Impact of electronic medical records and COVID-19 on adult Goals-of-Care document completion and revision in hospitalised general medicine patients.

BACKGROUND: Conversion from paper-based to electronic medical records (EMR) may affect the quality and timeliness of the completion of Goals-of-Care (GOC) documents during hospital admissions and this may have been further impacted by the COVID-19 pandemic. AIMS: To determine the impact of EMR and COVID-19 on the proper completion of GOC forms and the factors associated with inpatient changes in GOC. METHODS: We conducted a cross-sectional study of adult general medicine admissions (August 2018-September 2020) at Dandenong Hospital (Victoria, Australia). We used interrupted time series to model the changes in the rates of proper GOC completion (adequate documented discussion, completed ≤2 days) after the introduction of EMR and the arrival of COVID-19. RESULTS: We included a total of 5147 patients. The pre-EMR GOC proper completion rate was 27.7% (overall completion, 86.5%). There was a decrease in the proper completion rate by 2.21% per month (95% confidence interval (CI): -2.83 to -1.58) after EMR implementation despite an increase in overall completion rates (91.2%). The main reason for the negative trend was a decline in adequate documentation despite improvements in timeliness. COVID-19 arrival saw a reversal of this negative trend, with proper completion rates increasing by 2.25% per month (95% CI: 1.35 to 3.15) compared with the EMR period, but also resulted in a higher proportion of GOC changes within 2 days of admission. CONCLUSIONS: EMR improved the timeliness and overall completion rates of GOC at the cost of a lower quality of documented discussion. COVID-19 reversed the negative trend in proper GOC completion but increased the number of early revisions.

Development, validation and initial evaluation of patient-decision aid (SUI-PDA©) for women considering stress urinary incontinence surgery.

INTRODUCTION AND HYPOTHESIS: Following the design, face validation and publication of a novel PDA for women considering SUI surgery, the main objective of the study is to evaluate the usefulness of SUI-PDA© by using a validated tool to obtain patient feedback. METHODS: From July 2018 to March 2019, the PDA, already incorporated into the patient care pathway, was objectively evaluated using the Decisional Conflict Scale (DCS) to determine patients' views. Patients recorded their values and reasons for requests and declines of treatment. The total DCS score, scores from each DCS subgroup and individual patient responses were calculated and analysed. RESULTS: The mean age of the first 20 patients to complete the DCS was 54 years, the mean BMI was 30.1 and the median parity was 3. The average total DCS score was only 9.29 out of 100 (range 0-29.69) suggesting that the PDA was quite useful for patients considering SUI surgery. Overall, the PDA had largely favourable responses across all five DCS subgroups. The 'informed' subgroup had the best score (6.67) while the 'uncertainty' subgroup had the least favourable score (14.58). Despite the procedure pause, the mesh tape option remained on the PDA; however, no patient had chosen this option, with a large proportion citing 'safety' issues as the main reason. Bulking agent injections were the most popular choice (40.0%) and the most commonly performed procedures (50.0%) mainly because of quicker 'recovery'. The second most popular participant choice was colposuspension (35.0%) followed by autologous fascial sling (25.0%), with women citing 'efficacy' as the main reason behind their choice. CONCLUSION: SUI-PDA© was reported by patients and clinicians to be useful with clinical decision-making for SUI surgery. Further validation in a larger patient group is underway.

NOACs Now Mainstream for the Use of Anticoagulation in Non-Valvular Atrial Fibrillation in Australia.

The management of stroke risk in patients with non-valvular atrial fibrillation has changed over the past few years. This change has occurred due to the introduction of novel oral anticoagulants (NOACs) such as apixaban, rivaroxaban and dabigatran for the management of non-valvular atrial fibrillation. These agents have shown comparable stroke risk reduction to warfarin in large international multicentre trials [1-3]. This has changed the clinical practice of many treating physicians since their introduction from 2011 to 2013. The purpose of this review was to highlight the now mainstream use of NOAC administration in preference to warfarin, by comparing the trends in the number of prescriptions filled since all three forms of oral anti-coagulant became available in 2013. These agents are being increasingly prescribed due to their ease of use compared to warfarin, which not only requires ongoing monitoring due to narrow therapeutic range but also has many drug and food interactions. Since November 2015, NOACs have become the mainstream choice for anticoagulation in atrial fibrillation likely given their ease of use compared to warfarin. The use of each anticoagulant remains divergent with the use of warfarin continuing to decrease.

Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms.

The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.

Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes.

A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1(mut) patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2(mut) patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2(mut) patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2(mut) patients. U2AF35(mut) patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2(mut)/TET2(wt) (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.

A qualitative study of binge eating and obesity from an addiction perspective.

The purpose of this study was to explore how obese women with and without binge eating disorder (BED) experience overeating in relation to the DSM-5 symptoms of addiction. Findings from this study demonstrate that food addiction can occur in obese individuals with and without BED. It is important that health care professionals identify individuals who may require a specific treatment approach that incorporates techniques used in the treatment of addictions.

EZH2 mutational status predicts poor survival in myelofibrosis.

We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P = .028 and P < .001, respectively); no such impact was seen for PPV/PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF.

Goals of Care, Critical Care Utilization and Clinical Outcomes in Obese Patients Admitted under General Medicine.

Obesity is associated with long-term morbidity and mortality, but it is unclear if obesity affects goals of care determination and intensive care unit (ICU) resource utilization during hospitalization under a general medicine service. In a cohort of 5113 adult patients admitted under general medicine, 15.3% were obese. Patients with obesity were younger and had a different comorbidity profile than patients who were not obese. In age-adjusted regression analysis, the distribution of goals of care categories for patients with obesity was not different to patients who were not obese (odds ratio for a lower category with more limitations, 0.94; 95% confidence interval [CI]: 0.79-1.12). Patients with obesity were more likely to be directly admitted to ICU from the Emergency Department, require more ICU admissions, and stayed longer in ICU once admitted. Hypercapnic respiratory failure and heart failure were more common in patients with obesity, but they were less likely to receive mechanical ventilation in favor of non-invasive ventilation. The COVID-19 pandemic was associated with 16% higher odds of receiving a lower goals of care category, which was independent of obesity. Overall hospital length of stay was not affected by obesity. Patients with obesity had a crude mortality of 3.8 per 1000 bed-days, and age-adjusted mortality rate ratio of 0.75 (95% CI: 0.49-1.14) compared to patients who were not obese. In conclusion, there was no evidence to suggest biased goals of care determination in patients with obesity despite greater ICU resource utilization.

Identification of FOXP1 and SNX2 as novel ABL1 fusion partners in acute lymphoblastic leukaemia.

We have identified two novel ABL1 fusion genes in two patients with B-cell acute lymphoblastic leukaemia (ALL) associated with a t(3;9)(p12;q34) and a t(5;9)(q23;q34), respectively. Molecular analysis revealed a FOXP1-ABL1 fusion for the t(3;9) and a SNX2-ABL1 fusion for the t(5;9). The fusions were confirmed by specific amplification of the genomic breakpoints using reverse transcription polymerase chain reaction. The identification of ALL with rare ABL1 fusion partners is important because the leukaemia may respond to tyrosine kinase inhibitors in the same way as ALL patients with a classical BCR-ABL1 fusion gene.

Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.

Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.

Evidence that 'food addiction' is a valid phenotype of obesity.

