Getting back 'home' after emergency laparotomy: how many never make it?

BACKGROUND: Emergency laparotomy (EL) is performed on about 15 500 patients in Australia each year. Aside from mortality there is significant concern about the possibility that previously independent patients discharged after EL will become reliant on long-term dependent care. This study aimed to establish the proportion of patients not returning to their pre-admission residence, a proxy for dependent care, following EL. METHODS: Data were collected on all adult patients who underwent EL across four Australian hospitals over 2 years. A total of 113 data points were collected including pre-hospital residence, discharge destination, mortality and place of residence at 90 and 365 days. RESULTS: A total of 782 patients underwent EL, the mean age was 64 years. Pre-admission, 95.5% of patients were living in their own home. Inpatient mortality was 7.0% and at discharge 72.4% of patients returned directly back to their pre-hospital residence. At 90 days, mortality was 10.5%, and 87% of patients had returned to their pre-hospital residence, including all patients under 70 years of age. By 365 days, overall mortality was 16.8%, and only 1.5% of patients (all aged >70 years) had not returned to their pre-hospital residence. CONCLUSION: Patients who survive 90 and 365 days following EL nearly all return to their pre-hospital residence, with only a very small proportion of previously independent patients entering dependent care. This should help inform shared decision-making regarding emergency laparotomy in the acute setting.

Combining sarcopenia and ASA status to inform emergency laparotomy outcomes: could it be that simple?

BACKGROUND: Risk assessment for emergency laparotomy (EL) is important for guiding decision-making and anticipating the level of perioperative care in acute clinical settings. While established tools such as the American College of Surgeons National Surgical Quality Improvement Program calculator (ACS-NSQIP), the National Emergency Laparotomy Audit Risk Prediction Calculator (NELA) and the Portsmouth Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity calculation (P-POSSUM) are accurate predictors for mortality, there has been increasing recognition of the benefits from including measurements for frailty in a simple and quantifiable manner. Psoas muscle to 3rd lumbar vertebra area ratio (PM:L3) measured on CT scans was proven to have a significant inverse association with 30-, 90- and 365-day mortality in EL patients. METHODS: A retrospective analysis was conducted of 500 patients admitted to four Australian hospitals who underwent EL during 2016-2017, and had contemporaneous abdomino-pelvic CT scans. Radiological sarcopenia was measured as PM:L3 ratios. ASC-NSQIP, NELA and P-POSSUM were retrospectively calculated. Univariate and multivariate logistic regression modelling was used to assess these ratios and scores, as well as American Society of Anaesthesiologists (ASA) classification separated into ASA I-III and IV/V (simplified ASA), as potential predictors of 30-, 90- and 365-day mortality. RESULTS: PM:L3, simplified ASA, ACS-NSQIP, NELA and P-POSSUM were each statistically significant predictors of 30-day, 90-day and 365-day mortality (P < 0.001). Logistic regression models of 30-, 90- and 365-day mortality combining PM:L3 (P = 0.001) and simplified ASA (P < 0.001) exhibited AUCs of 0.838 (0.780, 0.896), 0.805 (0.751, 0.860) and 0.775 (0.729, 0.822), respectively, which were comparable to that of ACS-NSQIP and NELA. CONCLUSION: Combining the semi-physiological parameter ASA classification with PM:L3 provides a quick and simple alternative to the more complex established risk assessment scores and is superior to PM:L3 alone.

The impact of COVID-19 vaccination for mental well-being.

We examine the impact of vaccination against Covid-19 for mental health. Our estimates suggest that vaccination led to a significant and substantive improvement in mental health. These positive impacts were however concentrated on those most at risk of hospitalisation and death from Covid-19, namely older and clinically vulnerable groups. Our proposed explanation is that in the absence of vaccination, anxiety about contracting COVID-19 has a deleterious impact on the mental health of this cohort. On the other hand, vaccination was much less impactful for the mental health of those least at risk from Covid-19. This may help to explain vaccine hesitancy amongst young people. For this group, a lack of uptake may be principally due to a lack of perceived benefits (and indeed perceived costs) for their own well-being as opposed to vaccine hesitancy.

Sarcopenia 'made simple' and outcomes from emergency laparotomy.

