Late-onset vitamin K deficiency bleeding in an extremely preterm infant fed an exclusively human milk-based diet.

All newborns need extra phylloquinone (vitamin K1; K1) to prevent vitamin K deficiency bleeding (VKDB). In preterm babies, the main sources are prophylactic K1 given at birth and parenteral and/or enteral feeding thereafter. Preterm babies are at risk of late-onset VKDB if ongoing K1 supplementation is inadequate. For extremely preterm infants fed an exclusive human milk diet, the low K1 content of human milk may predispose them to vitamin K deficiency. Human milk fortification with either bovine milk-derived fortifier or human milk-based fortifier (HMF) made from pooled donor milk is a widely used strategy to improve the micronutrient and growth status of preterm infants. However, the K1 content of HMF is markedly lower than that of bovine-based preparations. We present an unusual case of late-onset VKDB in an extremely preterm infant who received an exclusive human milk diet and HMF and quantify total K1 intake prior to the bleeding.

Gender gaps at the academies.

Historically, a large majority of newly elected members of the National Academy of Science (NAS) and the American Academy of Arts and Science (AAAS) were men. Within the past two decades, however, that situation has changed, and in the last 3 y, women made up about 40% of the new members in both academies. We build lists of active scholars from publications in the top journals in three fields-psychology, mathematics, and economics-and develop a series of models to compare changes in the probability of selection of women as members of the NAS and AAAS from the 1960s to today, controlling for publications and citations. In the early years of our sample, women were less likely to be selected as members than men with similar records. By the 1990s, the selection process at both academies was approximately gender neutral, conditional on publications and citations. In the past 20 y, however, a positive preference for female members has emerged and strengthened in all three fields. Currently, women are 3 to 15 times more likely to be selected as members of the AAAS and NAS than men with similar publication and citation records. The positive preference for women may be in part a reflection of concerns that women face higher barriers to publishing in top journals and may receive less credit for their work.

Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth.

BACKGROUND: There is near-global consensus that all newborns be given parenteral vitamin K1 (VK1 ) at birth as prophylaxis against VK deficiency bleeding (VKDB). Breastmilk has a low VK content and cases of late VKDB are reported in exclusively breastmilk-fed preterm infants despite VK prophylaxis at birth. OBJECTIVES: To assess the prevalence of functional VK insufficiency in preterm infants based on elevated under-γ-carboxylated (Glu) species of Gla proteins, factor II (PIVKA-II), and osteocalcin (GluOC), synthesized by liver and bone, respectively. PATIENTS/METHODS: Prospective, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after discharge at 2-3 months' corrected age. Outcome measures were serum VK1 , PIVKA-II, and %GluOC (GluOC as a percentage of the sum of GluOC plus GlaOC) compared between exclusively breastmilk-fed and formula/mixed-fed infants after discharge. RESULTS: After discharge, breastmilk-fed babies had significantly lower serum VK1 (0.15 vs. 1.81 µg/L), higher PIVKA-II (0.10 vs. 0.02 AU/ml) and higher %GluOC (63.6% vs. 8.1%) than those receiving a formula/mixed-feed diet. Pre-discharge (based on elevated PIVKA-II), only one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies. CONCLUSIONS: Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.

Characterization and traceability of two generations of standard reference material for the measurement of vitamin K1 (phylloquinone) at endogenous concentrations in human plasma and serum.

Vitamin K is an essential micronutrient required for blood coagulation, regulation of vascular calcification and bone mineralization. Plasma and serum measurements of vitamin K1 (phylloquinone, K1 ) made using high-performance liquid chromatography with fluorescence detection, or tandem mass spectrometry are used clinically and in population studies to assess vitamin K status. Standard reference materials provide a validation tool for laboratories, helping assure clinical diagnosis and the comparability of data from different populations. We manufactured two K1 standard reference materials, in 2009 (KEQAS SRM-001) and in 2019 (KEQAS SRM-002). The target concentrations of K1 were assigned to each SRM using the All Laboratory Trimmed Mean of results reported by selected laboratories enrolled in the Vitamin K External Quality Assurance Scheme (KEQAS). The assigned concentrations of K1 for KEQAS SRM-001 and SRM-002 were 0.25 and 0.36 µg/L respectively. In 2019 KEQAS SRM-001 was re-analysed simultaneously with KEQAS SRM-002 to provide traceability between the two standards, therefore aiding comparability of analysis performed using these materials. Both standards were stored as aliquots at -80°C in the dark; annual re-analysis of the materials indicated that K1 is stable for at least 12 years in these conditions.

