Characterization of a chromatin-associated TCF7L1 complex in human embryonic stem cells.

Human embryonic stem cells (hESCs) resemble the pluripotent epiblast cells found in the early postimplantation human embryo and represent the "primed" state of pluripotency. One factor that helps primed pluripotent cells retain pluripotency and prepare genes for differentiation is the transcription factor TCF7L1, a member of a small family of proteins known as T cell factors/Lymphoid enhancer factors (TCF/LEF) that act as downstream components of the WNT signaling pathway. Transcriptional output of the WNT pathway is regulated, in part, by the activity of TCF/LEFs in conjunction with another component of the WNT pathway, ß-CATENIN. Because TCF7L1 plays an important role in regulating pluripotency, we began to characterize the protein complex associated with TCF7L1 when bound to chromatin in hESCs using rapid immunoprecipitation of endogenous proteins (RIME).  Data are available via ProteomeXchange with identifier PXD047582. These data identify known and new partners of TCF7L1 on chromatin and provide novel insights into how TCF7L1 and pluripotency itself might be regulated.

The impact of transition to a digital hospital on medication errors (TIME study).

Digital transformation in healthcare improves the safety of health systems. Within our health service, a new digital hospital has been established and two wards from a neighbouring paper-based hospital transitioned into the new digital hospital. This created an opportunity to evaluate the impact of complete digital transformation on medication safety. Here we discuss the impact of transition from a paper-based to digital hospital on voluntarily reported medication incidents and prescribing errors. This study utilises an interrupted time-series design and takes place across two wards as they transition from a paper to a digital hospital. Two data sources are used to assess impacts on medication incidents and prescribing errors: (1) voluntarily reported medication incidents and 2) a chart audit of medications prescribed on the study wards. The chart audit collects data on procedural, dosing and therapeutic prescribing errors. There are 588 errors extracted from incident reporting software during the study period. The average monthly number of errors reduces from 12.5 pre- to 7.5 post-transition (p < 0.001). In the chart audit, 5072 medication orders are reviewed pre-transition and 3699 reviewed post-transition. The rates of orders with one or more error reduces significantly after transition (52.8% pre- vs. 15.7% post-, p < 0.001). There are significant reductions in procedural (32.1% pre- vs. 1.3% post-, p < 0.001), and dosing errors (32.3% pre- vs. 14% post-, p < 0.001), but not therapeutic errors (0.6% pre- vs. 0.7% post-, p = 0.478). Transition to a digital hospital is associated with reductions in voluntarily reported medication incidents and prescribing errors.

Toilet Paper, Minced Meat and Diabetes Medicines: Australian Panic Buying Induced by COVID-19.

The COVID-19 pandemic has impacted the management of non-communicable diseases in health systems around the world. This study aimed to understand the impact of COVID-19 on diabetes medicines dispensed in Australia. Publicly available data from Australia's government subsidised medicines program (Pharmaceutical Benefits Scheme), detailing prescriptions by month dispensed to patients, drug item code and patient category, was obtained from January 2016 to November 2020. This study focused on medicines used in diabetes care (Anatomical Therapeutical Chemical code level 2 = A10). Number of prescriptions dispensed were plotted by month at a total level, by insulins and non-insulins, and by patient category (general, concessional). Total number of prescriptions dispensed between January and November of each year were compared. A peak in prescriptions dispensed in March 2020 was identified, an increase of 35% on March 2019, compared to average growth of 7.2% in previous years. Prescriptions dispensed subsequently fell in April and May 2020 to levels below the corresponding months in 2019. These trends were observed across insulins, non-insulins, general and concessional patient categories. The peak and subsequent dip in demand have resulted in a small unexpected overall increase for the period January to November 2020, compared to declining growth for the same months in prior years. The observed change in consumer behaviour prompted by COVID-19 and the resulting public health measures is important to understand in order to improve management of medicines supply during potential future waves of COVID-19 and other pandemics.

Monitoring for valproate and phenytoin toxicity in hypoalbuminaemia: A retrospective cohort study.

