention regarding VWP, during which the farmers could decide when they wished to start the inseminations. This was done in a randomized-controlled study on 16 high-yielding commercial herds in southern Sweden, containing a total of 531 primiparous cows of the Holstein and Red Dairy Cattle breeds. Data from the Swedish national dairy herd recording scheme collected between August 2018 and September 2021 were used in the analysis, including records on breed, calvings, estrus intensity, inseminations, disease, somatic cell count, culling date, and culling reason. During first lactation, more cows receiving the extended VWP treatment showed strong estrus intensity (score 4-5, 55% vs. 48%) and fewer showed moderate estrus intensity (score 3, 35% vs. 43%) at first insemination, compared with cows receiving the conventional VWP treatment. First service conception rate (FSCR) was higher (67% vs. 51%) and number of inseminations per conception (NINS) was lower (1.6 vs. 2.0) during the first lactation for cows receiving the extended compared with the conventional VWP treatment. For disease incidence rate or culling rate expressed as number of events per cow-time in the study, we found no differences between the cows receiving the 2 VWP treatments in any lactation. Calving to first service interval during second lactation was longer (86 vs. 74 d) for cows with extended compared with conventional VWP. In conclusion, primiparous cows with extended VWP showed improved reproductive functions, in the form of higher estrus intensity, greater FSCR, and lower NINS, during the first lactation. However, we observed no apparent effect on these fertility measures during the following lactation (without VWP intervention) and no differences in disease prevalence or culling between cows receiving the 2 different VWP treatments in either lactation. Compliance with the planned VWP treatment was lower for cows with planned extended compared with planned conventional VWP treatment. We studied the "intention-to-treat" effect (i.e., the results for all cows randomized to each treatment regardless of whether the planned VWP was achieved or not) to identify any bias arising due to degree of compliance. However, we found no difference in culling rate between cows randomized to an extended VWP compared with those randomized to a conventional VWP. These findings can be used to support management decisions on VWP length in high-yielding dairy herds.

Personalized circulating tumor DNA in patients with hepatocellular carcinoma: a pilot study.

BACKGROUND: Mutational analysis of circulating tumor DNA (ctDNA) can potentially be used for early detection of recurrence after resection for hepatocellular carcinoma (HCC). Mutations from tumor may be identified in plasma as an early sign of recurrence. We conducted a pilot study investigating if somatic mutations could be detected in plasma in patients undergoing liver resection for HCC and in patients with advanced non-resectable HCC. METHODS AND RESULTS: We prospectively included patients undergoing curative liver resection for HCC. Tumor tissue was investigated with whole exome sequencing and preoperative blood samples were evaluated for ctDNA using targeted next-generation sequencing (NGS) with TruSight Oncology 500 including 523 cancer-associated genes. Subsequently, the method was evaluated in patients with advanced HCC. We included eight patients curatively resected for HCC, where tumor tissue mutations were identified in seven patients. However, only in one patient tumor specific mutations were found in the preoperative blood sample. In all three patients with advanced HCC, tumor mutations were detected in the blood. CONCLUSIONS: In patients with resectable HCC, ctDNA could not be reliably detected using the applied targeted NGS method. In contrast, ctDNA was detected in all patients with advanced HCC. Small tumors, tumor heterogeneity and limited sequencing coverage may explain the lack of detectable ctDNA.

Weight of salivary gland ultrasonography compared to other items of the 2016 ACR/EULAR classification criteria for Primary Sjögren's syndrome.

OBJECTIVE: Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion. METHODS: A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS. RESULTS: A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%. CONCLUSION: SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria.

Incidence and predictors of recurrent and other new diabetic foot ulcers: a retrospective cohort study.