Mortality among US veterans after emergency visits to Veterans Affairs and other hospitals: retrospective cohort study.

OBJECTIVE: To measure and compare mortality outcomes between dually eligible veterans transported by ambulance to a Veterans Affairs hospital and those transported to a non-Veterans Affairs hospital. DESIGN: Retrospective cohort study using data from medical charts and administrative files. SETTING: Emergency visits by ambulance to 140 Veteran Affairs and 2622 non-Veteran Affairs hospitals across 46 US states and the District of Columbia in 2001-18. PARTICIPANTS: National cohort of 583 248 veterans (aged ≥65 years) enrolled in both the Veterans Health Administration and Medicare programs, who resided within 20 miles of at least one Veterans Affairs hospital and at least one non-Veterans Affairs hospital, in areas where ambulances regularly transported patients to both types of hospitals. INTERVENTION: Emergency treatment at a Veterans Affairs hospital. MAIN OUTCOME MEASURE: Deaths in the 30 day period after the ambulance ride. Linear probability models of mortality were used, with adjustment for patients' demographic characteristics, residential zip codes, comorbid conditions, and other variables. RESULTS: Of 1 470 157 ambulance rides, 231 611 (15.8%) went to Veterans Affairs hospitals and 1 238 546 (84.2%) went to non-Veterans Affairs hospitals. The adjusted mortality rate at 30 days was 20.1% lower among patients taken to Veterans Affairs hospitals than among patients taken to non-Veterans Affairs hospitals (9.32 deaths per 100 patients (95% confidence interval 9.15 to 9.50) v 11.67 (11.58 to 11.76)). The mortality advantage associated with Veterans Affairs hospitals was particularly large for patients who were black (-25.8%), were Hispanic (-22.7%), and had received care at the same hospital in the previous year. CONCLUSIONS: These findings indicate that within a month of being treated with emergency care at Veterans Affairs hospitals, dually eligible veterans had substantially lower risk of death than those treated at non-Veterans Affairs hospitals. The nature of this mortality advantage warrants further investigation, as does its generalizability to other types of patients and care. Nonetheless, the finding is relevant to assessments of the merit of policies that encourage private healthcare alternatives for veterans.

Micronutrients in critically ill patients with severe acute kidney injury - a prospective study.

Malnutrition is common in patients with acute kidney injury (AKI) and the risk of mortality is high, especially if renal replacement therapy is needed. Between April 2013 through April 2014, we recruited critically ill adult patients (≥18 years) with severe AKI in two University hospitals in London, UK, and measured serial plasma concentrations of vitamin B1, B6, B12, C and D, folate, selenium, zinc, copper, iron, carnitine and 22 amino acids for six consecutive days. In patients receiving continuous renal replacement therapy (CRRT), the concentrations of the same nutrients in the effluent were also determined. CRRT patients (n = 31) had lower plasma concentrations of citrulline, glutamic acid and carnitine at 24 hrs after enrolment and significantly lower plasma glutamic acid concentrations (74.4 versus 98.2 µmol/L) at day 6 compared to non-CRRT patients (n = 24). All amino acids, trace elements, vitamin C and folate were detectable in effluent fluid. In >30% of CRRT and non-CRRT patients, the plasma nutrient concentrations of zinc, iron, selenium, vitamin D3, vitamin C, trytophan, taurine, histidine and hydroxyproline were below the reference range throughout the 6-day period. In conclusion, altered micronutrient status is common in patients with severe AKI regardless of treatment with CRRT.

The Role of Matrix Gla Protein (MGP) in Vascular Calcification.