AIMS: Equations to calculate albumin-adjusted total concentrations have been validated to correlate with measured free concentrations for both phenytoin and valproate, but there is a lack of data to assess correlation with clinical outcomes. We aimed to assess the association of hypoalbuminaemia and albumin-adjusted total concentrations with concentration-dependent toxicity for phenytoin and valproate and review the impact on management decisions following concentration monitoring in hypoalbuminaemia. METHODS: Patients undergoing concentration monitoring for phenytoin or valproate between January and December 2018 were included. Patients were identified using a centralised laboratory database with data extracted from medical records. RESULTS: Total phenytoin concentrations were measured for 144 patients, with hypoalbuminaemia (≤30 g L-1 ) recorded in 59 (41%) patients. Albumin-adjusted phenytoin concentration >20 mg L-1 was associated with increased neurological adverse effects (77% vs. 43%, P < .001). On logistic regression, higher albumin-adjusted phenytoin concentration was an independent risk factor for neurotoxicity (OR 1.06, 95% CI 1.01-1.12, P = .011). Total valproate concentrations were measured for 383 patients, with hypoalbuminaemia (≤30 g L-1 ) noted in 53 (14%) patients. For the valproate cohort, hypoalbuminaemia (42% vs. 28%, P = .039) and albumin-adjusted valproate concentration >100 mg L-1 (49% vs. 23%, P < .001) were both associated with increased neurotoxicity. On multiple logistic-regression, valproate daily dose (aOR = 1.01, 95% CI 1.00-1.02, P = .006) and albumin-adjusted valproate concentration (aOR 1.01, 95% CI 1.00-1.02, P = .033) were independent risk factors for neurotoxicity after accounting for confounders. CONCLUSION: While measuring free drug concentrations in hypoalbuminaemia would be ideal, the adjustment equations can help identify vulnerable patients needing further assessment of potential concentration-dependent toxicity.

Multidisciplinary quality improvement programme for older patients admitted to a vascular surgery ward.

BACKGROUND: Older vascular surgical patients are at high risk of hospital-associated complications and prolonged stays. AIMS: To implement a multidisciplinary co-management model for older vascular patients and evaluate impact on length of stay (LOS), delirium incidence, functional decline, medical complications and discharge destination. METHODS: Prospective pre-post evaluation of a quality improvement intervention, enrolling pre-intervention (August 2012-January 2013) and post-intervention cohort (September 2013-March 2014). Participants were consenting patients aged 65 years and over admitted to the vascular surgical ward of a metropolitan teaching hospital for at least 3 days. Intervention was physician-led co-management plus a multidisciplinary improvement programme targeting delirium and functional decline. Primary outcomes were LOS, delirium and functional decline. Secondary outcomes were medical complications and discharge destination. Process measures included documented consultation patterns. Administrative data were also compared for all patients aged 65 and older for 12 months pre- and post-intervention. RESULTS: We enrolled 112 participants pre-intervention and 123 participants post-intervention. LOS was reduced post-intervention (geometric mean 7.6 days vs 9.3 days; ratio of geometric means 0.82 (95% confidence interval CI0.68-1.00), P = 0.04). There was a trend to less delirium (18 (14.6%) vs 24 (21.4%), P = 0.17) and functional decline (18 (14.6%) vs 27 (24.3%), P = 0.06), with greatest reductions in the urgently admitted subgroup. Administrative data showed reduced median LOS (5.2 days vs 6 days, P = 0.03) and greater discharge home (72% vs 50%, P < 0.01). CONCLUSIONS: Physician-led co-management plus a multidisciplinary improvement programme may reduce LOS and improve functional outcomes in older vascular surgical patients.

Trends in opioid prescribing in Australia: a systematic review.