There is growing evidence of 'food addiction' (FA) in sugar- and fat-bingeing animals. The purpose of this study was to investigate the legitimacy of this disorder in the human condition. It was also our intention to extend the validation of the Yale Food Addiction Scale (YFAS) - the first tool developed to identify individuals with addictive tendencies towards food. Using a sample of obese adults (aged 25-45 years), and a case-control methodology, we focused our assessments on three domains relevant to the characterization of conventional substance-dependence disorders: clinical co-morbidities, psychological risk factors, and abnormal motivation for the addictive substance. Results were strongly supportive of the FA construct and validation of the YFAS. Those who met the diagnostic criteria for FA had a significantly greater co-morbidity with Binge Eating Disorder, depression, and attention-deficit/hyperactivity disorder compared to their age- and weight-equivalent counterparts. Those with FA were also more impulsive and displayed greater emotional reactivity than obese controls. They also displayed greater food cravings and the tendency to 'self-soothe' with food. These findings advance the quest to identify clinically relevant subtypes of obesity that may possess different vulnerabilities to environmental risk factors, and thereby could inform more personalized treatment approaches for those who struggle with overeating and weight gain.

Fusion of PDGFRB to two distinct loci at 3p21 and a third at 12q13 in imatinib-responsive myeloproliferative neoplasms.

We identified four patients who presented with BCR-ABL1 negative myeloproliferative neoplasms and cytogenetically visible abnormalities of chromosome band 5q31-35. Fluorescence in situ hybridization indicated that the platelet-derived growth factor receptor beta gene (PDGFRB) was disrupted in all four cases and 5' rapid amplification of cDNA ends identified in-frame mRNA fusions between PDGFRB and WDR48 (3p21), GOLGA4 (3p21) and BIN2 (12q13). Strikingly, all three genes encode proteins involving intracellular trafficking. Imatinib, a known inhibitor of PDGFRbeta, selectively blocked the growth of t(3;5) myeloid colonies and produced clinically significant responses in all patients. We conclude that PDGFRB fuses to diverse partner genes in atypical myeloproliferative neoplasms (MPNs). Although very rare, identification of these fusions is critical for proper management of affected individuals.

Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms.

BACKGROUND: Aberrant activation of tyrosine kinases, caused by either mutation or gene fusion, is of major importance for the development of many hematologic malignancies, particularly myeloproliferative neoplasms. We hypothesized that hitherto unrecognized, cytogenetically cryptic tyrosine kinase fusions may be common in non-classical or atypical myeloproliferative neoplasms and related myelodysplastic/myeloproliferative neoplasms. DESIGN AND METHODS: To detect genomic copy number changes associated with such fusions, we performed a systematic search in 68 patients using custom designed, targeted, high-resolution array comparative genomic hybridization. Arrays contained 44,000 oligonucleotide probes that targeted 500 genes including all 90 tyrosine kinases plus downstream tyrosine kinase signaling components, other translocation targets, transcription factors, and other factors known to be important for myelopoiesis. RESULTS: No abnormalities involving tyrosine kinases were detected; however, nine cytogenetically cryptic copy number imbalances were detected in seven patients, including hemizygous deletions of RUNX1 or CEBPA in two cases with atypical chronic myeloid leukemia. Mutation analysis of the remaining alleles revealed non-mutated RUNX1 and a frameshift insertion within CEBPA. A further mutation screen of 187 patients with myelodysplastic/myeloproliferative neoplasms identified RUNX1 mutations in 27 (14%) and CEBPA mutations in seven (4%) patients. Analysis of other transcription factors known to be frequently mutated in acute myeloid leukemia revealed NPM1 mutations in six (3%) and WT1 mutations in two (1%) patients with myelodysplastic/myeloproliferative neoplasms. Univariate analysis indicated that patients with mutations had a shorter overall survival (28 versus 44 months, P=0.019) compared with patients without mutations, with the prognosis for cases with CEBPA, NPM1 or WT1 mutations being particularly poor. CONCLUSIONS: We conclude that mutations of transcription and other nuclear factors are frequent in myelodysplastic/myeloproliferative neoplasms and are generally mutually exclusive. CEBPA, NPM1 or WT1 mutations may be associated with a poor prognosis, an observation that will need to be confirmed by detailed prospective studies.

Immediate pleasures and future consequences. A neuropsychological study of binge eating and obesity.