BACKGROUND: Emergency Laparotomy (EL) is recognized as high-risk surgery with high mortality. Established surgical risk assessment tools (NELA Risk Prediction Calculator, P-POSSUM, ACS-NSQIP) are accurate predictors of morbidity and mortality. However, their multicomponent complexity limits their use in practice. Sarcopenia is associated with poorer surgical outcomes. This study tests for an association between a simple measure of radiological sarcopenia and mortality in EL patients in an Australian cohort. METHODS: A retrospective analysis was conducted of 500 patients admitted to four Australian hospitals who underwent EL during 2016-2017. All patients had a contemporaneous abdomino-pelvic CT scan. Radiological sarcopenia was measured as the ratio of total psoas muscle area (PM) to L3 vertebral body cross sectional area (PM:L3). Patients were followed up to 12 months. Primary outcomes were 30-, 90- and 365-day mortality. RESULTS: The mean 30-day mortality predictions for NELA, P-POSSUM and ACS-NSQIP were 11.36%, 17.28% and 11.30% respectively. PM:L3 ratio was associated with 30-, 90- and 365-day mortality (P < 0.001) and sex (P < 0.001) and negatively correlated with age (r = -0.4612; P < 0.001). Radiological sarcopenia had a weak negative correlation with NELA (r = -0.2737; P < 0.001), P-POSSUM (r = -0.1880; P < 0.001) and ACS-NSQIP (r = -0.2351; P < 0.001). The latter three metrics were significantly correlated (r > 0.5696; P < 0.001). CONCLUSION: Radiological sarcopenia (CT-assessed PM:L3) is a significant predictor of mortality in EL patients in Australia. The results of this study suggest that radiological sarcopenia is equivalent to established risk assessment tools. The more timely and easily accessible CT-assessed PM:L3 metric is potentially automatable and may have significant utility in clinical practice.

Identification of MicroRNAs That Stabilize p53 in Human Papillomavirus-Positive Cancer Cells.

Etiologically, 5% of all cancers worldwide are caused by the high-risk human papillomaviruses (hrHPVs). These viruses encode two oncoproteins (E6 and E7) whose expression is required for cancer initiation and maintenance. Among their cellular targets are the p53 and the retinoblastoma tumor suppressor proteins. Inhibition of the hrHPV E6-mediated ubiquitylation of p53 through the E6AP ubiquitin ligase results in the stabilization of p53, leading to cellular apoptosis. We utilized a live cell high-throughput screen to determine whether exogenous microRNA (miRNA) transfection had the ability to stabilize p53 in hrHPV-positive cervical cancer cells expressing a p53-fluorescent protein as an in vivo reporter of p53 stability. Among the miRNAs whose transfection resulted in the greatest p53 stabilization was 375-3p, which has previously been reported to stabilize p53 in HeLa cells, providing validation of the screen. The top 32 miRNAs, in addition to 375-3p, were further assessed using a second cell-based p53 stability reporter system, as well as in nonreporter HeLa cells to examine their effects on endogenous p53 protein levels, resulting in the identification of 23 miRNAs whose transfection increased p53 levels in HeLa cells. While a few miRNAs that stabilized p53 led to decreases in E6AP protein levels, all targeted HPV oncoprotein expression. We further examined subsets of these miRNAs for their abilities to induce apoptosis and determined whether it was p53-mediated. The introduction of specific miRNAs revealed surprisingly heterogeneous responses in different cell lines. Nonetheless, some of the miRNAs described here have potential as therapeutics for treating HPV-positive cancers. IMPORTANCE Human papillomaviruses cause approximately 5% of all cancers worldwide and encode genes that contribute to both the initiation and maintenance of these cancers. The viral oncoprotein E6 is expressed in all HPV-positive cancers and functions by targeting the degradation of p53 through the engagement of the cellular ubiquitin ligase E6AP. Inhibiting the degradation of p53 leads to apoptosis in HPV-positive cancer cells. Using a high-throughput live cell assay, we identified several miRNAs whose transfection stabilize p53 in HPV-positive cells. These miRNAs have the potential to be used in the treatment of HPV-positive cancers.

Screening Practices for Disordered Eating in Paediatric Type 1 Diabetes Clinics.

BACKGROUND: Type 1 Diabetes (T1D) is associated with increased risk of eating disorders. This study aimed to (1) assess adherence of Australasian paediatric T1D clinics to international guidelines on screening for disordered eating and (2) identify barriers and enablers to the use of screening tools for the identification of disordered eating. METHODS: A 24-item survey covering five content domains: clinic characteristics, identification of disordered eating, screening tool use, training and competence, and pathways for referral, was sent to Australasian clinics caring for ≥150 children and adolescents with T1D. RESULTS: Of 13 eligible clinics, 10 participated. Two reported rates of disordered eating of >20%, while eight reported rates < 5%. All clinics used the routine clinical interview as the primary method of screening for disordered eating. Only one used screening tools; these were not diabetes-specific or routinely used. Barriers to use of screening tools included shortage of time and lack of staff confidence around use (n = 7, 70%). Enablers included staff training in disordered eating. CONCLUSIONS: Screening tools for disordered eating are not utilised by most Australasian paediatric T1D clinics. Overall, low reported rates of disordered eating suggest that it may be undetected, potentially missing an opportunity for early intervention.

Live cell, image-based high-throughput screen to quantitate p53 stabilization and viability in human papillomavirus positive cancer cells.

