Prognostic value of temporal patterns of left atrial reservoir strain in patients with heart failure with reduced ejection fraction.

BACKGROUND: We investigated whether repeatedly measured left atrial reservoir strain (LASr) in heart failure with reduced ejection fraction (HFrEF) patients provides incremental prognostic value over a single baseline LASr value, and whether temporal patterns of LASr provide incremental prognostic value over temporal patterns of other echocardiographic markers and NT-proBNP. METHODS: In this prospective observational study, 153 patients underwent 6-monthly echocardiography, during a median follow-up of 2.5 years. Speckle tracking echocardiography was used to measure LASr. Hazard ratios (HRs) were calculated for LASr from Cox models (baseline) and joint models (repeated measurements). The primary endpoint (PEP) comprised HF hospitalization, left ventricular assist device, heart transplantation, and cardiovascular death. RESULTS: Mean age was 58 ± 11 years, 76% were men, 82% were in NYHA class I/II, mean LASr was 20.9% ± 11.3%, and mean LVEF was 29% ± 10%. PEP was reached by 50 patients. Baseline and repeated measurements of LASr (HR per SD change (95% CI) 0.20 (0.10-0.41) and (0.13 (0.10-0.29), respectively) were both significantly associated with the PEP, independent of both baseline and repeated measurements of other echo-parameters and NT-proBNP. Although LASr was persistently lower over time in patients with PEP, temporal trajectories did not diverge in patients with versus without the PEP as the PEP approached. CONCLUSION: LASr was associated with adverse events in HFrEF patients, independent of baseline and repeated other echo-parameters and NT-proBNP. Temporal trajectories of LASr showed decreased but stable values in patients with the PEP, and do not provide incremental prognostic value for clinical practice compared to single measurements of LASr.

The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

Financial opportunity costs and deaths among close kin are independently associated with reproductive timing in a contemporary high-income society.

Evolutionary demography predicts that variation in reproductive timing stems from socio-ecologically contingent trade-offs between current and future reproduction. In contemporary high-income societies, the costs and benefits of current reproduction are likely to vary by socioeconomic status (SES). Two influential hypotheses, focusing on the parenthood 'wage penalty', and responses to local mortality have separately been proposed to influence the timing of parenthood. Economic costs of reproduction (i.e. income loss) are hypothesized to delay fertility, especially among high childhood SES individuals who experience greater opportunities to build capital through advantageous education and career opportunities. On the other hand, relatively low childhood SES individuals experience higher mortality risk, which may favour earlier reproduction. Here, we examine both hypotheses with a representative register-based, multigenerational dataset from contemporary Finland (N = 47 678). Consistent with each hypothesis, the predicted financial cost of early parenthood was smaller, and mortality among close kin was higher for individuals with lower childhood SES. Within the same dataset, lower predicted adulthood income and more kin deaths were also independently associated with earlier parenthood. Our results provide a robust demonstration of how economic costs and mortality relate to reproductive timing. We discuss the implications of our findings for demographic theory and public policy.

Addition of routinely measured blood biomarkers significantly improves GRACE risk stratification in patients with myocardial infarction.

AIM: To investigate whether blood biomarkers measured routinely at hospital admission in myocardial infarction (MI) patients can improve the admission GRACE score for the composite endpoint of all-cause mortality and non-fatal MI at 6 months. METHODS: 2055 patients treated for MI in the Northwest clinics, the Netherlands, between 2013 and 2016 were examined. As part of the prevailing MI treatment protocol, 19 biomarkers were measured and the GRACE score was ascertained. Information on the composite endpoint was derived from municipal registries and electronic medical records. We applied elastic net logistic regression (LR) analysis to select biomarkers that had statistically significant additive prognostic value on top of the GRACE score. We then studied the prognostic performance of the LR model containing the GRACE score and the selected biomarkers. RESULTS: At six months follow-up 143 (6.96%) reached the composite endpoint. Nine variables were included in the final LR model: GRACE score, urea, sodium, potassium, alkaline phosphatase, LDL cholesterol, glucose, hemoglobin and C-reactive protein. This extended GRACE score model showed improved discrimination (C-statistic 0.76 vs 0.70, p = <0.001) and classification (continuous net reclassification index 0.49, p < 0.001) compared with the GRACE score only. CONCLUSION: The ability of the GRACE score for detecting MI patients at high risk for mortality or MI within 6 months, was significantly improved by adding several biomarkers measured routinely at admission.

Thyroid homeostasis in mother-child pairs in relation to maternal iodine status: the MISA study.

