Beyond high-risk: analysis of the outcomes of extreme-risk patients in the National Emergency Laparotomy Audit.

Patients who require emergency laparotomy are defined as high risk if their 30-day predicted risk of mortality is ≥ 5%. Despite a large difference in the characteristics of patients with a mortality risk score of between 5% and 50%, these outcomes are aggregated by the National Emergency Laparotomy Audit (NELA). Our aim was to describe the outcomes of the cohort of patients at extreme risk of death, which we defined as having a NELA-predicted 30-day mortality of ≥ 50%. All patients enrolled in the NELA database between December 2012 and 2020 were included. We compared patient characteristics; length of hospital stay; rates of unplanned return to the operating theatre; and 90-day survival in extreme-risk groups (predicted ≥ 50%) and high-risk patients (predicted 5-49%). Of 161,337 patients, 5193 (3.2%) had a predicted mortality of ≥ 50%. When patients were further subdivided, 2437 (47%) had predicted mortality of 50-59% (group 50-59); 1484 (29%) predicted mortality of 60-69% (group 60-69); 840 (16%) predicted mortality of 70-79% (group 70-79); and 423 (8%) predicted mortality of ≥ 80% (group 80+). Extreme-risk patients were significantly more likely to have been admitted electively than high-risk patients (p < 0.001). Length of stay increased from a median (IQR [range]) of 26 (16-43 [0-271]) days in group 50-59 to 35 (21-56 [0-368]) days in group 80+, compared with 17 (10-30 [0-1136]) days for high-risk patients. Rates of unplanned return to the operating theatre were higher in extreme-risk groups compared with high-risk patients (11% vs. 8%). The 90-day survival was 43% in group 50-59, 34% in group 60-69, 27% in group 70-79 and 17% in group 80+. These data underscore the need for a differentiated approach when discussing risk with patients at extreme risk of mortality following an emergency laparotomy. Clinicians should focus on patient priorities on quantity and quality of life during informed consent discussions before surgery. Future work should extend beyond the immediate postoperative period to encompass the longer-term outcomes (survival and function) of patients who have emergency laparotomies.

The influence of frailty on outcomes for older adults admitted to hospital with benign biliary disease: a single-centre, observational cohort study.

INTRODUCTION: The prevalence and complications of biliary disease increase with age. Frailty has been associated with adverse outcomes in the hospital setting. We describe the prevalence of frailty in older patients hospitalised with benign biliary disease and its association with duration of hospital stay, and 90-day and 1-year mortality. METHODS: We performed a retrospective cohort study of patients aged 75 years and over admitted with acute biliary disease between 17 September 2014 and 20 March 2017. Clinical Frailty Scale (CFS) score was recorded on admission. RESULTS: We included 200 patients with a median age of 82 (75-99) years, 60% were female; 154 (77%) were independent for personal activities of daily living (ADLs) and 99 (49.5%) for instrumental ADLs. Cholecystitis was the most common diagnosis (43%) followed by cholangitis (36%) and pancreatitis (21%). Ninety-nine patients were non frail (NF; CFS 1-4) and 101 were frail (F; CFS 5-9). Some 104 patients received medical treatment only. Surgery was more common in NF patients (11% vs F 2%), percutaneous drainage more frequently performed in F patients (15% vs NF 5%) and endoscopic cholangiopancreatography was similar in both groups (F 32% vs NF 31%). Frailty was associated with worse clinical outcomes in F vs NF: functional deconditioning (34% vs 11%), increased care level (19% vs 3%), length of stay (12 vs 7 days), 90-day mortality (8% vs 3%) and 1-year mortality (48% vs 24%). CONCLUSIONS: Half of patients in our cohort were frail and spent longer in hospital, were less likely to undergo surgery and were less likely to remain alive at 1 year after discharge.

Characterizing a New Fluorescent Protein for a Low Limit of Detection Sensing in the Cell-Free System.