Approximately 5% of cancers are caused by high-risk human papillomaviruses. Although very effective preventive vaccines will reduce this cancer burden significantly over the next several decades, they have no therapeutic effect for those already infected and remaining at risk for malignant progression of hrHPV lesions. HPV-associated cancers are dependent upon the expression of the viral E6 and E7 oncogenes. The oncogenic function of hrHPV E6 relies partially on its ability to induce p53 degradation. Since p53 is generally wildtype in hrHPV-associated cancers, p53 stabilization arrests proliferation, induces apoptosis and/or results in senescence. Here we describe a live cell, image-based high-throughput screen to identify compounds that stabilize p53 and/or affect viability in HPV-positive cancer HeLa cells. We validate the robustness and potential of this screening assay by assessing the activities of approximately 6,500 known bioactive compounds, illustrating its capability to function as a platform to identify novel therapeutics for hrHPV.

In children and young people with type 1 diabetes using Pump therapy, an additional 40% of the insulin dose for a high-fat, high-protein breakfast improves postprandial glycaemic excursions: A cross-over trial.

AIM: To determine the insulin requirement for a high-fat, high-protein breakfast to optimise postprandial glycaemic excursions in children and young people with type 1 diabetes using insulin pumps. METHODS: In all, 27 participants aged 10-23 years, BMI <95th percentile (2-18 years) or BMI <30 kg/m2 (19-25 years) and HbA1c ≤64 mmol/mol (≤8.0%) consumed a high-fat, high-protein breakfast (carbohydrate: 30 g, fat: 40 g and protein: 50 g) for 4 days. In this cross-over trial, insulin was administered, based on the insulin-to-carbohydrate ratio (ICR) of 100% (control), 120%, 140% and 160%, in an order defined by a randomisation sequence and delivered in a combination bolus, 60% » hr pre-meal and 40% over 3 hr. Postprandial sensor glucose was assessed for 6 hr. RESULTS: Comparing 100% ICR, 140% ICR and 160% ICR resulted in significantly lower 6-hr areas under the glucose curves: mean (95%CI) (822 mmol/L.min [605,1039] and 567 [350,784] vs 1249 [1042,1457], p ≤ 0.001) and peak glucose excursions (4.0 mmol/L [3.0,4.9] and 2.7 [1.7,3.6] vs 6.0 [5.0,6.9],p < 0.001). Rates of hypoglycaemia for 100%-160% ICR were 7.7%, 7.7%, 12% and 19% respectively (p ≥ 0.139). With increasing insulin dose, a step-wise reduction in mean glucose excursion was observed from 1 to 6 hr (p = 0.008). CONCLUSIONS: Incrementally increasing the insulin dose for a high-fat, high-protein breakfast resulted in a predictable, dose-dependent reduction in postprandial glycaemia: 140% ICR improved postprandial glycaemic excursions without a statistically significant increase in hypoglycaemia. These findings support a safe, practical method for insulin adjustment for high-fat, high-protein meals that can be readily implemented in practice to improve postprandial glycaemia.

For a high fat, high protein breakfast, preprandial administration of 125% of the insulin dose improves postprandial glycaemic excursions in people with type 1 diabetes using multiple daily injections: A cross-over trial.

AIM: To determine the glycaemic impact of an increased insulin dose, split insulin dose and regular insulin for a high fat, high protein breakfast in people with type 1 diabetes using multiple daily injections (≥4/day). METHODS: In this cross-over trial, participants received the same high fat, high protein breakfast (carbohydrate:30 g, fat:40 g, protein:50 g) for 4 days. Four different insulin strategies were randomly allocated and tested; 100% of the insulin-to-carbohydrate ratio (ICR) given in a single dose using aspart insulin (100Asp), 125% ICR given in a single dose using aspart (125Asp) or regular insulin (125Reg) and 125% ICR given in a split dose using aspart insulin (100:25Asp). Insulin was given 0.25 hr pre-meal and for 100:25Asp, also 1 hr post-meal. Postprandial sensor glucose was measured for 5 hr. RESULTS: In all, 24 children and adults were participated. The 5-hr incremental area under the curves for 100Asp, 125Asp, 125Reg and 100:25Asp were 620 mmol/L.min [95% CI: 451,788], 341 mmol/L.min [169,512], 675 mmol/L.min [504,847] and 434 mmol/L.min [259,608], respectively. The 5-hr incremental area under the curve for 125Asp was significantly lower than for 100Asp (p = 0.016) and for 125Reg (p = 0.002). There was one episode of hypoglycaemia in 125Reg. CONCLUSIONS: For a high fat, high protein breakfast, giving 125% ICR preprandially, using aspart insulin significantly improved postprandial glycaemia without hypoglycaemia. There was no additional glycaemic benefit from giving insulin in a split dose (100:25%) or replacing aspart with regular insulin.