BACKGROUND/OBJECTIVES: Iodine deficiency during pregnancy may influence maternal and foetal thyroid function with the risk of causing neurocognitive and psychomotor deficits in the offspring. The objective of this study was to assess iodine status in pregnant women from Northern Norway and to investigate the influence of iodine status on maternal and infant thyroid function. SUBJECTS/METHODS: Women from the Northern Norway Mother-and-Child contaminant Cohort Study (MISA) donated a blood and urine sample at three visits during their pregnancy and postpartum period (in second trimester, 3 days and 6 weeks after delivery. N=197). Women were assigned to iodine status groups according to urine iodine concentrations (UICs) in second trimester and mixed effects linear models were used to investigate potential associations between iodine status and repeated measurements of thyroid-stimulating hormone (TSH), thyroid hormones (THs), TH-binding proteins and thyroid peroxidase antibodies. Associations between maternal iodine status and TSH in heel prick samples from the infants were investigated with linear regression. RESULTS: Median UIC in second trimester was 84 µg/l (range 18-522) and 80% had UIC below recommended level (<150 µg/l). Iodine-deficient women had higher concentrations of T3, FT3 and FT4 (estimated differences (confidence intervals) of 0.10 nmol/l (0.01, 0.17), 0.16 pmol/l (0.05, 0.26) and 0.45 pmol/l (0.10, 0.78), respectively) compared with iodine-sufficient women. The concentrations varied within normal reference ranges, but the majority of women with subclinical hypothyroidism were iodine deficient. Maternal iodine status did not influence infant TSH concentrations. CONCLUSIONS: This study indicate iodine deficiency among pregnant women in Norway. Iodine status during pregnancy influences maternal thyroid homeostasis and is therefore a risk factor for foetal and infant development.

Pica Practices among Apparently Healthy Women and Their Young Children in Ghana.

BACKGROUND: Pica is an increased appetite/craving for food or non-food substances like clay, and chalk, and is strongly associated with iron deficiency (ID) anemia. This study assessed pica practices among non-pregnant mothers and their children, 12-to-59 months, in an anaemia endemic population in Ghana. SUBJECTS AND METHODS: A cross-sectional quantitative survey was conducted in two randomly selected districts in Northern Ghana. The researchers developed semi-structured questionnaires with components on pica practice, history and experiences and administered via structured face-to-face interviews with mothers (N=161) and all their children 6-59 months. Of this population, 132 mothers had children 12-to-59 months (N=139) in April 2012. Pica practice among children was reported by their mothers. Data was analysed using SPSS version 23.0. RESULTS: Few mothers (3%) spontaneously reported pica (for uncommon food and/or non-food substances) at the time of the interview, however, 16 (12.1%) mothers with pica were confirmed after further probing. Twelve (8.6%) children were reported to have ingested/craved clay/soil/dust (11 / 91.7 %), paper (1 / 7.1%) and chalk (1/7.1%) prior to the interview. One child had poly-pica (pica for two substance). Pica was reported to have been practised by expecting mothers during 37 (26.6%) of the pregnancies of the children involved in the study, and was mostly for clay/soil (33 / 89.1%), kola nut (5 / 3.6%), uncooked rice and bambara beans. Children's pica practices were significantly associated (χ2=6.33; p=0.011) with their mothers' pica practices during pregnancy as well as with mothers' pica practices at the time of the study (χ2=5.98; p=0.035). A logistic regression analysis seemed to show that pica of the mother during pregnancy was more strongly associated with the child's pica than later pica behaviour of the mother. Many myths and misconceptions associated with the practice of pica were also reported in these communities. CONCLUSIONS: The reported pica practice among mothers and their children was lower than what has been observed in other studies. Knowledge and perceptions regarding pica were mostly inaccurate. Education on pica and associated dangers of its practices should be included in nutrition interventions in communities with known high anemia prevalence.

Early failures in large head metal-on-metal total hip arthroplasty.

Concerns have recently been raised about large head metal-on-metal total hip arthroplasties (LDH THA). Metal ion release due to wear may cause osteolysis, pseudotumours and necrosis. In addition, fixation of certain acetabular components is thought to be suboptimal. We present the short term outcome of the Durom LDH THA. Retrospectively, a consecutive series of 64 implants in 60 patients was analysed with a mean follow-up of 37 months. Clinical and radiological evaluation was performed on a regular basis, followed by additional evaluations when indicated. The 10-year revision percentage was calculated and compared with National Institute for Health and Clinical Excellence (NICE) standards. Six patients (six hips) underwent cup revision (9%). Four of these cups showed no or minimal bone fixation. Three patients had a pseudotumour. In two revision cases, ALVAL (aseptic lymphocyte-dominated vasculitis-associated lesion) was present. Lack of bone ingrowth and the presence of ARMD (adverse reaction to metal debris) seem to contribute to a high failure rate of the Durom LDH THA. The predicted ten-year revision rate of 14.2% (95% CI 5.6-22.8) is, given the broad confidence interval, not significantly outside NICE recommended standards. However, it is not clear which factors, if any, predict implant failure. Therefore, we do not advocate the use of this implant.

Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance?

BACKGROUND: We aimed to investigate whether fluid therapy with a goal of near-maximal stroke volume (SV) guided by oesophageal Doppler (ED) monitoring result in a better outcome than that with a goal of maintaining bodyweight (BW) and zero fluid balance in patients undergoing colorectal surgery. METHODS: In a double-blinded clinical multicentre trial, 150 patients undergoing elective colorectal surgery were randomized to receive fluid therapy after either the goal of near-maximal SV guided by ED (Doppler, D group) or the goal of zero balance and normal BW (Zero balance, Z group). Stratification for laparoscopic and open surgery was performed. The postoperative fluid therapy was similar in the two groups. The primary endpoint was postoperative complications defined and divided into subgroups by protocol. Analysis was performed by intention-to-treat. The follow-up was 30 days. The trial had 85% power to show a difference between the groups. RESULTS: The number of patients undergoing laparoscopic or open surgery and the patient characteristics were similar between the groups. No significant differences between the groups were found for overall, major, minor, cardiopulmonary, or tissue-healing complications (P-values: 0.79; 0.62; 0.97; 0.48; and 0.48, respectively). One patient died in each group. No significant difference was found for the length of hospital stay [median (range) Z: 5.00 (1-61) vs D: 5.00 (2-41); P=0.206]. CONCLUSIONS: Goal-directed fluid therapy to near-maximal SV guided by ED adds no extra value to the fluid therapy using zero balance and normal BW in patients undergoing elective colorectal surgery.

Effects of mixtures of persistent organic pollutants (POPs) derived from cod liver oil on H295R steroidogenesis.

Crude cod liver oil and liver oil supplements are consumed as a source of vitamin A, D and polyunsaturated fatty acids; during winter and early pregnancy. Crude cod liver oil however constitutes a considerable source of persistent organic pollutants (POPs). This paper aimed at characterizing and quantifying the influence of POP mixtures extracted from three different steps in the cod liver oil industrial process on hormone production and the expression of steroidogenesis-related genes in H295R cells. Exposure to extracts from crude cod liver oil and from its industrial waste increased progesterone (P4), cortisol (Cort), testosterone (T) and estradiol (E2) production; and among others, the expression of MC2R, CYP11B1 and HSD3B2 genes. Observed effects after exposure to pharmaceutical cod liver oil extract were considerably lower. The type of effects on gene expression and hormone production were similar to those induced by forskolin and PCBs, the latter being the major contaminants within the extracts. Additional research is required to further unveil the mechanisms behind the observed steroidogenic effects and to assess whether the potential risk might outweigh the potential benefits of crude and processed cod liver oil consumption.

Total blubber burden of organochlorine pollutants in phocid seals; methods and suggested standardization.

The purpose of the present paper was to investigate methods for calculating the total blubber burden of organochlorine pollutants (OCs) in phocid seals. Harp seals (Phoca groenlandica) were used as the model species. A sample of fat pre-breeding adult females (N = 9) and a sample of thin moulting adult females (N = 7) were collected. From each animal blubber samples from five different body sites (complete blubber columns and samples from different blubber layers), in addition to a sample from a homogenate derived from the entire blubber mass, were analyzed for selected OCs. Significant differences in the concentrations of major OC contaminants were found between inner and outer blubber layer. Within each seal group, no significant difference in OC concentrations was found between homogenates from whole blubber columns from the five different sites of the animals or when comparing these with the OC concentrations found in the blubber sample deriving from a homogenate of the entire blubber mass. When comparing the two seal groups, the mean OC concentrations were significantly higher in the thin seals. However, blubber burden of OCs measured directly and calculated indirectly were not significantly different, and did not vary between the two groups of seals. Since these seals are of the same age and sex group and from the same population, this is not an unexpected result. The present results suggest that comparison of blubber concentrations of OCs in phocid seals should be avoided, especially when comparing differences between geographical areas or for time-trend analyses. For this type of study, we suggest that the blubber burden of OCs is applied as standard in the future. Furthermore, since blubber depth at a specific sampling site is required when using the estimator for calculation of the percent blubber content in phocid seals (the LMD-index), we suggest that this sampling site (central dorsally) is introduced as a standard when sampling blubber for OC analyses in phocid seals.

