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.

Association between unstable diabetes mellitus and risk of pancreatic cancer.

BACKGROUND: Deterioration of glycaemic control in people with long-standing diabetes mellitus (diabetes) may be a possible indicator of pancreatic cancer. However, the magnitude of the association between diabetes deterioration and pancreatic cancer has received little attention. METHODS: We conducted a matched cohort study, nested within a population-based cohort of Australian women with diabetes. Women with unstable diabetes, defined as a change in medication after a 2-year period of stable medication use, were matched by birth year to those with stable diabetes, in a 1:4 ratio. We used flexible parametric survival models to estimate hazard ratios (HRs) and 95% confidence intervals (CI). RESULTS: We included 134,954 and 539,789 women in the unstable and stable diabetes cohorts, respectively (mean age 68 years). In total, 1,315 pancreatic cancers were diagnosed. Deterioration of stable diabetes was associated with a 2.5-fold increased risk of pancreatic cancer (HR 2.55; 95% CI 2.29-2.85). The risk was particularly high within the first year after diabetes deteriorated. HRs at 3 months, 6 months and 1 year were: 5.76 (95% CI 4.72-7.04); 4.56 (95% CI 3.81-5.46); and 3.33 (95% CI 2.86-3.89), respectively. The risk was no longer significantly different after 7 years. CONCLUSIONS: Deterioration in glycaemic control in people with previously stable diabetes may be an indicator of pancreatic cancer, suggesting investigations of the pancreas may be appropriate. The weaker longer-term (3-7 years) association between diabetes deterioration and pancreatic cancer may indicate that poor glycaemic control can be a risk factor for pancreatic cancer.

Predicting the risk of pancreatic cancer in women with new-onset diabetes mellitus.

BACKGROUND AND AIM: People with new-onset diabetes mellitus (diabetes) could be a possible target population for pancreatic cancer surveillance. However, distinguishing diabetes caused by pancreatic cancer from type 2 diabetes remains challenging. We aimed to develop and validate a model to predict pancreatic cancer among women with new-onset diabetes. METHODS: We conducted a retrospective cohort study among Australian women newly diagnosed with diabetes, using first prescription of anti-diabetic medications, sourced from administrative data, as a surrogate for the diagnosis of diabetes. The outcome was a diagnosis of pancreatic cancer within 3 years of diabetes diagnosis. We used prescription medications, severity of diabetes (i.e., change/addition of medication within 2 months after first medication), and age at diabetes diagnosis as potential predictors of pancreatic cancer. RESULTS: Among 99 687 women aged ≥ 50 years with new-onset diabetes, 602 (0.6%) were diagnosed with pancreatic cancer within 3 years. The area under the receiver operating curve for the risk prediction model was 0.73. Age and diabetes severity were the two most influential predictors followed by beta-blockers, acid disorder drugs, and lipid-modifying agents. Using a risk threshold of 50%, sensitivity and specificity were 69% and the positive predictive value (PPV) was 1.3%. CONCLUSIONS: Our model doubled the PPV of pancreatic cancer in women with new-onset diabetes from 0.6% to 1.3%. Age and rapid progression of diabetes were important risk factors, and pancreatic cancer occurred more commonly in women without typical risk factors for type 2 diabetes. This model could prove valuable as an initial screening tool, especially as new biomarkers emerge.

Clinical efficacy and safety of treatments for exocrine pancreatic insufficiency: A systematic literature review.

INTRODUCTION: Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis (CF) and chronic pancreatitis (CP). Standard management of EPI includes Pancreatic Enzyme Replacement Therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI. METHODS: A systematic literature review was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010-2022; conference proceedings from 2020-2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against pre-defined eligibility criteria. RESULTS: We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n=12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE 1.2] versus Zenpep® 80.9% [SE 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated. CONCLUSIONS: This systematic literature review confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes.

Queensland Inpatient Diabetes Survey (QuIDS): patient experience survey evaluation.