AIMS: To estimate progression rates, evaluate risk factors for progression, and study rate ratios for progression among people with a healed diabetic foot ulcer according to whether the healed ulcer was neuropathic, neuro-ischaemic or critically ischaemic. METHODS: We conducted a retrospective cohort study in all individuals with a healed diabetic foot ulcer treated at the Steno Diabetes Centre Copenhagen foot clinic in the period 2010 to 2016. The outcome of interest was recurrent/other new diabetic foot ulcers. RESULTS: A total of 780 people had a healed diabetic foot ulcer in the study period (2010-2016). The participants were followed for 1249 person-years [median (Q1-Q3) 1.04 (0.38-2.46) person-years] in total. One-third (33.1%) developed a recurrent/other new diabetic foot ulcer per year. Male gender, people with Type 2 diabetes and smokers had a statistically significantly higher risk of progression to a recurrent/other new diabetic foot ulcer compared to participants without these risk factors. Participants with neuro-ischaemic or critically ischaemic diabetic foot ulcers had statistically significantly higher progression rates than participants with neuropathic diabetic foot ulcers. CONCLUSIONS: Focus should be on preventing future recurrent/other new diabetic foot ulcers especially in people with ischaemia.

Decreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades.

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.

Training and validation of a novel 4-miRNA ratio model (MiCaP) for prediction of postoperative outcome in prostate cancer patients.

Background: New molecular biomarkers for prostate cancer (PC) prognosis are urgently needed. Ratio-based models are attractive, as they require no additional normalization. Here, we train and independently validate a novel 4-miRNA prognostic ratio model for PC. Patients and methods: By genome-wide miRNA expression profiling of PC tissue samples from 123 men who underwent radical prostatectomy (RP) (PCA123, training cohort), we identified six top candidate prognostic miRNAs and systematically tested their ability to predict postoperative biochemical recurrence (BCR). The best miRNA-based prognostic ratio model (MiCaP) was validated in two independent cohorts (PCA352 and PCA476) including >800 RP patients in total. Clinical end points were BCR and prostate cancer-specific survival (CSS). The prognostic potential of MiCaP was assessed by univariate and multivariate Cox-regression analyses and Kaplan-Meier analyses. Results: We identified a 4-miRNA ratio model, MiCaP (miR-23a-3p×miR-10b-5p)/(miR-133a×miR-374b-5p), that predicted time to BCR independently of routine clinicopathologic variables in the training cohort (PCA123) and was successfully validated in two independent RP cohorts. In addition, MiCaP was a significant predictor of CSS in univariate analysis [HR 3.35 (95% CI 1.34 - 8.35), P = 0.0096] and in multivariate analysis [HR 2.43 (95% CI 1.45-4.07), P = 0.0210]. As proof-of-principle, we also analyzed MiCaP in plasma samples from 111 RP patients. A high MiCaP score in plasma was significantly associated with BCR (P = 0.0036, Kaplan-Meier analysis). Limitations include low mortality rates (CSS: 5.4%). Conclusions: We identified a novel 4-miRNA ratio model (MiCaP) with significant independent prognostic value in three RP cohorts, indicating promising potential to improve PC risk stratification.

The effect of basal-bolus therapy varies with baseline 1,5-anhydroglucitol level in people with Type 2 diabetes: a post hoc analysis.

AIMS: To investigate the impact of baseline 1,5-anhydroglucitol on the treatment effect of basal-bolus therapy in people with Type 2 diabetes. METHODS: Post hoc analysis of onset 3, an 18-week, randomized, phase 3 trial evaluating the efficacy and safety of fast-acting insulin aspart in basal-bolus therapy (n = 116) vs. basal insulin-only therapy (n = 120) in people with Type 2 diabetes. The estimated treatment difference in change from baseline in HbA1c was investigated for different cut-off values of baseline 1,5-anhydroglucitol (2, 3, 4, 5 and 6 µg/ml). RESULTS: The estimated treatment difference in change from baseline in HbA1c between basal-bolus therapy and basal insulin-only therapy was statistically significantly greater in participants with baseline 1,5-anhydroglucitol ≤3 µg/ml (n = 34) vs. >3 µg/ml (n = 198) [estimated treatment difference (95% CI): -1.53% (-2.12; -0.94) vs. -0.82% (-1.07; -0.57); P-value for interaction = 0.03]. The estimated treatment difference became more pronounced when comparing participants with 1,5-anhydroglucitol ≤2 µg/ml (n = 15) vs. >2 µg/ml (n = 217) [estimated treatment difference (95% CI): -2.26% (-3.15; -1.36) vs. -0.85% (-1.08; -0.62); P-value for interaction = 0.003]. For cut-off values ≥4 µg/ml, estimated treatment differences were numerically greater below the cut-off compared with above, although the interaction terms were not statistically significant. CONCLUSION: This analysis indicates that people with Type 2 diabetes with low 1,5-anhydroglucitol have an added treatment benefit with basal-bolus therapy compared with people with higher 1,5-anhydroglucitol. Further research is needed to clarify any clinical utility of these findings. Clinical Trials Registry No: NCT01850615.

