Exploring Lin28 proteins: Unravelling structure and functions with emphasis on nervous system malignancies.

Cancer and stem cells share many characteristics related to self-renewal and differentiation. Both cell types express the same critical proteins that govern cellular stemness, which provide cancer cells with the growth and survival benefits of stem cells. LIN28 is an example of one such protein. LIN28 includes two main isoforms, LIN28A and LIN28B, with diverse physiological functions from tissue development to control of pluripotency. In addition to their physiological roles, LIN28A and LIN28B affect the progression of several cancers by regulating multiple cancer hallmarks. Altered expression levels of LIN28A and LIN28B have been proposed as diagnostic and/or prognostic markers for various malignancies. This review discusses the structure and modes of action of the different LIN28 proteins and examines their roles in regulating cancer hallmarks with a focus on malignancies of the nervous system. This review also highlights some gaps in the field that require further exploration to assess the potential of targeting LIN28 proteins for controlling cancer.

Comparison of COVID-19 with influenza A in the ICU: a territory-wide, retrospective, propensity matched cohort on mortality and length of stay.

OBJECTIVES: Direct comparisons between COVID-19 and influenza A in the critical care setting are limited. The objective of this study was to compare their outcomes and identify risk factors for hospital mortality. DESIGN AND SETTING: This was a territory-wide, retrospective study on all adult (≥18 years old) patients admitted to public hospital intensive care units in Hong Kong. We compared COVID-19 patients admitted between 27 January 2020 and 26 January 2021 with a propensity-matched historical cohort of influenza A patients admitted between 27 January 2015 and 26 January 2020. We reported outcomes of hospital mortality and time to death or discharge. Multivariate analysis using Poisson regression and relative risk (RR) was used to identify risk factors for hospital mortality. RESULTS: After propensity matching, 373 COVID-19 and 373 influenza A patients were evenly matched for baseline characteristics. COVID-19 patients had higher unadjusted hospital mortality than influenza A patients (17.5% vs 7.5%, p<0.001). The Acute Physiology and Chronic Health Evaluation IV (APACHE IV) adjusted standardised mortality ratio was also higher for COVID-19 than influenza A patients ((0.79 (95% CI 0.61 to 1.00) vs 0.42 (95% CI 0.28 to 0.60)), p<0.001). Adjusting for age, PaO2/FiO2, Charlson Comorbidity Index and APACHE IV, COVID-19 (adjusted RR 2.26 (95% CI 1.52 to 3.36)) and early bacterial-viral coinfection (adjusted RR 1.66 (95% CI 1.17 to 2.37)) were directly associated with hospital mortality. CONCLUSIONS: Critically ill patients with COVID-19 had substantially higher hospital mortality when compared with propensity-matched patients with influenza A.

Restrictive and liberal transfusion strategies in extracorporeal membrane oxygenation: A retrospective observational study.

BACKGROUND: To compare the outcomes of patients requiring extracorporeal membrane oxygenation (ECMO) support who had a restrictive transfusion strategy with those who had a liberal strategy. STUDY DESIGN AND METHODS: We retrospectively reviewed all adult patients from 2010 to 2019 who received a minimum of one packed red blood cell (pRBC) during ECMO. Hemoglobin values before each transfusion were retrieved. Restrictive transfusion strategy was defined as a transfusion threshold ≤8.5 g/dl in all transfusion episodes for a single patient, while liberal transfusion strategy was defined as a transfusion threshold >8.5 g/dl in any transfusion episode. RESULTS: The analysis included 763 patients, with 138 (18.1%) patients in the restrictive and 625 (81.9%) in the liberal transfusion strategy group. The median hemoglobin level, taking into account all measured hemoglobin values, during ECMO support was 8.3 and 9.9 g/dl, and the average units of pRBC received per day were 0.7 (0.3-1.8) and 1.2 (0.6-2.3), respectively. There were no significant differences in intensive care unit (ICU) mortality (adjusted odds ratio (OR), 0.86; 95% CI 0.56-1.30; p = .47), hospital mortality (adjusted OR, 0.79; 95% CI 0.52-1.21; p = .28), and 90-day mortality (adjusted OR, 0.84; 95% CI 0.55-1.28; p = .42) between the two groups. Among subgroup analyses, a restrictive transfusion strategy was associated with decreased risk of ICU mortality in patients on veno-venous ECMO (adjusted OR, 0.36; 95% CI 0.17-0.73; p = .005). There was no heterogeneity on outcomes across patients stratified by age, APACHE IV score, or need for large volume transfusion. DISCUSSION: Our data suggested it may be safe to adopt a restrictive red cell transfusion threshold of 8.5 g/dl in patients on ECMO, and highlighted the need for prospective trials in this heavily-transfused population.