Objective This review systematically identified studies that estimated the prevalence of prescription opioid use in Australia, assessed the prevalence estimates for bias and identified areas for future research. Methods Literature published after 2000 containing a potentially representative estimate of prescription opioid use in adults, in the community setting, in Australia was included in this review. Studies that solely assessed opioid replacement, illicit opioid usage or acute hospital in-patient use were excluded. Databases searched included PubMed, EMBASE, Web of Science and the grey literature. Results The search identified 2253 peer-reviewed publications, with 34 requiring full-text review. Of these, 20 were included in the final qualitative analysis, in addition to four publications from the grey literature. Most studies included analysed prescription claims data for medicines dispensed via Australia's national medicines subsidy scheme (the Pharmaceutical Benefits Scheme). Although data sources were good quality, all prevalence estimates were at least at moderate risk of bias, predominantly due to incompleteness of data or potential confounding. Included publications demonstrated a significant rise in opioid use up to 2017 (including a 15-fold increase in prescriptions dispensed over the 20 years to 2015), predominantly driven by a sharp rise in oxycodone use. Although opioid prescription numbers continue to escalate, usage, as measured by oral morphine equivalent per capita, may have plateaued since 2014. Codeine remains the most prevalently obtained opioid, followed by oxycodone and tramadol. There was a substantial delay (median 30 months; interquartile range 20-37 months) to publication of opioid usage data from time of availability. Conclusions Australia has experienced a marked increase in opioid prescribing since the 1990s. Current published literature is restricted to incomplete, delayed and historical data, limiting the ability of clinicians and policy makers to intervene appropriately. What is known about the topic? Opioid prescriptions in Australia have continued to increase since the 1990s and may be mirroring the epidemic being seen in the US. What does this paper add? This paper systematically identifies all publications that have examined the prevalence of prescription opioid use in Australia since 2000, and only identified prevalence estimates that were at moderate or high risk of bias, and found significant delays to publication of these estimates. What are the implications for practitioners? Because published literature on the prevalence of prescription opioid consumption is restricted to incomplete, delayed and historical data, the ability of clinicians and policy makers to appropriately intervene to curb prescription opioid use is limited. A national policy of real-time monitoring and reporting of opioid prescribing may support improvements in practice.

Distribution and Function of Prostaglandin E2 Receptors in Mouse Uterus: Translational Value for Human Reproduction.

Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE2 analogs were used to investigate the functional E-type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus (n = 12), term gestation (n = 14), and labor (n = 12) and from the lower uterus of women undergoing hysterectomy (n = 12) or Caesarean section (n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both nonpregnant species, while the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP3 receptors have clear translational value.

The impact of a Post-Take Ward Round Pharmacist on the Risk Score and Enactment of Medication-Related Recommendations.

There is a scarcity of published research describing the impact of a pharmacist on the post-take ward round (PTWR) in addition to ward-based pharmacy services. The aim of this paper was to evaluate the impact of clinical pharmacists' participation on the PTWR on the risk assessment scores of medication-related recommendations with and without a pharmacist. This includes medication-related recommendations occurring on the PTWR and those recommendations made by the ward-based pharmacist on the inpatient ward. A pre-post intervention study was undertaken that compared the impact of adding a pharmacist to the PTWR compared with ward-based pharmacist services alone. A panel reviewed the risk of not acting on medication recommendations that was made on the PTWR and those recorded by the ward-based pharmacist. The relationship between the risk scores and the number and proportion of recommendations that led to action were compared between study groups. There were more medication-related recommendations on the PTWR in the intervention group when a pharmacist was present. Proportionately fewer were in the 'very high and extreme' risk category. Although there was no difference in the number of ward pharmacist recommendations between groups, there was a significantly higher proportion of ward pharmacist recommendations in the "very high and extreme" category in those patients who had been seen on a PTWR attended by a pharmacist than when a pharmacist was not present. There were a greater proportion of "low and medium" risk actionable medication recommendations actioned on the PTWR in the intervention group; and no difference in the risk scores in ward pharmacist recommendations actioned between groups. Overall, the proportion of recommendations that were actioned was higher for those made on the PTWR compared with the ward. The addition of a pharmacist to the PTWR resulted in an increase in low, medium, and high risk recommendations on the PTWR, more very high and extreme risk recommendations made by the ward-based pharmacist, plus an increased number of recommendations being actioned during the patients' admission.

Mitochondrial Akt Signaling Modulated Reprogramming of Somatic Cells.

The signaling mechanisms controlling somatic cell reprogramming are not fully understood. In this study, we report a novel role for mitochondrial Akt1 signaling that enhanced somatic cell reprogramming efficiency. The role of mitochondrial Akt1 in somatic cell reprogramming was investigated by transducing fibroblasts with the four reprogramming factors (Oct4, Sox2, Klf4, c-Myc) in conjunction with Mito-Akt1, Mito-dnAkt1, or control virus. Mito-Akt1 enhanced reprogramming efficiency whereas Mito-dnAkt1 inhibited reprogramming. The resulting iPSCs formed embryoid bodies in vitro and teratomas in vivo. Moreover, Oct4 and Nanog promoter methylation was reduced in the iPSCs generated in the presence of Mito-Akt1. Akt1 was activated and translocated into mitochondria after growth factor stimulation in embryonic stem cells (ESCs). To study the effect of mitochondrial Akt in ESCs, a mitochondria-targeting constitutively active Akt1 (Mito-Akt1) was expressed in ESCs. Gene expression profiling showed upregulation of genes that promote stem cell proliferation and survival and down-regulation of genes that promote differentiation. Analysis of cellular respiration indicated similar metabolic profile in the resulting iPSCs and ESCs, suggesting comparable bioenergetics. These findings showed that activation of mitochondrial Akt1 signaling was required during somatic cell reprogramming.