Sentinel node localization in breast cancer patients using intradermal dye injection.

In a series of 161 consecutive breast cancer operations, intradermal injection of Patent Blue was used to localize the sentinel node (SN). The surgical localization rate was 60%. Including the blue lymph nodes found by the pathologist, localization rate was 70%. After the first 103 operations, the surgical procedure was changed, resulting in a localization rate of 83%. Ten surgeons participated, but only one had previous experience with SN dissection. The others experienced a steep learning curve. Metastasis was found in 42 of 97 SNs (43%). In 15 cases (36%) metastasis was recognized only after step-sectioning and immunohistochemical staining for cytokeratin. In one case a benign epithelial inclusion was found. The sentinel node was false negative in 9.1% of cases. The consensus from the literature is that the best results are achieved using a combination of dye and isotopic techniques.

Mercury, cadmium, lead, and selenium in fish from a Norwegian fjord and off the coast, the importance of sampling locality.

Hepatic levels of mercury, cadmium, lead, and selenium and levels of mercury and selenium in muscle tissue were analysed in tusk from the Nordfjord in Norway. With the exception of selenium in the muscle tissue, the metal levels were significantly higher in the fjord fish than in fish caught off the coast. No local source is known to explain the difference in levels, and this indicates that the fjord efficiently accumulates atmospheric contaminants. The present results demonstrate the importance of sampling area when determining levels of metals in marine organisms far from point sources. The liver was increasingly used as a storage compartment for mercury and selenium with increasing exposure.

Organochlorines in deep-sea fish from the Nordfjord.

Hepatic levels of OCs (Organochlorines) were analysed in deep-sea fish from the Nordfjord in Norway. Levels of PCBs in the present study exceed background levels in fish from Norwegian water by a factor of 1.5 to 50, and DDTs by one to two orders of magnitude. DDTs in fish from the Nordfjord have previously been attributed to DDT use in fruit orchards. The present levels of DDTs show that the decline usually found in biota in Scandinavia since the 1970s is not found in the deep-sea fish in Nordfjord. There is no known local PCB source that can explain the elevated levels in the present study. This indicates that the fjord efficiently accumulates atmospheric contaminants. Chlordanes and HCB were less important, and HCHs were not detected.

A zinc-dependent DNA-binding activity co-operates with cAMP-responsive-element-binding protein to activate the human thyroglobulin enhancer.

Footprinting experiments involving the human thyroglobulin gene enhancer and thyroid nuclear extracts revealed a protected region called X2, containing an incomplete cAMP-responsive element (CRE). Band-shift experiments identified two binding activities recognizing the X2 element: a CRE-binding protein (CREB)/activating transcription factor (ATF) relative that binds the half CRE motif and a second factor that interacts with a G-rich motif located just upstream from the CRE. The first factor appears to be CREB itself, as indicated by the supershifting when using an antibody directed against CREB, and the second DNA-binding activity involved was shown to be zinc-dependent and exhibited an apparent molecular mass of 42-44 kDa in South-Western blotting experiments. This factor may represent a novel entity, which we named CAF, for 'CREB Associated Factor'. Three copies of X2 sequence conferred a strong cAMP-dependent transcriptional activation to a heterologous promoter in transient transfection assay in cAMP-stimulated primary thyrocytes and HeLa cells. Transfection experiments of constructs containing the X2 element mutated in either the CRE or the G-rich site showed that both motifs were required for this transcription activating function. Moreover, the combination of several individual X2 elements mutated in either the CRE or the G-rich motif did not exhibit full transcriptional activity. This suggests that, in the context of the X2 element, CREB requires a close interaction with CAF to achieve both basal and cAMP-dependent transcriptional activation.

Identification of a thyroid-specific and cAMP-responsive enhancer in the upstream sequences of the human thyroglobulin promoter.

Functional analysis of remote 5'-flanking sequences from the human thyroglobulin gene in primary cultured dog thyrocytes led to the identification of a partly cAMP-responsive enhancer, located between -3.6 to -2.2 kb from the transcriptional start site. Deletion analysis of the 1.4 kb-long region localised the enhancer activity in a 0.5 kb-long fragment (located between -3.2 and -2.7 kb relative to transcription start), which could be divided into two functional sub-fragments of 0.2 and 0.3 kb. A potential binding site for the CREB/ATF transcription factors was found in the 0.3 kb element. The complete enhancer region had no detectable activity when assayed in Hela cells, suggesting that it constituted a thyroid-specific regulatory element. Accordingly, footprinting experiments revealed the presence of several binding sites for Thyroid Transcription Factor-1 (TTF-1) in both the 0.2 and 0.3 kb elements.