BACKGROUND: Measurement of inpatient experience can allow for treatment tailored to patient preferences and needs. The patient experience of diabetes care has not been explored in Queensland hospitals. AIMS: To investigate the experiences of patients with diabetes when hospitalised using the Queensland Inpatient Diabetes Survey (QuIDS). METHODS: In 2019 and 2021, patient experience surveys were collected as part of the statewide QuIDS, a cross-sectional study assessing the quality of inpatient care received by people with diabetes in Queensland, Australia. Patient responses were categorised and frequencies reported as percentages. Free text comments were analysed using thematic analysis methods. Pooled descriptive data were presented. RESULTS: Responses were collected from 27 hospitals in 2019 (n = 526, 52.4% of all patients with diabetes) and 35 hospitals in 2021 (n = 709, 55.5%). Overall, patients were satisfied with their inpatient diabetes care. Areas for improvement identified by surveyed patients include the choice and timing of meals, staff knowledge about diabetes and increased diabetes self-management. Access to a specialist diabetes team was also identified as being potentially underutilised. Patient comments fell into four major themes: communication, food choices, patient autonomy and education. CONCLUSION: Many patients reported positive inpatient experiences; however, patients also expressed dissatisfaction with their inpatient diabetes care. Our data provide unique insight and an opportunity to improve standards of care and service provision for inpatients with diabetes.

Can a novel constructivist theory-informed feedback intervention reduce prescribing errors ? A pre-post study.

CONTEXT: Medical interns (interns) find prescribing challenging and many report lacking readiness when commencing work. Errors in prescribing puts patients' safety at risk. Yet error rates remain high, despite education, supervision and pharmacists' contributions. Feedback on prescribing may improve performance. Yet, work-based prescribing feedback practices focus on rectifying errors. We aimed to explore if prescribing can be improved using a theory-informed feedback intervention. METHODS: In this pre-post study, we designed and implemented a constructivist-theory informed prescribing feedback intervention, informed by Feedback-Mark 2 Theory. Interns commencing internal medicine terms in two Australian teaching hospitals were invited to engage in the feedback intervention. Their prescribing was evaluated by comparing errors per medication order of at least 30 orders per intern. Pre/baseline (weeks 1-3) were compared with post intervention (weeks 8-9). Interns' baseline prescribing audit findings were analysed and discussed at individualised feedback sessions. These sessions were with a clinical pharmacologist (Site 1) and a pharmacist educator (Site 2). RESULTS: Eighty eight intern's prescribing over five 10-week terms was analysed from two hospitals. The frequency of prescribing errors significantly reduced at both sites after the intervention, across all five terms (p < 0.001).There were initially 1598 errors in 2750 orders (median [IQR] 0.48 [0.35-0.67] errors per order) and after the intervention 1113 errors in 2694 orders (median [IQR] 0.30 [0.17-0.50] errors per order). CONCLUSION: Our findings suggest interns' prescribing practices may improve as a result of constructivist -theory learner centred, informed feedback with an agreed plan. This novel intervention, contributed, to a reduction in interns' prescribing errors. This study suggests new strategies for improving prescribing safety should include the design and implementation of theory-informed feedback interventions.

Developing a framework for implementing opioid stewardship programmes in Australian hospital settings.

There is growing interest in strategies to improve patient safety with prescription opioids, collectively known as opioid stewardship (OS). This study aimed to develop a framework to facilitate the implementation of OS in the Australian acute hospital setting. Using a Modified Delphi Technique, a diverse stakeholder panel (including patient representatives and multidisciplinary healthcare professionals) was selected. A survey based on the results of a literature review was sent to the panel for appraisal. In line with standard Delphi methodology, the primary outcome for each element was reaching consensus of at least 70% of the participants on the importance of its inclusion in the framework. The survey allowed the participants to suggest new items for inclusion in subsequent rounds or rephrase existing items. Of the 29 participants who completed the survey, the majority (23/29) were regularly involved in providing direct patient care. Twenty-six of 27 items reached the 70% threshold for agreement for importance after the first round. The remaining item not agreed on in the initial round was modified based on comments received and reached 100% agreement on importance at the second round. There was greater than 85% agreement on importance of 24 of 27 items for inclusion in a framework with 8 of 27 reaching a 100% level of agreement. We have developed a framework for OS in the Australian acute hospital settings that may be used to guide health services to prioritise and plan strategies to improve opioid use.