Proteome Profile of Endogenous Retrotransposon-Associated Complexes in Human Embryonic Stem Cells.

Long Interspersed Element-1 (LINE-1 or L1) are transposable elements similar to retroviruses that have existed in the genome of primates for millions of years. They encode two Open Reading Frame (ORF) proteins (ORF1p and ORF2p) that bind L1 RNA to form a ribonucleoprotein (RNP) complex and are required for L1 integration into the host genome. Humans have evolved with L1 and found ways to limit L1 activity. To identify partners of the L1 RNP, previous studies used ectopic expression of L1 ORF1/2p or RNA in various cancer cells, which express low levels of the ORF proteins. Whether naturally occurring L1 RNP interacts with the same proteins in non-cancer cells is unknown. Here, the aim is to examine the natural assembly of endogenous L1 RNPs in normal human cells. L1 elements are expressed in human embryonic stem cells (hESCs), derived from pre-implantation embryos. Therefore, these cells are used to immunoprecipitate ORF1p followed by MS to identify proteins that associate with the naturally-occurring L1 ORF1p. Some of the same proteins as well as unique proteins are found interacting with the endogenous L1 ORF1p complexes. The analysis of ORF1p-associated proteins in hESCs can help address important questions in both retrotransposon biology and the biology of hESCs.

TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency.

Human embryonic stem cells (hESCs) are exquisitely sensitive to WNT ligands, which rapidly cause differentiation. Therefore, hESC self-renewal requires robust mechanisms to keep the cells in a WNT inactive but responsive state. How they achieve this is largely unknown. We explored the role of transcriptional regulators of WNT signaling, the TCF/LEFs. As in mouse ESCs, TCF7L1 is the predominant family member expressed in hESCs. Genome-wide, it binds a gene cohort involved in primitive streak formation at gastrulation, including NODAL, BMP4 and WNT3 Comparing TCF7L1-bound sites with those bound by the WNT signaling effector ß-catenin indicates that TCF7L1 acts largely on the WNT signaling pathway. TCF7L1 overlaps less with the pluripotency regulators OCT4 and NANOG than in mouse ESCs. Gain- and loss-of-function studies indicate that TCF7L1 suppresses gene cohorts expressed in the primitive streak. Interestingly, we find that BMP4, another driver of hESC differentiation, downregulates TCF7L1, providing a mechanism of BMP and WNT pathway intersection. Together, our studies indicate that TCF7L1 plays a major role in maintaining hESC pluripotency, which has implications for human development during gastrulation.

Cost-utility analysis comparing radioactive iodine, anti-thyroid drugs and total thyroidectomy for primary treatment of Graves' disease.

OBJECTIVE: Little data is in existence about the most cost-effective primary treatment for Graves' disease. We performed a cost-utility analysis comparing radioactive iodine (RAI), anti-thyroid drugs (ATD) and total thyroidectomy (TT) as first-line therapy for Graves' disease in England and Australia. METHODS: We used a Markov model to compare lifetime costs and benefits (quality-adjusted life-years (QALYs)). The model included efficacy, rates of relapse and major complications associated with each treatment, and alternative second-line therapies. Model parameters were obtained from published literature. One-way sensitivity analyses were conducted. Costs were presented in 2015£ or Australian Dollars (AUD). RESULTS: RAI was the least expensive therapy in both England (£5425; QALYs 34.73) and Australia (AUD5601; 30.97 QALYs). In base case results, in both countries, ATD was a cost-effective alternative to RAI (£16 866; 35.17 QALYs; incremental cost-effectiveness ratio (ICER) £26 279 per QALY gained England; AUD8924; 31.37 QALYs; ICER AUD9687 per QALY gained Australia), while RAI dominated TT (£7115; QALYs 33.93 England; AUD15 668; 30.25 QALYs Australia). In sensitivity analysis, base case results were stable to changes in most cost, transition probabilities and health-relative quality-of-life (HRQoL) weights; however, in England, the results were sensitive to changes in the HRQoL weights of hypothyroidism and euthyroidism on ATD. CONCLUSIONS: In this analysis, RAI is the least expensive choice for first-line treatment strategy for Graves' disease. In England and Australia, ATD is likely to be a cost-effective alternative, while TT is unlikely to be cost-effective. Further research into HRQoL in Graves' disease could improve the quality of future studies.