Longitudinal data indicate that our capacity for adaptive self-regulation is a relatively stable predisposition that appears in childhood and predicts future life successes. In 2004, we published the first study demonstrating decision-making deficits in overweight/obese adult women. The present study is an extension of these findings. We assessed obese women with (n=65) and without (n=73) binge-eating disorder (BED), and a group (n=71) of normal-weight women, on two neuropsychological tests: the Iowa Gambling Task and a Delay Discounting measure. The BED and obese groups had worse performance scores on both tasks compared to normal controls, but did not differ from each other. These findings suggest that adaptive decision-making and the ability to delay gratification may influence our eating behaviours, particularly in a food environment where effortful control of energy intake is essential for the maintenance of a healthy body weight. There were also group differences in education level with fewer BED and obese individuals having a post-secondary degree, in accord with established links between socioeconomic status and body weight. Interestingly, when education level was added to the models, those with a higher education performed better on both tasks, and the group differences were not significant.

The t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA processing proteins SFPQ (PSF) and CPSF6 to ABL and FGFR1.

We have investigated two patients with acquired chromosomal rearrangements, a male presenting with a t(1;9)(p34;q34) and B cell progenitor acute lymphoid leukemia and a female presenting with a t(8;12)(p11;q15) and the 8p11 myeloproliferative syndrome. We determined that the t(1;9) fused ABL to SFPQ (also known as PSF), a gene mapping to 1p34 that encodes a polypyrimidine tract-binding protein-associated splicing factor. The t(8;12) fused CPSF6, a cleavage and polyadenylation specificity factor, to FGFR1. The fusions were confirmed by amplification of the genomic breakpoints and RT-PCR. The predicted oncogenic products of these fusions, SFPQ-ABL and CPSF6-FGFR1, are in-frame and encode the N-terminal domain of the partner protein and the entire tyrosine kinase domain and C-terminal sequences of ABL and FGFR1. SFPQ interacts with two FGFR1 fusion partners, ZNF198 and CPSF6, that are functionally related to the recurrent PDGFRalpha partner FIP1L1. Our findings thus identify a group of proteins that are important for pre-mRNA processing as fusion partners for tyrosine kinases in hematological malignancies.

Reward sensitivity and the D2 dopamine receptor gene: A case-control study of binge eating disorder.

OBJECTIVE: The sensitivity of dopamine reward pathways has been implicated in the risk for various psychiatric disorders including compulsive overeating. The evidence is divided, however, about the direction of causal association. One argument is that a Reward Deficiency Syndrome is the risk factor, while others contend that hyper-sensitivity to reward enhances the motivation for pleasurable activities like eating. Unfortunately, little human research has bridged the gap between psychological and neurobiological approaches to brain reward functioning and disorder. The present study addressed this issue by implementing psychological and biological markers of reward sensitivity in the assessment protocol. METHODS: Adults with binge eating disorder (BED) were compared to samples of normal-weight and obese controls on two personality measures of reward sensitivity and were genotyped for six markers of the DRD2 dopamine receptor gene. RESULTS: Genotype x Group ANOVAs revealed significant main effects and an interaction on the personality measures for Taq1A. BED and obese subjects reported greater reward sensitivity than normal-weight controls, but only among those carrying the A1 allele. We also found that normal-weight controls with at least one copy of the T allele of the C957T marker had significantly lower reward sensitivity scores than any of the other groups who did not differ from each other. CONCLUSIONS: Given evidence linking the A1 allele with reduced receptor density, an inverse relationship was expected between psychological measures of reward sensitivity and presence of the A1 allele. One explanation for our findings could be that the BED and obese participants possess another genetic variant that interacts with the A1 allele to produce higher dopamine activity. These findings have implications for future studies of the molecular genetics of BED and obesity, and for behavioural and pharmacologic therapies targeting these conditions.

Education level moderates learning on two versions of the Iowa Gambling Task.