Population study on diagnosis, treatment and outcomes of critically ill patients with tuberculosis (2008-2018).

BACKGROUND: Tuberculosis (TB) is a preventable and curable disease, but mortality remains high among those who develop sepsis and critical illness from TB. METHODS: This was a population-based, multicentre retrospective cohort study of patients admitted to all 15 publicly funded Hong Kong adult intensive care units (ICUs) between 1 April 2008 and 31 March 2019. 940 adult critically ill patients with at least one positive Mycobacterium tuberculosis (MTB) culture were identified out of 133 858 ICU admissions. Generalised linear modelling was used to determine the impact of delay in TB treatment on hospital mortality. Trend of annual Acute Physiology and Chronic Health Evaluation (APACHE) IV-adjusted standardised mortality ratio (SMR) over the 11-year period was analysed by Mann-Kendall's trend test. RESULTS: ICU and hospital mortality were 24.7% (232/940) and 41.1% (386/940), respectively. Of those who died in the ICU, 22.8% (53/232) never received antituberculosis drugs. SMR for ICU patients with TB remained unchanged over the study period (Kendall's τb=0.37, p=0.876). After adjustment for age, Charlson comorbidity index, APACHE IV, albumin, vasopressors, mechanical ventilation and renal replacement therapy, delayed TB treatment was directly associated with hospital mortality. In 302/940 (32.1%) of patients, TB could only be established from MTB cultures alone as Ziehl-Neelsen staining or PCR was either not performed or negative. Among this group, only 31.1% (94/302) had concurrent MTB PCR performed. CONCLUSIONS: Survival of ICU patients with TB has not improved over the last decade and mortality remains high. Delay in TB treatment was associated with higher hospital mortality. Use of MTB PCR may improve diagnostic yield and facilitate early treatment.

Effect of hospital case volume on clinical outcomes of patients requiring extracorporeal membrane oxygenation: a territory-wide longitudinal observational study.

Background: The utilization of extracorporeal membrane oxygenation (ECMO) has increased rapidly around the world. Being an overall low-volume high-cost form of therapy, the effectiveness of having care delivered in segregated units across a geographical locality is debatable. Methods: All adult extracorporeal membrane oxygenation cases admitted to public hospitals in Hong Kong between 2010 and 2019 were included. "High-volume" centers were defined as those with >20 extracorporeal membrane oxygenation cases in the respective calendar year, while "low-volume" centers were those with ≤20. Clinical outcomes of patients who received extracorporeal membrane oxygenation care in high-volume centers were compared with those in low-volume centers. Results: A total of 911 patients received extracorporeal membrane oxygenation-297 (32.6%) veno-arterial extracorporeal membrane oxygenation, 450 (49.4%) veno-venous extracorporeal membrane oxygenation, and 164 (18.0%) extracorporeal membrane oxygenation-cardiopulmonary resuscitation. The overall hospital mortality was 456 (50.1%). The annual number of extracorporeal membrane oxygenation cases in high- and low-volume centers were 29 and 11, respectively. Management in a high-volume center was not significantly associated with hospital mortality (adjusted odds ratio (OR) 0.86, 95% confidence interval (CI): 0.61-1.21, P=0.38), or with intensive care unit mortality (adjusted OR 0.76, 95% CI: 0.54-1.06, P=0.10) compared with a low-volume center. Over the 10-year period, the overall observed mortality was similar to the Acute Physiology And Chronic Health Evaluation IV-predicted mortality, with no significant difference in the standardized mortality ratios between high- and low-volume centers (P=0.46). Conclusions: In a territory-wide observational study, we observed that case volumes in extracorporeal membrane oxygenation centers were not associated with hospital mortality. Maintaining standards of care in low-volume centers is important and improves preparedness for surges in demand.