THE ROMANIAN VERSION OF THE THYROID-RELATED PATIENT-REPORTED OUTCOMES THYPRO AND THYPRO-39. TRANSLATION AND ASSESSMENT OF RELIABILITY AND CROSS-CULTURAL VALIDITY.

BACKGROUND: ThyPRO is a recently developed thyroid-specific quality of life (QoL) questionnaire applicable to patients with benign thyroid disorders(BTD). The aim of the present study was to translate ThyPRO and ThyPRO-39 into Romanian, and to evaluate reliability and cross-cultural validity. METHODS: Standard methodology for translation and linguistic validation of patient-reported outcomes (PRO) was applied. The questionnaire was completed by 130 patients with benign thyroid diseases seen at Department of Endocrinology in the Emergency County Hospital, Tîrgu Mures, Romania, between October 2015 and March 2016. Internal reliability of the Romanian version of the ThyPRO (ThyPROro) scales was assessed for multi-item scales using Cronbach's alpha coefficient. An efficient method for testing cross-cultural validity is analysis of differential item functioning (DIF). Uniform DIF between the Romanian and the original Danish sample was investigated using ordinal logistic regression. The translation process proceeded without difficulties, and any disagreements were revised by one of the developers and the language coordinator. RESULTS: Internal reliability for ThyPRO was satisfactory. Cronbach`s alpha coefficients for the 13 scales ranged from 0.78 to 0.93 for the ThyPROro and 0.78 to 0.87 for the ThyPROro-39. In the 85-item ThyPRO, nine instances of DIF were found. Most were minor, explaining <3% of the variation in scale score, but DIF in positively worded items were larger, with explained variance (R2's) around 10-15%. CONCLUSION: The ThyPROro questionnaire is ready for assessment of health-related quality of life in Romanian patients with benign thyroid diseases.

The clinical utility of FDG PET/CT among solid organ transplant recipients suspected of malignancy or infection.

PURPOSE: Solid organ transplant (SOT) recipients are at high risk of developing infections and malignancies. 18F-FDG PET/CT may enable timely detection of these diseases and help to ensure early intervention. We aimed to describe the clinical utility of FDG PET/CT in consecutive, diagnostic unresolved SOT recipients transplanted from January 2004 to May 2015. METHODS: Recipients with a post-transplant FDG PET/CT performed as part of diagnostic work-up were included. Detailed chart reviews were done to extract relevant clinical information and determine the final diagnosis related to the FDG PET/CT. Based on á priori defined criteria and the final diagnosis, results from each scan were classified as true or false, and diagnostic values determined. RESULTS: Among the 1,814 recipients in the cohort, 145 had an FDG PET/CT performed; 122 under the indication of diagnostically unresolved symptoms with a suspicion of malignancy or infection. The remaining (N = 23) had an FDG PET/CT to follow-up on a known disease or to stage a known malignancy. The 122 recipients underwent a total of 133 FDG PET/CT scans performed for a suspected malignancy (66 %) or an infection (34 %). Sensitivity, specificity, and positive and negative predictive values of the FDG PET/CT in diagnosing these conditions were 97, 84, 87, and 96 %, respectively. CONCLUSION: FDG PET/CT is an accurate diagnostic tool for the work-up of diagnostic unresolved SOT recipients suspected of malignancy or infection. The high sensitivity and NPV underlines the potential usefulness of PET/CT for excluding malignancy or focal infections in this often complex clinical situation.

Risk of infectious diseases among first-degree relatives of transplant recipients who develop CMV infection: is the infectious phenotype inheritable?