Access to inpatient diabetes resources: hospital characteristics from the inaugural Queensland Inpatient Diabetes Survey.

BACKGROUND: Diabetes is common in hospitalised patients and despite this inpatient diabetes care in Queensland has not had large scale benchmarking or audit. AIMS: To establish the prevalence of diabetes in Queensland hospitals and assess the availability of specialised diabetes staff, educational resources and policies for inpatient diabetes management, including assessing equity of access to these resources. METHODS: The hospital capacity, prevalence of diabetes, diabetes-related resources and the availability of diabetes-related guidelines were assessed in 25 hospitals medical, surgical, mental health, high-dependency and intensive care wards across Queensland. Dedicated diabetes staffing measured in full-time equivalents (FTE), care delivery resources, access to educational resources, standard policies and procedures for care were assessed. RESULTS: Twenty-five hospitals included 4265 occupied beds. The median prevalence of diabetes was 22.9% (interquartile range (IQR) 17.3-28.5%) with an average 2.9 FTE per 100 patients with diabetes (IQR 0-6.3). There was difficulty in accessing a diabetes educator in 48% (n = 12), diabetes specialist in 44% (n = 11), orthopaedic surgeon in 48% (n = 12), podiatrist in 58% (n = 14) and vascular surgeon in 64% (n = 16) of hospitals. Small hospitals had more difficulty accessing all members of the diabetes team compared with large hospitals including credentialled diabetes educators 33% (n = 4) versus 62% (n = 8) (P < 0.01), diabetes specialists 17% (n = 2) versus 69% (n = 9) (P < 0.01) and vascular surgeons 33% (n = 4) versus 92% (n = 12) (P < 0.01). Diabetes-related staff education and regular nurse training was available in 40% (n = 10) of hospitals. A multi-disciplinary foot care team was available in 28% (n = 7) of hospitals. CONCLUSIONS: Queensland has a high prevalence of diabetes in hospitalised patients and they have limited and inequitable access to inpatient diabetes-related care.

Cost and Capability Compromises in STEM Instrumentation for Low-Voltage Imaging.

Low-voltage transmission electron microscopy (≤80 kV) has many applications in imaging beam-sensitive samples, such as metallic nanoparticles, which may become damaged at higher voltages. To improve resolution, spherical aberration can be corrected for in a scanning transmission electron microscope (STEM); however, chromatic aberration may then dominate, limiting the ultimate resolution of the microscope. Using image simulations, we examine how a chromatic aberration corrector, different objective lenses, and different beam energy spreads each affect the image quality of a gold nanoparticle imaged at low voltages in a spherical aberration-corrected STEM. A quantitative analysis of the simulated examples can inform the choice of instrumentation for low-voltage imaging. We here demonstrate a methodology whereby the optimum energy spread to operate a specific STEM can be deduced. This methodology can then be adapted to the specific sample and instrument of the reader, enabling them to make an informed economical choice as to what would be most beneficial for their STEM in the cost-conscious landscape of scientific infrastructure.

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.

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.

The Queensland Inpatient Diabetes Survey (QuIDS) 2019: the bedside audit of practice.