Cell-free protein synthesis-based biosensors have been developed as highly accurate, low-cost biosensors. However, since most biomarkers exist at low concentrations in various types of biopsies, the biosensor's dynamic range must be increased in the system to achieve low limits of detection necessary while deciphering from higher background signals. Many attempts to increase the dynamic range have relied on amplifying the input signal from the analyte, which can lead to complications of false positives. In this study, we aimed to increase the protein synthesis capability of the cell-free protein synthesis system and the output signal of the reporter protein to achieve a lower limit of detection. We utilized a new fluorescent protein, mNeonGreen, which produces a higher output than those commonly used in cell-free biosensors. Optimizations of DNA sequence and the subsequent cell-free protein synthesis reaction conditions allowed characterizing protein expression variability by given DNA template types, reaction environment, and storage additives that cause the greatest time constraint on designing the cell-free biosensor. Finally, we characterized the fluorescence kinetics of mNeonGreen compared to the commonly used reporter protein, superfolder green fluorescent protein. We expect that this finely tuned cell-free protein synthesis platform with the new reporter protein can be used with sophisticated synthetic gene circuitry networks to increase the dynamic range of a cell-free biosensor to reach lower detection limits and reduce the false-positive proportion.

Development and validation of health system performance measures for opioid use disorder in British Columbia, Canada.

BACKGROUND: Performance measurement provides an evidence-based means to inform development of interventions to improve the quality of care for people who use opioids. We aimed to develop and assess the predictive validity of health system performance measures for opioid use disorder (OUD) in British Columbia (BC), Canada. METHODS: Performance measures were generated using retrospective population-level administrative datasets (both provincial and regional) and publicly-reported retrospective data according to four domains (care engagement, clinical guideline compliance, integration, and healthcare utilization). The adjusted odds ratio was estimated via generalized linear mixed models to determine predictive validity for all-cause hospitalization or mortality within 6 months of measurement. FINDINGS: A total of 102 performance measures were constructed. We identified 55,470 diagnosed PWOUD, and 39,456 ever engaged in opioid agonist treatment (OAT). We found divergent rates of treatment for concurrent conditions (7.4% for alcohol use disorder to 80.1% for HIV/AIDS), low levels of linkage to OAT and other outpatient care following acute care, and increasing levels of service provision, including increases in OAT prescribers and pharmacies, naloxone kit distribution and overdose prevention site visitation. Our analyses on the predictive validity measures largely supported a priori hypotheses on the direction of effect on the outcome. CONCLUSIONS: We identified a range of priorities to improve the quality of care for PWOUD, with critical gaps in linkage to care through acute care settings and long-term engagement in OAT. The proposed measures can be derived for geographic and clinical subgroups and updated over time, providing a basis to monitor and evaluate efforts to address the public health burden of OUD.

Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate.

BACKGROUND: Recombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing. METHODS: MDNA11 was evaluated using in vitro and in vivo studies including: binding analyses to measure receptor affinity, IL-2 pathway signaling, PK studies in mice, and efficacy studies in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors. Finally, the safety and pharmacodynamic profile of MDNA11 was assessed in non-human primate (NHP). RESULTS: Binding studies with MDNA11 demonstrated increased affinity for IL-2Rß (CD122) and no binding to IL-2Rα (CD25). As a result, MDNA11 exhibits reduced/limited Treg stimulation while triggering an enhanced activation of natural killer and naïve CD8 T cells compared with rhIL-2. When administered to animals with pre-established tumors, MDNA11 controlled tumor growth in a monotherapy setting and in combination with anti-PD1 or anti-CTLA4 to induce durable tumor clearance with a once weekly dosing regimen. In a NHP model, MDNA11 was well tolerated while triggering durable and potent immune responses including expansion of lymphocytes without significant effect on Tregs and eosinophils, the latter been linked to an increased risk of vascular leak syndrome. CONCLUSION: MDNA11 is a next generation long-acting IL-2 immunotherapeutic with a highly favorable pharmacodynamic profile that translates to a strong therapeutic efficacy in preclinical tumor models and a strong and durable immune response in NHP.