Transplant recipients are at high risk of cytomegalovirus (CMV) infection. Mechanisms explaining the variation in risk of infections are far from fully elucidated. We hypothesised that host genetics explains part of the variation in risk of infection and examined if relatives of recipients with CMV infection have higher rates of severe infections compared to relatives of recipients without this infectious phenotype. In a register-based study, we included first-degree relatives of transplant recipients and examined the risk of hospitalisation due to overall infection or viral infection and risk of death among relatives of recipients who developed CMV infection within the first year of transplantation compared to relatives of recipients without CMV. Analyses were adjusted for sex, age and calendar year. We included 4470 relatives who were followed for 103,786 person-years, median follow-up 24 years [interquartile range (IQR) 12-36]. There were a total of 1360 infection-related hospitalisations in the follow-up period, incidence rate (IR) 13.1/1000 person-years [95% confidence interval (CI), 12.4; 13.8]. 206 relatives were hospitalised with viral infection, IR 1.8/1000 person-years (95% CI, 1.6; 2.0). There was no increased risk of hospitalisation due to infections, IR ratio (IRR) 0.99 (95% CI, 0.88; 1.12), nor specifically viral infections, IRR 0.87 (95% CI, 0.63; 1.19), in relatives of recipients with CMV compared to relatives of recipients without CMV. Also, no difference was seen in analyses stratified by transplant type, family relation and CMV serostatus. The risk of hospitalisation due to infection is not increased among first-degree relatives of transplant recipients with CMV infection compared to relatives of recipients without CMV.

Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years' experience from the Nordic countries.

Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 µmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.

Survival and growth of isolated pre-antral follicles from human ovarian medulla tissue during long-term 3D culture.

STUDY QUESTION: Can human pre-antral follicles isolated enzymatically from surplus medulla tissue survive and grow in vitro during long-term 3D culture? SUMMARY ANSWER: Secondary human follicles can develop to small antral follicles and remain hormonally active in an alginate-encapsulation culture system for more than 30 days. WHAT IS KNOWN ALREADY: Ovarian tissue cryopreservation followed by transplantation is a promising fertility preservation approach for cancer patients. However, transplantation of cryopreserved tissue to patients may carry the risk of re-implanting malignant cells. Grafting of follicles enzymatically isolated from ovarian tissue or developing a method for follicular culture and maturation in vitro may provide fertility to such patients without the risk of reintroducing the malignancy. However, the growth of pre-antral follicles isolated by enzymatic digestion from medulla tissue during long-term culture has received only little attention. STUDY DESIGN, SIZE, DURATION: Two to ten human pre-antral follicles were encapsulated together within an alginate bead and cultured with or without ovarian interstitial tissue for either 7 days or >30 days. Follicles were cultured in either 20% oxygen or 5% oxygen or encapsulated in a lower concentration of alginate together with a lower concentration of FSH in high oxygen. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 395 pre-antral follicles from 16 cancer patients, aged 9-37 years, were co-cultured for either 7 days or >30 days. A proportion of follicle (64) were removed from culture on Day 7 and assessed for viability using confocal fluorescence microscopy following calcein-AM and ethidium homodimer-1 staining or histology. The remaining follicles (331) were continued in culture for >30 days then assessed for survival and growth. Anti-Müllerian hormone (AMH) and estradiol levels were quantified in the medium. MAIN RESULTS AND THE ROLE OF CHANCE: An optimized protocol for isolation of intact healthy pre-antral follicles from ovarian medulla was developed. After 7 days of culture, secondary follicles had a significantly higher survival rates compared with primary and primordial follicles (70 versus <38%). Primordial and primary follicles did not develop into the antral follicle stage. In contrast, secondary follicles continued to develop in all culture conditions examined. Based on growth rate and morphology, four distinct cohorts of surviving follicles, 'fast growth', 'slow growth', 'no growth' and 'extruded oocyte' were identified. From Day 1 to Day 30, the mean diameter of follicles increased from 184 ± 35 to 661 ± 120 µm (significant from Day 18), 145 ± 19 to 318 ± 68 µm and 136 ± 15 to 162 ± 25 µm (mean ± SD) in the 'fast growth', 'slow growth' and 'no growth' patterns, respectively. The fast growth follicles also contained a larger diameter oocyte than other follicle groups. From the pre-antral follicle to antral stage, follicles became steroidogenically active and secretion of AMH and estradiol increased. No significant difference between the follicles cultured with or without ovarian interstitial tissue was observed. LIMITATIONS, REASONS FOR CAUTION: The number of surviving follicles at the end of study was low in each of the culture conditions therefore whether there is a benefit with any of the conditions is difficult to ascertain. Multiple pre-antral follicles were cultured within the same alginate bead which may affect the in vitro development of the secondary follicles. WIDER IMPLICATIONS OF THE FINDINGS: These findings show that pre-antral follicles, isolated enzymatically from surplus medulla tissue that is normally discarded, possess a developmental potential which may be used to devise safer fertility preservation methods for patients who are at high risk of malignant contamination of their ovarian tissue. STUDY FUNDING/COMPETING INTERESTS: The Child Cancer Foundation in Denmark (2012-26) and the EU interregional project ReproHigh are thanked for having funded this study; and the Key Program of Medical Science and Technology Innovation of Nanjing Military Area Command in China (14ZX06; 11Z010). They had no role in the study design, collection and analysis of data, data interpretation or in writing the report. The authors have no conflicts of interest to disclose.

Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review.

BACKGROUND: Prevention of foot ulcers in patients with diabetes is extremely important to help reduce the enormous burden of foot ulceration on both patient and health resources. A comprehensive analysis of reported interventions is not currently available, but is needed to better inform caregivers about effective prevention. The aim of this systematic review is to investigate the effectiveness of interventions to prevent first and recurrent foot ulcers in persons with diabetes who are at risk for ulceration. METHODS: The available medical scientific literature in PubMed, EMBASE, CINAHL and the Cochrane database was searched for original research studies on preventative interventions. Both controlled and non-controlled studies were selected. Data from controlled studies were assessed for methodological quality by two independent reviewers. RESULTS: From the identified records, a total of 30 controlled studies (of which 19 RCTs) and another 44 non-controlled studies were assessed and described. Few controlled studies, of generally low to moderate quality, were identified on the prevention of a first foot ulcer. For the prevention of recurrent plantar foot ulcers, multiple RCTs with low risk of bias show the benefit for the use of daily foot skin temperature measurements and consequent preventative actions, as well as for therapeutic footwear that demonstrates to relieve plantar pressure and that is worn by the patient. To prevent recurrence, some evidence exists for integrated foot care when it includes a combination of professional foot treatment, therapeutic footwear and patient education; for just a single session of patient education, no evidence exists. Surgical interventions can be effective in selected patients, but the evidence base is small. CONCLUSION: The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong, but is small for the use of other, sometimes widely applied, interventions and is practically nonexistent for the prevention of a first foot ulcer and non-plantar foot ulcer.

Recurrent ischemic stroke is associated with the burden of risk factors.

AIM: To determine the characteristics of acute ischemic stroke patients admitted to hospital with history of prior ischemic stroke(s). We hypothesized that there is an association between the number of risk factors and prior ischemic stroke irrespective of age. METHODS: All patients with acute ischemic stroke admitted to Haukeland University Hospital between 2006 and 2013 were registered in the NORSTROKE database. Variables included prior ischemic stroke(s) (based on self-report and patient records), risk factors, TOAST classification, and CT and MRI findings. Comparison was made between patients with prior ischemic stroke and first-ever ischemic stroke. Multivariate analyses were performed. RESULTS: In total, 2697 patients were included and 461 (17.1%) had a history of prior ischemic stroke(s). Logistic regression analyses showed that prior ischemic stroke was associated with the number of risk factors, leukoaraiosis, hypertension, atrial fibrillation, and atherosclerosis. CONCLUSION: History of prior ischemic stroke in patients with acute ischemic stroke was associated with the burden of risk factors, atherosclerosis, and atrial fibrillation compared to first-ever ischemic stroke. This has important implications for secondary preventive treatment.

Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial).