Matrix Gla protein (MGP) is a vitamin K-dependent protein, which is synthesized in bone and many other mesenchymal cells, which is also highly expressed by vascular smooth muscle cells (VSMCs) and chondrocytes. Numerous studies have confirmed that MGP acts as a calcification-inhibitor although the mechanism of action is still not fully understood. The modulation of tissue calcification by MGP is potentially regulated in several ways including direct inhibition of calcium-phosphate precipitation, the formation of matrix vesicles (MVs), the formation of apoptotic bodies (ABs), and trans-differentiation of VSMCs. MGP occurs as four species, i.e. fully carboxylated (cMGP), under-carboxylated, i.e. poorly carboxylated (ucMGP), phosphorylated (pMGP), and non-phosphorylated (desphospho, dpMGP). ELISA methods are currently available that can detect the different species of MGP. The expression of the MGP gene can be regulated via various mechanisms that have the potential to become genomic biomarkers for the prediction of vascular calcification (VC) progression. VC is an established risk factor for cardiovascular disease and is particularly prevalent in those with chronic kidney disease (CKD). The specific action of MGP is not yet clearly understood but could be involved with the functional inhibition of BMP-2 and BMP-4, by blocking calcium crystal deposition and shielding the nidus from calcification.

Laboratory assessment of vitamin K status.

Vitamin K is required for the É£-carboxylation of specific glutamic acid residues within the Gla domain of the 17 vitamin K-dependent proteins (VKDPs). The timely detection and correction of vitamin K deficiency can protect against bleeding. Vitamin K also plays a role in bone metabolism and vascular calcification. Patients at increased risk of vitamin K deficiency include those with a restricted diet or malnutrition, lipid malabsorption, cancer, renal disease, neonates and the elderly. Coagulation assays such as the prothrombin time have been used erroneously as indicators of vitamin K status, lacking sufficient sensitivity and specificity for this application. The measurement of phylloquinone (K1) in serum is the most commonly used marker of vitamin K status and reflects abundance of the vitamin. Concentrations <0.15 µg/L are indicative of deficiency. Disadvantages of this approach include exclusion of the other vitamin K homologues and interference from recent dietary intake. The cellular utilisation of vitamin K is determined through measurement of the prevalence of undercarboxylated VKDPs. Most commonly, undercarboxylated prothrombin (Protein Induced by Vitamin K Absence/antagonism, PIVKA-II) is used (reference range 17.4-50.9 mAU/mL (Abbott Architect), providing a retrospective indicator of hepatic vitamin K status. Current clinical applications of PIVKA-II include supporting the diagnosis of vitamin K deficiency bleeding of the newborn, monitoring exposure to vitamin K antagonists, and when used in combination with α-fetoprotein, as a diagnostic marker of hepatocellular carcinoma. Using K1 and PIVKA-II in tandem is an approach that can be used successfully for many patient cohorts, providing insight into both abundance and utilisation of the vitamin.

Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate.

Cerebrospinal fluid (CSF) flows through the brain, transporting chemical signals and removing waste. CSF production in the brain is balanced by a constant outflow of CSF, the anatomical basis of which is poorly understood. Here, we characterized the anatomy and physiological function of the CSF outflow pathway along the olfactory sensory nerves through the cribriform plate, and into the nasal epithelia. Chemical ablation of olfactory sensory nerves greatly reduced outflow of CSF through the cribriform plate. The reduction in CSF outflow did not cause an increase in intracranial pressure (ICP), consistent with an alteration in the pattern of CSF drainage or production. Our results suggest that damage to olfactory sensory neurons (such as from air pollution) could contribute to altered CSF turnover and flow, providing a potential mechanism for neurological diseases.

The Effects of Parenteral K1 Administration in Pseudoxanthoma Elasticum Patients Versus Controls. A Pilot Study.