OBJECTIVES: To assess the quality of care for patients with diabetes in Queensland hospitals, including blood glucose control, rates of hospital-acquired harm, the incidence of insulin prescription and management errors, and appropriate foot and peri-operative care. DESIGN, SETTING: Cross-sectional audit of 27 public hospitals in Queensland: four of five tertiary/quaternary referral centres, four of seven large regional or outer metropolitan hospitals, seven of 13 smaller outer metropolitan or small regional hospitals, and 12 of 88 hospitals in rural or remote locations. PARTICIPANTS: 850 adult inpatients with diabetes mellitus in medical, surgical, mental health, high dependency, or intensive care wards. RESULTS: Twenty-seven of 115 public hospitals that admit acute inpatients participated in the audit, including 4175 of 6652 eligible acute hospital beds in Queensland. A total of 1003 patients had diabetes (24%), and data were collected for 850 (85%). Their mean age was 65.9 years (SD, 15.1 years), 357 were women (42%), and their mean HbA1c level was 66 mmol/mol (SD, 26 mmol/mol). Rates of good diabetes days (appropriate monitoring, no more than one blood glucose measurement greater than 10 mmol/L, and none below 5 mmol/L) were low in patients with type 1 diabetes (22.1 per 100 patient-days) or type 2 diabetes treated with insulin (40.1 per 100 patient-days); hypoglycaemia rates were high for patients with type 1 diabetes mellitus (24.1 episodes per 100 patient-days). One or more medication errors were identified for 201 patients (32%), including insulin prescribing errors for 127 patients (39%). Four patients with type 1 diabetes experienced diabetic ketoacidosis in hospital (8%); 121 patients (14%) met the criteria for review by a specialist diabetes team but were not reviewed by any diabetes specialist (medical, nursing, allied health). CONCLUSIONS: We identified several deficits in inpatient diabetes management in Queensland, including high rates of medication error and hospital-acquired harm and low rates of appropriate glycaemic control, particularly for patients treated with insulin. These deficits require attention, and ongoing evaluation of outcomes is necessary.

Whole-exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer.

Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1 year of treatment or exceptional cases of complete response to trastuzumab for ≥10 years. Identification of the underlying genomic aberrations of "exceptional responders (ExRs)" compared to "rapid non-responders (NRs)" increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole-exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P = 0.07), while more significantly pronounced in copy number gains (P = 0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within Chr8 (P = 0.02) and in Chr17 (P = 0.06) and conferred a statistically significant benefit in overall survival. Clinical trial number: NCT01722890 [ICORG 12/09].

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.

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.

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.

Burden of illness of follicular lymphoma and marginal zone lymphoma.

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs. $8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area.

Systematic review of interventions to improve safety and quality of anticoagulant prescribing for therapeutic indications for hospital inpatients.

PURPOSE: Anticoagulation-associated adverse drug events are common in hospitalised patients and result in morbidity, mortality, increased length of hospital stay and higher costs of care. Many are preventable. We reviewed the literature to identify and assess interventions intended to improve safety or quality anticoagulant prescribing. METHODS: A systematic search of EMBASE, MEDLINE, the Cochrane Library, Pretty Darn Quick-Evidence and Health Systems Evidence was undertaken to identify controlled studies assessing system-level interventions to improve prescribing of oral or parenteral therapeutic anticoagulation for any indication in hospitalised adults. Data were extracted for safety and quality outcomes, with studies grouped by intervention type for meta-analysis and narrative review. RESULTS: Of 10,640 records screened, 19 trials evaluating 12,742 participants were included for analysis. No study specifically evaluated prescribing of low molecular weight heparins (LMWHs) or direct acting oral anticoagulants (DOACs). Our findings suggest that physician-led anticoagulation consultation services may reduce bleeding rates in high-risk patients. On meta-analysis, decision supported warfarin dosing resulted in higher proportion of time with international normalised ratio in therapeutic range (p = 0.0007). Studies of other clinical decision support systems and heparin monitoring systems did not demonstrate improved safety, and quality findings were inconsistent. Systematic education and feedback programs were not efficacious. CONCLUSIONS: There is currently insufficient high-quality evidence to recommend any reviewed intervention, though several warrant closer evaluation. Adequately powered controlled trials assessing safety outcomes and evidence-based quality markers in high-risk patient groups and studies of interventions to improve safety of LMWH and DOAC prescribing are needed.

Ethambutol Is Cleared by a Contemporary High-Flux Hemodialyzer, and Drug Monitoring Ensures Safety and Therapeutic Effect.

It is uncertain, given the lack of recent data and the inconclusive nature of previous data, whether ethambutol is cleared by hemodialysis using contemporary dialyzers. We measured serum ethambutol concentrations before, during, and 1 h after hemodialysis in a 75-year-old Caucasian man receiving ethambutol for disseminated Bacille Calmette-Guérin infection. There was a mean 41% decrease in serum ethambutol concentration during dialysis, confirming the hemodialyzability of ethambutol and the utility of drug monitoring in ensuring safety.