An Inconspicuous Offender: Apixaban-Induced Anticoagulant-Related Nephropathy.

Direct oral anticoagulants (DOACs) have shifted the landscape of anticoagulation over the past decade, becoming a frequently used pharmaceutical agent. The increased use of DOACs for long-term anticoagulation has led to a rise in reported anticoagulant-related adverse reactions, such as anticoagulant-related nephropathy (ARN). The occurrence of ARN is well reported with warfarin; however, there are few cases of ARN reported with DOAC use. We report the case of an elderly man with coronary artery disease and hypertension who was initiated on apixaban for atrial fibrillation three years prior to presentation but developed rapid renal decline over the six months prior to presentation. The estimated glomerular filtration rate (eGFR) had decreased precipitously from 48 mL/min/1.73 m2 to 19 mL/min/1.73 m2 with a concurrent drop in hemoglobin in the setting of persistent microscopic hematuria. A renal biopsy showed red blood cell casts consistent with glomerular hematuria, despite no crescents or signs of other forms of glomerulonephritis. The patient's renal function ceased to deteriorate and had a 35% recovery (serum creatinine 2.6 mg/dL, eGFR 25 mL/min/1.73 m2) after the discontinuation of apixaban and conversion to rivaroxaban without the use of corticosteroids. The patient reported at follow-up that he discontinued rivaroxaban four days after initiation on his own accord due to extrarenal bleeding. Our case highlights the importance of prompt recognition and treatment of the underreported but potentially significant incidence of ARN with apixaban in a patient with an otherwise unexplained kidney injury.

Hans Frederick Bettinger (1897-1975) - "Father of Australian obstetrical and gynecological pathology" and victim of Nazism.

The German-Australian Hans Bettinger is regarded as one of the most important and influential pathologists of his time. Bettinger's research focused on gynecological pathology, with a particular interest in intersexuality, ovarian and cervical cancer. He received global recognition for his achievements: among others, he was a Honorary Fellow at the International Academy of Cytology, the Royal Australian College of Physicians, the Royal College of Pathologists of Australia, the Royal College of Obstetricians and Gynaecologists and a Fellow of the Royal College of Pathologists, London. Far less well-known is German-born Bettinger's role as a victim of Nazism. This significant yet hitherto "blind spot" in Bettinger's life is the focus of this paper. Previously undiscovered archival material from the German Federal Archives in Koblenz, supplemented by documents from the Public Record Office Victoria, Australia, and the University of Melbourne Archives, served as the central sources for this study. This paper reveals that Bettinger, as the husband of a Jewish woman in Nazi Germany, was disenfranchised, and subsequently forced to emigrate. After considerable efforts, he succeeded in building a new life in Australia, where he became the "father of obstetrical and gynecological pathology". In the 1950s Bettinger submitted an application for "reparations" to the Federal Republic of Germany. The legal claim was successful: From April 1951 onwards, Bettinger received a substantial pension and was thus officially recognized as a victim of Nazism. He was, however, never able to bring himself to return to Germany, and spent the rest of his life in Australia.

Review of Transthyretin Silencers, Stabilizers, and Fibril Removal Agents in the Treatment of Transthyretin Cardiac Amyloid.

PURPOSE OF REVIEW: To provide a functional review for practicing clinicians on the current and emerging treatment considerations for transthyretin (TTR) cardiac amyloidosis (ATTR-CA). RECENT FINDINGS: Current treatment considerations are characterized as those silencing TTR translation, stabilizing TTR tetramers, and disrupting amyloid fibril deposition. Historically considered a rare disease state, ATTR-CA is increasingly recognized as an important mediator of heart failure morbidity and mortality. The emergence of widely available therapies for ATTR-CA has developed hope for patients where little was previously present. Thus, it is important that all cardiology clinicians have a functional understanding of the disease state and treatment options. This review will discuss agents within each of the above classes with expanded discussion on tafamidis given its favorable efficacy, safety, and availability. ATTR-CA diagnostic considerations are reviewed with regard to the identification of potential tafamidis candidates, and practical economic considerations are also reviewed.

A Risk Assessment Tool for Predicting Fragility Fractures and Mortality in the Elderly.

Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged ≥60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7-15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with a T-score of -1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles. © 2020 American Society for Bone and Mineral Research.

Primary versus Tertiary Care Follow-Up of Low-Risk Differentiated Thyroid Cancer: Real-World Comparison of Outcomes and Costs for Patients and Health Care Systems.

BACKGROUND: An unprecedented rise in the prevalence of low-risk well-differentiated thyroid cancer (TC) has been reported in several countries, which is partly due to an increased utility of sensitive imaging techniques. The outcome of these cancers has generally remained excellent and the overall 5-year survival is almost 100%. However, the extended follow-up strategy for these patients remains unclear and while the initial management is done in specialist centres some experts opt to follow them on a long-term basis while others discharge them to primary care after the initial management. The effectiveness of one strategy versus the other has not been studied. METHODS: We conducted a real-world comparison to assess the outcome of low-risk TC (AJCC stage I) with undetectable thyroglobulin (TG) 2 years after radio-iodine (I-131) therapy. The outcome from Halifax (NS, Canada) and London (ON, Canada), where all TC patients are routinely followed by the tertiary care team, was compared with that from Edmonton (AB, Canada), where patients are routinely discharged to primary care. RESULTS: All patients were diagnosed between January 1, 2006, and December 31, 2011. The mean follow-up in primary care after discharge was 62.2 months and in tertiary care it was 64.6 months (p = 0.43). Rates of recurrence were similar in both groups, i.e., 1.1% in primary care and 1.3% in tertiary care (p = 0.69). Ultrasound surveillance was conducted in 56.5% of the patients in primary care and 52.6% of the tertiary care group (p = 0.26). The rate of annual unstimulated TG testing per patient was 0.58 (range 0-14) in primary care and 0.96 (range 0-6) in tertiary care (p = 0.06). More patients in primary care (86%) than in tertiary care (29.9%) consistently had thyroid-stimulating hormone levels within the target range (p < 0.001). The mean healthcare cost, based on a single follow-up visit with a blood test and ultrasound in the primary care group was CAD 118.01 and in the tertiary care group it was CAD 164.12. CONCLUSION: Our study shows that extended follow-up of low-risk TC patients is perfectly feasible in primary care and provides significant economic benefit for the healthcare system.

Placental-Specific Overexpression of sFlt-1 Alters Trophoblast Differentiation and Nutrient Transporter Expression in an IUGR Mouse Model.

Since it is known that placental overexpression of the human anti-angiogenic molecule sFlt-1, the main candidate in the progression of preeclampsia, lead to intrauterine growth restriction (IUGR) in mice by lentiviral transduction of mouse blastocysts, we hypothesize that sFlt-1 influence placental morphology and physiology resulting in fetal IUGR. We therefore examined the effect of sFlt-1 on placental morphology and physiology at embryonic day 18.5 with histologic and morphometric analyses, transcript analyses, immunoblotting, and methylation studies. Interestingly, placental overexpression of sFlt-1 leads to IUGR in the fetus and results in lower placental weights. Moreover, we observed altered trophoblast differentiation with reduced expression of IGF2, resulting in a smaller placenta, a smaller labyrinth, and the loss of glycogen cells in the junctional zone. Changes in IGF2 are accompanied by small changes in its DNA methylation, whereas overall DNA methylation is unaffected. In addition, the expression of placental nutrient transporters, such as the glucose diffusion channel Cx26, is decreased. In contrast, the expression of the fatty acid transporter CD36 and the cholesterol transporter ABCA1 is significantly increased. In conclusion, placental sFlt-1 overexpression resulted in a reduction in the differentiation of the spongiotrophoblast into glycogen cells. These findings of a reduced exchange area of the labyrinth and glycogen stores, as well as decreased expression of glucose transporter, could contribute to the intrauterine growth restriction phenotype. All of these factors change the intrauterine availability of nutrients. Thus, we speculate that the alterations triggered by increased anti-angiogenesis strongly affect fetal outcome and programming. J. Cell. Biochem. 118: 1316-1329, 2017. © 2016 Wiley Periodicals, Inc.

Tpbpa-Cre-mediated deletion of TFAP2C leads to deregulation of Cdkn1a, Akt1 and the ERK pathway, causing placental growth arrest.