Management of Circuit Air in Extracorporeal Membrane Oxygenation: A Single Center Experience.

Air in circuit in patients receiving extracorporeal membrane oxygenation (ECMO) is an emergency. Different protocols have been suggested to deal with this rare but fatal complication, but their efficacies are rarely reported. We report our institutions' experience in the management of circuit air in Cardiohelp HLS ECMO system. Between October 2009 and July 2020, 4 out of 116 patients developed gas bubbles in ECMO circuit or systemic gas embolism. The clinical characteristics of these patients, source of air, presence of arterial air or pump airlock, cardiorespiratory status during the event, techniques employed to re-establish flow, ECMO downtime, neurologic, and other clinical outcomes were reported. In all cases, the source of air was located, with three of them being on the venous side of the circuit. Centrifugal pump airlock with cessation of ECMO flow was reported in two patients. Strategies used to re-establish ECMO flow included circuit change or deairing using backflush technique. All patients were weaned from ECMO, and three of them were discharged from hospital alive. With effective management, systemic gas embolism could be avoided during air in circuit emergencies. Backflush technique is a safe and effective deairing method to overcome centrifugal pump airlock in Cardiohelp HLS system.

Characteristics and outcomes of patients admitted to adult intensive care units in Hong Kong: a population retrospective cohort study from 2008 to 2018.

BACKGROUND: Globally, mortality rates of patients admitted to the intensive care unit (ICU) have decreased over the last two decades. However, evaluations of the temporal trends in the characteristics and outcomes of ICU patients in Asia are limited. The objective of this study was to describe the characteristics and risk adjusted outcomes of all patients admitted to publicly funded ICUs in Hong Kong over a 11-year period. The secondary objective was to validate the predictive performance of Acute Physiology And Chronic Health Evaluation (APACHE) IV for ICU patients in Hong Kong. METHODS: This was an 11-year population-based retrospective study of all patients admitted to adult general (mixed medical-surgical) intensive care units in Hong Kong public hospitals. ICU patients were identified from a population electronic health record database. Prospectively collected APACHE IV data and clinical outcomes were analysed. RESULTS: From 1 April 2008 to 31 March 2019, there were a total of 133,858 adult ICU admissions in Hong Kong public hospitals. During this time, annual ICU admissions increased from 11,267 to 14,068, whilst hospital mortality decreased from 19.7 to 14.3%. The APACHE IV standard mortality ratio (SMR) decreased from 0.81 to 0.65 during the same period. Linear regression demonstrated that APACHE IV SMR changed by - 0.15 (95% CI - 0.18 to - 0.11) per year (Pearson's R = - 0.951, p < 0.001). Observed median ICU length of stay was shorter than that predicted by APACHE IV (1.98 vs. 4.77, p < 0.001). C-statistic for APACHE IV to predict hospital mortality was 0.889 (95% CI 0.887 to 0.891) whilst calibration was limited (Hosmer-Lemeshow test p < 0.001). CONCLUSIONS: Despite relatively modest per capita health expenditure, and a small number of ICU beds per population, Hong Kong consistently provides a high-quality and efficient ICU service. Number of adult ICU admissions has increased, whilst adjusted mortality has decreased over the last decade. Although APACHE IV had good discrimination for hospital mortality, it overestimated hospital mortality of critically ill patients in Hong Kong.

An audit of mortality by using ECMO specific scores and APACHE II scoring system in patients receiving extracorporeal membrane oxygenation in a tertiary intensive care unit in Hong Kong.