INTRODUCTION: Pseudoxanthoma elasticum (PXE) is a rare disease caused by mutations in the ABCC6 gene. Vitamin K1 is involved in the posttranslational carboxylation of some proteins related to inhibition of the calcification process. Our aim was to investigate, in patients affected by PXE, baseline levels of vitamin K1-dependent proteins and -metabolites and whether parenteral administration of phytomenadione was effective in modulating their levels. METHODS: We included eight PXE patients with typical clinical symptoms (skin, retina, and vascular calcification) and two ABCC6 causative mutations; 13 clinically unaffected first-degree patients' relatives (9 carrying one ABCC6 mutation and 4 non-carriers). We assessed urinary vitamin K1 metabolites and serum Glu- and Gla-OC, Gas6 and undercaboxylated prothrombin (PIVKA-II), at baseline and after 1 and 6 weeks after a single intramuscular injection of 10 mg vitamin K1. RESULTS: Comparison of PXE patients, heterozygous, and non-carriers revealed differences in baseline levels of serum MK-4 and of urinary vitamin K metabolites. The response to phytomenadione administration on vitamin K-dependent proteins was similar in all groups. CONCLUSION: The physiological axis between vitamin K1 and vitamin K-dependent proteins is preserved; however, differences in the concentration of vitamin K metabolites and of MK-4 suggest that vitamin K1 metabolism/catabolism could be altered in PXE patients.

Universal screening increases the representation of low-income and minority students in gifted education.

Low-income and minority students are substantially underrepresented in gifted education programs. The disparities persist despite efforts by many states and school districts to broaden participation through changes in their eligibility criteria. One explanation for the persistent gap is that standard processes for identifying gifted students, which are based largely on the referrals of parents and teachers, tend to miss qualified students from underrepresented groups. We study this hypothesis using the experiences of a large urban school district following the introduction of a universal screening program for second graders. Without any changes in the standards for gifted eligibility, the screening program led to large increases in the fractions of economically disadvantaged and minority students placed in gifted programs. Comparisons of the newly identified gifted students with those who would have been placed in the absence of screening show that Blacks and Hispanics, free/reduced price lunch participants, English language learners, and girls were all systematically "underreferred" in the traditional parent/teacher referral system. Our findings suggest that parents and teachers often fail to recognize the potential of poor and minority students and those with limited English proficiency.

Superwarfarin poisoning and its management.

Difenacoum is a long-acting superwarfarin-type anticoagulant that exerts its effect through inhibiting vitamin K 2,3-epoxide reductase. Inhibition of this enzyme leads to reduced bioavailability of the metabolically active form of vitamin K resulting in decreased production of vitamin K-dependent proteins including coagulation factors II, VII, IX and X. A 45-year-old woman with psychiatric illness presented with haematuria. Laboratory test results indicated she had been exposed to a vitamin K antagonist which was subsequently identified as difenacoum. She was initially treated with phytomenadione, red cell suspension and octaplex. She was discharged on 30 mg phytomenadione daily but monitoring of vitamin K markers indicated that compliance was poor, and 152 days post-admission she presented with haemoptysis. Difenacoum and other superwarfarin rodenticides are freely available for purchase by the public. Cases such as this continue to raise issues about their availability and regulation.

Vitamin K metabolism: current knowledge and future research.

Vitamin K is an essential fat-soluble micronutrient that is required for the post-translational γ-carboxylation of specific glutamic acid residues in hepatic and extra-hepatic proteins involved in blood coagulation and preventing cartilage and vasculature calcification. In humans, sources of vitamin K are derived from plants as phylloquinone and bacteria as the menaquinones. Menadione is a synthetic product used as a pharmaceutical but also represents an intermediate in the tissue-specific conversion of vitamin K to menaquinone-4, which preferentially resides in tissues such as brain. Research into vitamin K metabolism is essential for the understanding of vitamin K biology in health and disease. Progress in this area, driven by knowledge of vitamin K and the availability of markers of vitamin K status, has already proved beneficial in many areas of medicine and further opportunities present themselves. Areas of interest discussed in this review include prophylactic administration of vitamin K1 in term and preterm neonates, interactions between vitamins K and E, the industrial conversion of vitamin K to dihydro-vitamin K in foods, tissue-specific conversion of vitamin K to menaquinone-4, the biological activity of the five and seven carbon metabolites of vitamin K and circadian variations.

Vitamin E decreases extra-hepatic menaquinone-4 concentrations in rats fed menadione or phylloquinone.