The Iowa Gambling Task (IGT) is the major plank of behavioral support for the Somatic Marker Hypothesis--a prominent theory of emotionally-based decision making. Despite its widespread use, some have questioned the ecological and discriminative validity of the IGT because a substantial proportion of neurologically-normal adults display a response pattern indistinguishable from those with ventromedial prefrontal cortical brain lesions. In a large sample of healthy adults, we examined the statistical influence of several demographic variables on two versions of the IGT, with the specific prediction that educational attainment would moderate learning across trials. Results confirmed a highly significant effect of education. On the commonly used original version of the IGT, performance tended to improve more rapidly, and reach a higher eventual positive score, as the level of education increased. Age and gender were nonsignificant effects in the model, and Caucasians had slightly better IGT performance than their non-Caucasian counterparts. Conclusions are that education level, among neurologically-normal adults, should be treated as a stratification or matching variable in case-control research using this task.

Personality and eating behaviors: a case-control study of binge eating disorder.

OBJECTIVE: Questions have been raised about the validity of binge eating disorder (BED) as psycho-pathologically distinct from other forms of overeating. Our purpose was to ascertain whether BED individuals differed in important ways from nonbinging obese adults. METHOD: BED adults were recruited from the community as were weight-matched (obese) and normal-weight control (NWC) groups. All groups were equivalent for age and gender distribution, and were assessed on several personality traits and eating behaviors. RESULTS: BED individuals and obese controls did not differ on the personality traits. Both were more reward sensitive, and had greater anxiousness, impulsivity, and addictive personality traits than NWC. However, BED individuals reported significantly greater hedonic eating compared with the obese, who had higher levels than NWC. CONCLUSION: Our findings provided no evidence of a psychological identity unique to obese adults with BED although their eating behaviors are markedly hedonically driven-i.e., more responsive to factors external to physiological needs.

Symptoms of attention-deficit/hyperactivity disorder, overeating, and body mass index in men.

BACKGROUND: The high prevalence of obesity currently poses a global health crisis. Previous research has identified a novel link between obesity and Attention-Deficit/Hyperactivity Disorder (AD(H)D). Davis, Levitan, Smith, Tweed and Curtis [Davis, C., Levitan, R. D., Smith, M., Tweed, S., & Curtis, C. (2006). Associations among overeating, overweight, and attention deficit/hyperactivity disorder: A structural equation modeling approach. Eating Behaviors, 7, 266-274] recently tested a structural equation model predicting that AD(H)D symptoms foster overeating and subsequently contribute to the variation in Body Mass Index (BMI) in a sample of healthy adult females. The data were an excellent fit to the model. PURPOSE: In order to extend the generalizability of these findings, the present study tested the same model in 145 non-clinical adult males. RESULTS: Similar to the findings in females, AD(H)D symptoms positively predicted overeating in males, which in turn positively predicted BMI. CONCLUSIONS: Results highlight mechanisms whereby AD(H)D symptoms could influence body mass and stress the importance of addressing AD(H)D symptoms in both the prevention and treatment of overeating and obesity.

Dopamine transporter gene (DAT1) associated with appetite suppression to methylphenidate in a case-control study of binge eating disorder.

Response to psychomotor stimulants is highly variable across individuals. Such inconsistencies are influenced by many factors including drug dose and polymorphic differences in genes that encode proteins, such as the dopamine transporter (DAT1), which are relevant to the site of action of these substances. The current study used a double blind, crossover (methylphenidate vs placebo) design to assess DAT1 genotype differences on appetite ratings to a snack-food cue in subjects with binge eating disorder (BED) (n=32) and healthy age-matched controls (n=46). ANOVA results indicated a significant genotype x diagnostic group interaction whereby BED subjects with at least one copy of the 9-repeat allele showed a significant suppression of appetite in response to methylphenidate compared with controls with this allele, or to subjects with the 10/10 genotype (irrespective of diagnosis) whose drug response was indistinguishable from placebo. The most probable explanation for these findings is that some, currently unknown, genetic variant, which is overrepresented in those with BED, interacts with DAT1 to suppress appetite in response to stimulant administration. The current findings have implications for treatment response to drugs currently in use (or being developed) for the treatment of overeating and overweight.