The management of adult appendicitis during the COVID-19 pandemic: an interim analysis of a UK cohort study.

BACKGROUND: Acute appendicitis (AA) is the most common general surgical emergency. Early laparoscopic appendicectomy is the gold-standard management. SARS-CoV-2 (COVID-19) brought concerns of increased perioperative mortality and spread of infection during aerosol generating procedures: as a consequence, conservative management was advised, and open appendicectomy recommended when surgery was unavoidable. This study describes the impact of the first weeks of the pandemic on the management of AA in the United Kingdom (UK). METHODS: Patients 18 years or older, diagnosed clinically and/or radiologically with AA were eligible for inclusion in this prospective, multicentre cohort study. Data was collected from 23rd March 2020 (beginning of the UK Government lockdown) to 1st May 2020 and included: patient demographics, COVID status; initial management (operative and conservative); length of stay; and 30-day complications. Analysis was performed on the first 500 cases with 30-day follow-up. RESULTS: The patient cohort consisted of 500 patients from 48 sites. The median age of this cohort was 35 [26-49.75] years and 233 (47%) of patients were female. Two hundred and seventy-one (54%) patients were initially treated conservatively; with only 26 (10%) cases progressing to an operation. Operative interventions were performed laparoscopically in 44% (93/211). Median length of hospital stay was significantly reduced in the conservatively managed group (2 [IQR 1-4] days vs. 3 [2-4], p < 0.001). At 30 days, complications were significantly higher in the operative group (p < 0.001), with no deaths in any group. Of the 159 (32%) patients tested for COVID-19 on admission, only 6 (4%) were positive. CONCLUSION: COVID-19 has changed the management of acute appendicitis in the UK, with non-operative management shown to be safe and effective in the short-term. Antibiotics should be considered as the first line during the pandemic and perhaps beyond.

Increased care at discharge from COVID-19: The association between pre-admission frailty and increased care needs after hospital discharge; a multicentre European observational cohort study.

BACKGROUND: The COVID-19 pandemic has placed significant pressure on health and social care. Survivors of COVID-19 may be left with substantial functional deficits requiring ongoing care. We aimed to determine whether pre-admission frailty was associated with increased care needs at discharge for patients admitted to hospital with COVID-19. METHODS: Patients were included if aged over 18 years old and admitted to hospital with COVID-19 between 27 February and 10 June 2020. The Clinical Frailty Scale (CFS) was used to assess pre-admission frailty status. Admission and discharge care levels were recorded. Data were analysed using a mixed-effects logistic regression adjusted for age, sex, smoking status, comorbidities, and admission CRP as a marker of severity of disease. RESULTS: Thirteen hospitals included patients: 1671 patients were screened, and 840 were excluded including, 521 patients who died before discharge (31.1%). Of the 831 patients who were discharged, the median age was 71 years (IQR, 58-81 years) and 369 (44.4%) were women. The median length of hospital stay was 12 days (IQR 6-24). Using the CFS, 438 (47.0%) were living with frailty (≥ CFS 5), and 193 (23.2%) required an increase in the level of care provided. Multivariable analysis showed that frailty was associated with an increase in care needs compared to patients without frailty (CFS 1-3). The adjusted odds ratios (aOR) were as follows: CFS 4, 1.99 (0.97-4.11); CFS 5, 3.77 (1.94-7.32); CFS 6, 4.04 (2.09-7.82); CFS 7, 2.16 (1.12-4.20); and CFS 8, 3.19 (1.06-9.56). CONCLUSIONS: Around a quarter of patients admitted with COVID-19 had increased care needs at discharge. Pre-admission frailty was strongly associated with the need for an increased level of care at discharge. Our results have implications for service planning and public health policy as well as a person's functional outcome, suggesting that frailty screening should be utilised for predictive modelling and early individualised discharge planning.