SCOPE: The mechanism for increased bleeding and decreased vitamin K status accompanying vitamin E supplementation is unknown. We hypothesized that elevated hepatic α-tocopherol (α-T) concentrations may stimulate vitamin K metabolism and excretion. Furthermore, α-T may interfere with the side chain removal of phylloquinone (PK) to form menadione (MN) as an intermediate for synthesis of tissue-specific menaquinone-4 (MK-4). METHODS AND RESULTS: In order to investigate these hypotheses, rats were fed phylloquinone (PK) or menadione (MN) containing diets (2 µmol/kg) for 2.5 weeks. From day 10, rats were given daily subcutaneous injections of either α-T (100 mg/kg) or vehicle and were sacrificed 24 h after the seventh injection. Irrespective of diet, α-T injections decreased MK-4 concentrations in brain, lung, kidney, and heart; and PK in lung. These decreases were not accompanied by increased excretion of urinary 5C- or 7C-aglycone vitamin K metabolites, however, the urinary α-T metabolite (α-CEHC) increased ≥ 100-fold. Moreover, α-T increases were accompanied by downregulation of hepatic cytochrome P450 expression and modified expression of tissue ATP-binding cassette transporters. CONCLUSION: Thus, in rats, high tissue α-T depleted tissue MK-4 without significantly increasing urinary vitamin K metabolite excretion. Changes in tissue MK-4 and PK levels may be a result of altered regulation of transporters.

Family violence and football: the effect of unexpected emotional cues on violent behavior.

We study the link between family violence and the emotional cues associated with wins and losses by professional football teams. We hypothesize that the risk of violence is affected by the "gain-loss" utility of game outcomes around a rationally expected reference point. Our empirical analysis uses police reports of violent incidents on Sundays during the professional football season. Controlling for the pregame point spread and the size of the local viewing audience, we find that upset losses (defeats when the home team was predicted to win by four or more points) lead to a 10% increase in the rate of at-home violence by men against their wives and girlfriends. In contrast, losses when the game was expected to be close have small and insignificant effects. Upset wins (victories when the home team was predicted to lose) also have little impact on violence, consistent with asymmetry in the gain-loss utility function. The rise in violence after an upset loss is concentrated in a narrow time window near the end of the game and is larger for more important games. We find no evidence for reference point updating based on the halftime score.

Urinary excretion of vitamin K metabolites in term and preterm infants: relationship to vitamin K status and prophylaxis.

Little is known about the metabolic turnover and excretion of vitamin K in healthy newborn infants and the metabolic consequences of prophylactic regimens designed to protect against vitamin K deficiency bleeding (VKDB). We measured the excretion of two urinary metabolites (≤ 24 h) of vitamin K (5C- and 7C-aglycones) in term infants before (n = 11) and after (n = 5) a 1000 µg i.m. dose of vitamin K1 (K1) and in preterm infants after 200 µg i.m. (n = 4), 500 µg i.m. (n = 4), or 200 µg i.v. (n = 5). In preterm infants, we also measured serum K1, vitamin K1 2,3-epoxide, and PIVKA-II at 5 d postpartum. Before prophylaxis, the rate of 5C- and 7C-aglycone excretion was 25 times lower than adults, reflecting low vitamin K stores at birth. After prophylaxis, the excretion rate correlated to K1 dose (r = 0.6) but was two orders of magnitude lower than that in adults, probably reflecting the immaturity of neonatal catabolism. All term and 10 of 13 preterm infants mainly excreted 5C-aglycone. We present evidence that increased excretion of the 7C-aglycone was associated with metabolic overload because of the exposure to high-tissue K1 concentrations. Measurement of the 5C- and 7C-aglycones may facilitate longitudinal studies of vitamin K status in neonates and aid the development of improved prophylactic regimens.

DOES MEDICARE SAVE LIVES?

Health insurance characteristics shift at age 65 as most people become eligible for Medicare. We measure the impacts of these changes on patients who are admitted to hospitals through emergency departments for conditions with similar admission rates on weekdays and weekends. The age profiles of admissions and comorbidities for these patients are smooth at age 65, suggesting that the severity of illness is similar on either side of the Medicare threshold. In contrast, the number of procedures performed in hospitals and total list charges exhibit small but statistically significant discontinuities, implying that patients over 65 receive more services. We estimate a nearly 1-percentage-point drop in 7-day mortality for patients at age 65, equivalent to a 20% reduction in deaths for this severely ill patient group. The mortality gap persists for at least 9 months after admission.