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.

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.

The use of commitment techniques to support weight loss maintenance in obese adolescents.

OBJECTIVES: Obesity is a rising problem in adolescents related to unhealthy behaviours. Commitment devises are one type of behavioural intervention that may help people change their behaviours. The current pilot trial tests whether commitment devices delivered via text message help adolescents maintain their recent weight loss. METHODS: During a 12-week pilot trial, adolescents who attended a weight loss camp were randomly assigned to either received text messages that contained only information, i.e. advice, about weight loss management (n = 13) or asked for them to commit to following the same advise (n = 14). RESULTS: The BMI of the adolescents in the commitment group did not change. In contrast, the BMI of adolescents in the information group increased. A linear regression revealed that group was a significant predictor of BMI change. A logistic regression revealed that adolescents in the information group were nearly eight times more likely to regain weight than those in the commitment group. CONCLUSIONS: This is the first study with adolescents to show weight maintenance using a commitment device. The results suggest that commitment devices can help adolescents maintain their recent weight loss.

Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations.

Two megalencephaly (MEG) syndromes, megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyriapolydactyly-hydrocephalus (MPPH), have recently been defined on the basis of physical and neuroimaging features. Subsequently, exome sequencing of ten MEG cases identified de-novo postzygotic mutations in PIK3CA which cause MCAP and de-novo mutations in AKT and PIK3R2 which cause MPPH. Here we present findings from exome sequencing three unrelated megalencephaly patients which identified a causal PIK3CA mutation in two cases and a causal PIK3R2 mutation in the third case. However, our patient with the PIK3R2 mutation which is considered to cause MPPH has a marked bifrontal band heterotopia which is a feature of MCAP. Furthermore, one of our patients with a PIK3CA mutation lacks syndactyly/polydactyly which is a characteristic of MCAP. These findings suggest that the overlap between MCAP and MPPH may be greater than the available studies suggest. In addition, the PIK3CA mutation in one of our patients could not be detected using standard exome analysis because the mutation was observed at a low frequency consistent with somatic mosaicism. We have therefore investigated several alternative methods of exome analysis and demonstrate that alteration of the initial allele frequency spectrum (AFS), used as a prior for variant calling in samtools, had the greatest power to detect variants with low mutant allele frequencies in our 3 MEG exomes and in simulated data. We therefore recommend non-default settings of the AFS in combination with stringent quality control when searching for causal mutation(s) that could have low levels of mutant reads due to post-zygotic mutation.

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.

Recurrent CEP85L-PDGFRB fusion in patient with t(5;6) and imatinib-responsive myeloproliferative neoplasm with eosinophilia.

Fusion genes involving the catalytic domain of tyrosine kinases (TKs) play an important role in the pathogenesis of hematological malignancies and solid tumors. In BCR-ABL1-negative myeloproliferative neoplasms (MPNs) several different tyrosine kinase fusion events have been described, most commonly involving the genes encoding the platelet-derived growth factor receptor alpha (PDGFRA) or beta (PDGFRB). Since the introduction of small molecule kinase inhibitors, TK fusions have emerged as prime therapeutic targets. Here, we report a recurrent CEP85L-PDGFRB fusion in a patient with eosinophilia and an MPN. The fusion was confirmed by specific amplification of the genomic breakpoints and reverse transcription polymerase chain reaction (PCR). The patient was treated with imatinib and achieved hematologic and cytogenetic remission. Minimal residual disease screening over 3 years with nested PCR failed to detect CEP85L-PDGFRB mRNA or genomic DNA, confirming a long-term molecular remission on imatinib.

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.

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.

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.

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.

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.

Is human seasonality implicated in the risk profile for obesity?

Although seasonality might once have been a successful energy conservation strategy for people living in temperate regions, this physiological phenomenon may now foster accumulating annual weight gain and thereby feature in the risk profile for obesity. We tested the hypothesis that seasonality relates to BMI, and that this association is mediated by a preference for carbohydrates and the tendency to binge eat. In a sample of men and women, gender significantly moderated the relationship between seasonality and BMI. In men, the relationship was positive, but these two variables did not co-vary in women. Reasons why seasonality is positively associated with BMI only in men are not immediately apparent. It is possible that other gender-specific risk factors for overeating may contribute to these findings.

Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders.

Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

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.

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.

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.

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.