BACKGROUND AND OBJECTIVES: This trial explores whether intravenous iron isomaltoside 1000 (Monofer®) results in a better regeneration of haemoglobin levels and prevents anaemia compared to placebo in preoperative non-anaemic patients undergoing cardiac surgery. STUDY DESIGN AND METHODS: The trial is a prospective, double-blind, comparative, placebo-controlled trial of 60 non-anaemic patients undergoing cardiac surgery. The patients were randomized 1:1 to either 1000 mg intravenous iron isomaltoside 1000 administered perioperatively by infusion or placebo. RESULTS: Mean preoperative haemoglobin in the active treatment group was 14·3 g/dl vs. 14·0 g/dl in the placebo group. At discharge 5 days after surgery, haemoglobin levels were reduced to 10·7 and 10·5 g/dl, respectively. One month after surgery, haemoglobin concentration had increased to an average of 12·6 g/dl vs. 11·8 g/dl (p = 0·012) and significantly more patients were non-anaemic in the intravenous iron isomaltoside 1000-treated group compared to the placebo group (38·5% vs. 8·0%; p = 0·019). There were no differences in side-effects between the groups. CONCLUSION: A single perioperative 1000 mg dose of intravenous iron isomaltoside 1000 significantly increased the haemoglobin level and prevented anaemia 4 weeks after surgery, with a short-term safety profile similar to placebo. Future trials on potential clinical benefits of preoperative treatment with intravenous iron in non-anaemic patients are needed.

Golgi cell activity during eyeblink conditioning in decerebrate ferrets.

Golgi cells have a central position in the cerebellar cortical network and are indirectly connected to Purkinje cells, which are important for the acquisition of learned responses in classical conditioning. In order to clarify the role of Golgi cells in classical conditioning, we made extracellular Golgi cell recordings during different stages of conditioning, using four different conditional stimuli. Our results show that forelimb and superior colliculus stimulation, but not mossy fiber stimulation, evokes a short latency increase in Golgi cell firing. These results suggest that Golgi cells are involved in modulating input to the cerebellar cortex. There were however no differences in Golgi cell activity between naïve and trained animals, which suggests that Golgi cells are not intimately involved in the plastic changes that occur during classical conditioning. The absence of long latency effects of the conditional stimulus also questions whether Golgi cells contribute to the generation of a temporal code in the granule cells.

Generic tacrolimus in solid organ transplantation.

The availability of a wide range of immunosuppressive therapies has revolutionized the management of patients who have undergone solid organ transplantation (SOT). However, the cost of immunosuppressive drugs remains high. This situation has led to the development of generic equivalents, which are similar in quality, safety, and efficacy to their approved innovator drugs. There are data available for three generic brands, tacrolimus (Intas), tacrolimus (PharOS), and tacrolimus (Sandoz). Bioequivalence has been demonstrated for generic tacrolimus (Sandoz) within a narrow therapeutic range to its innovator tacrolimus drug (Prograf) in both healthy volunteers and kidney transplant patients. Clinical experience with this generic tacrolimus formulation has also been established in both de novo and conversion patients who have undergone kidney and liver transplantation, as well as in conversion of other SOT patients, including lung and heart recipients.

Community analysis of biting midges (Culicoides Latr.) on livestock farms in Denmark.

This study presents descriptive statistics and community analysis of adult biting midges trapped at 16 livestock farms by means of light traps on Zealand and Lolland-Falster, Denmark. A total of 9,047 male and female Culicoides divided into 24 species, were caught. Biotic and abiotic factors ranging from presence of different host species (cattle or sheep/goats), presence of small woody areas or wetlands in the surrounding landscape, and agricultural practice (organic or conventional) were included in the community analysis. Only differences in the Culicoides communities between conventional and organic practices were tested significantly different. Total numbers of Culicoides individuals were higher on the organic farms than on the conventional farms. The larger loads of biting midges on the organic farms may be due to free-ranging animals that attracted the midges on pastures and carried them to the stable environment (the cattle of the conventional farms were held inside the stables). Presence of deciduous trees within 500 m of the farms resulted in higher numbers of Culicoides obsoletus s.s., while presence of wetlands increased the numbers of Culicoides punctatus and Culicoides pulicaris. Furthermore, Culicoides riethi and Culicoides puncticollis (subgenus Monoculicoides) were recorded in high numbers on individual farms. C. puncticollis was found for the first time in Denmark and so far only recorded from Zealand.