BACKGROUND: Outcomes of patients receiving extracorporeal membrane oxygenation (ECMO) therapies risk-adjusted by ECMO specific scores have rarely been reported. Our primary aim was to determine the risk adjusted outcome of these patients by the use of Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP), Survival After Veno-Arterial-ECMO (SAVE) and APACHE II scores. The differences in predicted mortality between these scoring systems were analyzed. METHODS: This is a single-center retrospective study reviewing 62 patients who received venous-venous ECMO (VV-ECMO) and venous-arterial ECMO (VA-ECMO) between 2009 and 2017 in a tertiary ICU. Demographic, clinical, laboratory, imaging data were analyzed. Primary outcome measures were the crude mortality and standardized mortality ratio (SMR), expressed as observed mortality divided by expected mortality predicted from RESP, SAVE and APACHE II scores, respectively. We also examined the difference in predicted mortality derived from RESP, SAVE, and APACHE II by using Bland Altman plots. RESULTS: Twenty and Forty-two patients received VV-ECMO (20 runs) and VA-ECMO (43 runs) respectively. For VV-ECMO, the mean RESP was 0.6 [standard deviation (SD) 4.86] with RESP-SMR of 1.16 [95% confidence interval (95% CI) =0.44-1.88]. For VA-ECMO, the mean SAVE score was -7.8 (SD 5.6), with SAVE-SMR of 0.69 (95% CI =0.39-0.98). In the Bland Altman plot for VA-ECMO, mean difference in predicted mortality between SAVE and APACHE II was 17.6% (95% CI: 7.6% to 27.6%, P<0.0001), with 95% limit of agreement of -30.2% to 65.5% and beta coefficient of -1.04. APACHE II predicted mortality for VA-ECMO was lower than that for SAVE until it crossed SAVE prediction at about 80% mortality. After this point, it becomes progressively higher than that for SAVE. CONCLUSIONS: The mortality outcome of our patients on VV-ECMO and VA-ECMO compares favorably with predicted mortality based on RESP and SAVE, respectively. In our cohort of patients receiving VA-ECMO, APACHE II tends to underestimate mortality in lower risk patients, and overestimate the mortality in patients at high risk of death.

Weaning adult patients with cardiogenic shock on veno-arterial extracorporeal membrane oxygenation by pump-controlled retrograde trial off.

BACKGROUND: There is a lack of consensus on the timing of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) liberation. VA-ECMO weaning usually consists of serial decrements until an idling flow is achieved, supported by echocardiographic and haemodynamic assessments. Even with minimal idling flow, right ventricular (RV) preload is reduced and, hence, right heart function is not fully tested under adequate loading conditions. Following the use of a novel technique called Pump Controlled Retrograde Trial Off (PCRTO) in neonate VA-ECMO weaning, we report the use of this technique in seven adult patients on VA-ECMO. METHODS: We retrospectively reviewed all adult VA-ECMO patients treated at a tertiary teaching hospital in Hong Kong since 2010. Clinical data, including diagnosis, echocardiography findings, ECMO configuration, PCRTO settings, survival after veno-arterial ECMO (SAVE) score and outcomes, were collected. Mortality and death due to cardiac failure was compared between PCRTO and conventional weaning. RESULTS: Seven patients underwent PCRTO, with a mean SAVE score of -4.4 ± 5.9. All seven patients were successfully decannulated without haemodynamic deterioration. In all cases, no clots or fibrin deposits were found in the circuit after the trial. There was no difference in mean SAVE scores among the seven patients in PCRTO and the 23 patients in the conventional group (-3.6, 95% CI -8.8 to 1.5). The number of deaths due to cardiac failure in the PCRTO group and the conventional group were 0 and 3, respectively (0% vs. 13%, p=0.99). Mortality after decannulation for PCRTO was 42.9% vs. conventional weaning 34.8% (p=0.99). CONCLUSION: Our study suggests that PCRTO is a simple, safe and reversible alternative weaning method. It may have a particular role in the assessment of patients who have marginal recovery and right heart failure. Prospective controlled studies are needed to establish the potential role of PCRTO in the liberation of patients from VA-ECMO support.