Loss of TFAP2C in mouse leads to developmental defects in the extra-embryonic compartment with lethality at embryonic day (E)7.5. To investigate the requirement of TFAP2C in later placental development, deletion of TFAP2C was induced throughout extra-embryonic ectoderm at E6.5, leading to severe placental abnormalities caused by reduced trophoblast population and resulting in embryonic retardation by E8.5. Deletion of TFAP2C in TPBPA(+) progenitors at E8.5 results in growth arrest of the junctional zone. TFAP2C regulates its target genes Cdkn1a (previously p21) and Dusp6, which are involved in repression of MAPK signaling. Loss of TFAP2C reduces activation of ERK1/2 in the placenta. Downregulation of Akt1 and reduced activation of phosphorylated AKT in the mutant placenta are accompanied by impaired glycogen synthesis. Loss of TFAP2C led to upregulation of imprinted gene H19 and downregulation of Slc38a4 and Ascl2. The placental insufficiency post E16.5 causes fetal growth restriction, with 19% lighter mutant pups. Knockdown of TFAP2C in human trophoblast choriocarcinoma JAr cells inhibited MAPK and AKT signaling. Thus, we present a model where TFAP2C in trophoblasts controls proliferation by repressing Cdkn1a and activating the MAPK pathway, further supporting differentiation of glycogen cells by activating the AKT pathway.

Morphometric changes correlate with poor psychological outcomes in patients with acromegaly.

OBJECTIVE: Acromegaly is frequently associated with altered facial appearance at the time of diagnosis. Furthermore, acromegaly is also associated with adverse psychological outcomes. We conducted a single-centre, cross-sectional study comparing patients with growth hormone vs non-functioning pituitary adenomas (NFA) to assess the association between morphometric changes and psychological outcomes and illness perception of patients with acromegaly. METHODS: A seven-step scale was developed to grade morphometric changes based on facial photographs. In addition, all patients were asked to draw an image of their own body and an image of what they considered to be an average healthy body and complete seven psychological questionnaires. We recruited 55 consecutive patients in each of the two groups who had undergone surgery with or without radiation therapy (RT). RESULTS: Our data showed that the clinician-rated morphometric scale was highly reliable in assessing facial changes, with 93/99 (Intraclass correlation coefficient (ICC)=0.95 (0.93-0.97)) graded as similar by independent raters. The mean (s.d.) grading for Acro and NFA patients on the clinician-rated morphometric scale were 3.5 (1.3) and 0.41 (0.35) respectively (P<0.0001). A higher clinician-rated morphometric score was also predictive of a poorer score on the drawing test. CONCLUSIONS: Our study demonstrates a correlation between physical changes associated with acromegaly and poor psychological outcomes, whereas no such correlation existed with modes of therapy, disease control status, RT, malignancy, initial or recent GH/IGF1 or secondary hormonal deficiency. Our data support the utility of the morphometric scale as a clinical tool for grading facial changes.

Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays.

OBJECTIVE: To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate "drug holiday." QUALITY OF EVIDENCE: MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials). MAIN MESSAGE: The antifracture efficacy of approved first-line bisphosphonates has been proven in randomized controlled clinical trials. However, with more extensive and prolonged clinical use of bisphosphonates, associations have been reported between their administration and the occurrence of rare, but serious, adverse events. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femur fractures might be related to the use of bisphosphonates in osteoporosis, but they are exceedingly rare and they often occur with other comorbidities or concomitant medication use. Drug holidays should only be considered in low-risk patients and in select patients at moderate risk of fracture after 3 to 5 years of therapy. CONCLUSION: When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, reassess the need for ongoing therapy.

The role of morning basal serum cortisol in assessment of hypothalamic pituitary-adrenal axis.