Variations in adjuvant chemotherapy and survival in women with epithelial ovarian cancer - a population-based study.

BACKGROUND: To investigate whether variations in primary chemotherapy were associated with survival in a nationally complete cohort of Australian women with epithelial ovarian cancer (EOC). MATERIAL AND METHODS: All 1192 women diagnosed with invasive EOC in Australia in 2005 were identified through state-based cancer registries. Medical record information including details of primary chemotherapy treatment was obtained and survival data updated in 2012. Those started on standard chemotherapy (carboplatin and paclitaxel given at three-weekly intervals) after primary cytoreductive surgery were included (n = 351) and the relative dose intensity (RDI) was calculated. Time interval between surgery and start of chemotherapy was analysed in weeks. Hazard ratios [HR, 95% confidence interval (CI)] were calculated using multivariable Cox proportional hazards models. RESULTS: Compared to women with RDI of 91-100%, those with RDI of ≤ 70% had significantly poor survival (HRadj = 1.62, 95% CI 1.05-2.49). This association was stronger among women with advanced (FIGO stage III/IV) disease at diagnosis (HRadj = 1.90, 95% CI 1.22-2.96). The interval between primary surgery and chemotherapy was not related to survival (HRadj = 0.98, 95% CI 0.93-1.03 for every week of delay), at least up to a period of five weeks. CONCLUSION: Our results suggest that RDI of 70% or less was associated with poorer survival, particularly in women with advanced stage EOC. In contrast, the interval duration between primary surgery and chemotherapy was not related to survival, irrespective of disease stage or residual disease. These results provide some reassurance that, at least up until five weeks post-surgery, timing of chemotherapy commencement has a negligible effect on survival.

PTHrP-mediated hypercalcemia: causes and survival in 138 patients.

CONTEXT: Hypercalcemia is a common complication of cancer with PTHrP an important mediator. Literature on the underlying causes of PTHrP-mediated hypercalcemia, in both malignant and benign conditions, is limited to small case series and case reports. OBJECTIVE: The purpose of this study was to systematically identify a large series of cases of PTHrP-mediated hypercalcemia and to document differences in demographics and the clinical course between malignant and benign etiologies. DESIGN, SETTING, AND PATIENTS: This was a hospital-based, retrospective case series that identified subjects from 1999 to 2010 from the public hospital system in Queensland, Australia. Included subjects were 18 years and older and had persistent hypercalcemia with simultaneously elevated PTHrP. RESULTS: A total of 138 cases were identified. Solid organ malignancies made up 82.6% (n = 114) of cases, with squamous cell carcinoma (28.2% of total) and adenocarcinomas (27.5%) almost equally as common. Hematological malignancy and benign conditions made up 8.7% (n = 12) each. Squamous cell carcinoma of the lung was the single most commonly identified etiology (10.9%). Causes not previously identified included myxoid sarcoma, plasma cell leukemia, duodenal adenocarcinoma, metastatic Merkel cell carcinoma, and epithelioid hemangioendothelioma. Median survival was different among the groups (52 days [interquartile range, 21-132 days] for solid organ malignancy, 362 days [18-652 days] for hematological malignancy, and 906 days [16 days to undefined] for the apparently benign group; P < .0001). There were no differences in PTHrP among the groups. Although the mean corrected calcium level was lower in the benign group (3.03 mmol/L [2.80-3.29 mmol/L]) compared with that in the solid organ (3.11 mmol/L [2.89-3.46 mmol/L]) and hematological malignancy groups (3.60 mmol/L [3.01-3.79 mmol/L]) groups (P = .046), it was not a useful discriminator of etiology. CONCLUSION: PTHrP-mediated hypercalcemia is most frequently caused by solid organ malignancy, and it portends a poor prognosis. Although the solid organ malignancy group had the shortest survival, the hematological malignancy and apparently benign causes groups still had relatively short overall survival.

Hypoxia induces pluripotency in primordial germ cells by HIF1α stabilization and Oct4 deregulation.

AIMS: To study the mechanisms of pluripotency induction, we compared gene expression in pluripotent embryonic germ cells (EGCs) and unipotent primordial germ cells (PGCs). RESULTS: We found 11 genes ≥1.5-fold overexpressed in EGCs. None of the genes identified was the Yamanaka genes but instead related to glycolytic metabolism. The prospect of pluripotency induction by cell metabolism manipulation was investigated by hypoxic culturing. Hypoxia induced a glycolytic program in PGCs in detriment of mitochondrial oxidative phosphorylation. We demonstrate that hypoxia alone induces reprogramming in PGCs, giving rise to hypoxia-induced EGC-like cells (hiEGLs), which differentiate into cells of the three germ layers in vitro and contribute to the internal cell mass of the blastocyst in vivo, demonstrating pluripotency. The mechanism of hypoxia induction involves HIF1α stabilization and Oct4 deregulation. However, hiEGL cannot be passaged long term. Self-renewal capacity is not achieved by hypoxia likely due to the lack of upregulation of c-Myc and Klf4. Gene expression analysis of hypoxia signaling suggests that hiEGLs have not reached the stabilization phase of cell reprogramming. INNOVATION AND CONCLUSION: Our data suggest that the two main properties of stemness, pluripotency and self-renewal, are differentially regulated in PGC reprogramming induced by hypoxia.

Growth and proliferation of human embryonic stem cells on fully synthetic scaffolds based on carbon nanotubes.

Here we show an industrially scalable and inexpensive method of fabricating entirely synthetic, non-xenogeneic carbon nanotube-based scaffolds by vacuum filtration for the culture of human embryonic stem cells. We show that controlled exposure of carbon nanotubes to sonication and the amount of energy delivered to the dispersion directly impacts the surface properties, allowing for control over the nanotopography of the resulting carbon nanotube films, which in turn has demonstrable effects upon in vitro human embryonic stem cells cultures. By altering the nanotube processing conditions before film fabrication, it is possible to influence cell adherence, proliferation and colony morphology. Such a tunable surface with capabilities of influencing stem cell behaviors, combined with the ability to slow or speed population doubling times, will provide crucial solutions for achieving applications envisioned by stem cell biologists to assist future industrial and clinical implementation of human embryonic stem cells.

Calcitriol-mediated hypercalcemia: causes and course in 101 patients.

CONTEXT: Hypercalcemia mediated by 1,25-dihydroxy vitamin D (calcitriol) is uncommon, with evidence on etiology limited to small case series or case reports. OBJECTIVE: The objective of the study was to systematically identify a large series of cases of calcitriol-mediated hypercalcemia and document the presentation, demographics, and clinical course across etiologies. DESIGN, SETTING, AND PATIENTS: The study was a hospital-based, retrospective case series, identifying subjects from 1999 through 2009 across the public hospital system in Queensland, Australia. All patients aged over 18 years were identified that had persistent hypercalcemia associated with elevated or inappropriately normal calcitriol concentration or elevated serum angiotensin-converting enzyme. RESULTS: A total of 101 cases were identified. Sarcoidosis was the most common etiology (49%), followed by hematological malignancy (17%) and infections (8%). Etiologies not previously described include squamous cell carcinoma of the tongue, ovarian cystadenocarcinoma, and chronic lymphocytic leukemia. Median serum angiotensin-converting enzyme was higher in sarcoid patients compared with all other causes [218 U/L (176-277) vs 155 U/L (110-208), P < .001], but a level above the normal range did not discriminate well between cases of sarcoidosis and other causes (specificity at cutoff of 130 U/L was only 31%). However, a value greater than 250 U/L was highly specific (89%) for sarcoidosis but lacked sensitivity (31%). A calcitriol level greater than 300 pmol/L was not seen in sarcoidosis but was seen with other etiologies. Cases with neoplastic etiologies were older (61.4 ± 11.4 y) than all other subjects (51.7 ± 15.0 y, P = .006). CONCLUSIONS: Hypercalcemia mediated by calcitriol remains a rare presentation. In almost half the cases, sarcoidosis was the underlying cause, whereas a third of patients had cancer or systemic infections.