PURPOSE: The use of morning basal serum cortisol levels as an alternative to dynamic testing for assessment of hypothalamic-pituitary-adrenal (HPA) axis has previously been reported. The purpose of this study was to determine the lower and upper cutoff values that would obviate subsequent HPA axis testing. METHODS: A single-centre, retrospective study from a tertiary care endocrinology clinic was conducted, analyzing data from 106 adult individuals referred for HPA axis testing who had undergone a 0800-0900 morning basal serum cortisol test followed by a standard dose (250 µg) adrenocorticotropin (ACTH) stimulation test. The ability of morning basal serum cortisol values to predict post-ACTH 30 or 60 minute peak cortisol value of >500 or >550 nmol/L was investigated. RESULTS: A morning basal cutoff of <128 nmol/L is sufficient for predicting a post-ACTH value<550 nmol/L, and morning basal cutoff levels of >243 nmol/L and >266 nmol/L predict peak post-ACTH values of >500 and >550 nmol/L respectively, obviating the need for dynamic testing. Regression analysis further demonstrated the log-linear relationship between morning basal and peak levels, while also finding a significant decrease in peak post-ACTH levels for patients diagnosed with secondary hypothyroidism (76 nmol/L lower, p=0.003) or secondary hypogonadism (61 nmol/L lower, p=0.02). These data suggest that the risk of cortisol deficiency is significantly higher in individuals with additional pituitary insufficiencies. The odds ratios for cortisol deficiency in patients with history of isolated secondary hypothyroidism was 3.41 (p=0.015), with isolated secondary hypogonadism was 4.77 (p=0.002) and with both was 7.45 (p=0.0002). CONCLUSION: Morning basal serum cortisol levels show promise as an effective screening test for HPA insufficiency for most patients. Clinicians should consider the high probability of HPA insufficiency in patients with one or more pituitary insufficiencies.

New pharmacologic methods to prevent venous thromboembolism in older adults: a meta-analysis.

OBJECTIVE: To conduct a meta-analysis of randomized controlled trials that used newly approved drugs to prevent venous thromboembolism (VTE) in older adults. DATA SOURCES: PubMed, EMBASE, and International Pharmaceutical Abstracts (through July 2012). STUDY SELECTION AND DATA EXTRACTION: Full-text clinical trial reports were included if they (1) had a randomized controlled design, (2) used a pharmacologic method approved or anticipated to be approved in the US, (3) enrolled at least 300 subjects, (4) enrolled subjects with a mean age of 65 years or older or performed a subgroup analysis in adults in that population, and (5) scored at least 7 of 8 on quality criteria for clinical trials. Twenty unique studies met the inclusion criteria. DATA SYNTHESIS: The most common indications for pharmacologic VTE prophylaxis in the identified studies were orthopedic procedures involving the lower extremities and general surgery. Only 2 studies enrolled acutely ill patients admitted to hospital medical services. Fondaparinux (5 studies) was more effective than enoxaparin in preventing VTE (OR 0.5, 95% CI 0.37-0.67; p < 0.00001) but had more bleeding (OR 1.48, 95% CI 1.05-2.08; p = 0.03). Dabigatran 150 mg once daily (3 studies) was less effective than enoxaparin in preventing VTE (OR 1.30, 95% CI 1.09-1.56; p = 0.004) with a similar bleeding risk (OR 0.74, 95% CI 0.46-1.22; p = 0.24). Dabigatran 220 mg once daily (4 studies) was as effective as enoxaparin in preventing VTE (OR 1.02, 95% CI 0.83-1.26; p = 0.84) and had similar bleeding (OR 1.08, 95% CI 0.66-1.76; p = 0.76). Rivaroxaban (4 studies) was more effective than enoxaparin in preventing VTE (OR 0.38, 95% CI 0.23-0.61; p < 0.0001) with a trend toward a higher rate of bleeding (OR 1.8, 95% CI 0.90-3.60; p = 0.09). Apixaban (5 studies) was more effective than enoxaparin in preventing VTE (OR 0.64, 95% CI 0.43-0.96; p = 0.0002) and had a similar rate of bleeding (OR 0.71, 95% CI 0.42-1.21; p = 0.21). CONCLUSIONS: When compared to enoxaparin, newer drugs exhibit slightly different safety and efficacy profiles when used for VTE prevention in older adults undergoing major orthopedic surgery. There are insufficient data for other indications. The benefits and risks of new pharmacologic methods of VTE prevention are unclear in the oldest old (age ≥ 85 years) and in those admitted to a hospital for an acute medical illness or to a skilled nursing facility.