Door-to-antibiotic time and mortality in patients with sepsis: Systematic review and meta-analysis.

OBJECTIVES: To evaluate whether the timing of initial antibiotic administration in patients with sepsis in hospital affects mortality. METHODS: This systematic review and meta-analysis included studies from inception up to 19 May 2022. Interventional and observational studies including adult human patients with suspected or confirmed sepsis and reported time of antibiotic administration with mortality were included. Data were extracted by two independent reviewers. Summary estimates were calculated by using random-effects model. The primary outcome was mortality. RESULTS: We included 42 studies comprising 190,896 patients with sepsis. Pooled data showed that the OR for patient mortality who received antibiotics ≤1 hr was 0.83 (95 %CI: 0.67 to 1.04) when compared with patients who received antibiotics >1hr. Significant reductions in the risk of death in patients with earlier antibiotic administration were observed in patients ≤3 hrs versus >3 hrs (OR: 0.80, 95 %CI: 0.68 to 0.94) and ≤6 hrs vs 6 hrs (OR: 0.57, 95 %CI: 0.39 to 0.82). CONCLUSIONS: Our findings show an improvement in mortality in sepsis patients with early administration of antibiotics at <3 and <6 hrs. Thus, these results suggest that antibiotics should be administered within 3 hrs of sepsis recognition or ED arrival regardless of the presence or absence of shock.

Comparison of diclofenac with tramadol, tizanidine or placebo in the treatment of acute low back pain and sciatica: multi-center randomized controlled trial.

BACKGROUND: Low back pain (LBP) is a leading cause of disability worldwide and has posed numerous health and socioeconomic challenges. This study compared whether nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with tramadol, tizanidine or placebo would be the best treatment regime to improve the Roland Morris Disability Questionnaire (RMDQ) scores at 1 week. METHODS: This was a multi-center, double-blind, randomized, and placebo-controlled trial including adult patients with acute LBP and sciatica in three emergency departments in Hong Kong. Patients were randomized to the receive tramadol 50 mg, tizanidine 2 mg, or placebo every 6 hours for 2 weeks in a 1:1:1 ratio. The RMDQ and other secondary outcomes were measured at baseline, Day 2, 7, 14, 21, and 28. Data were analyzed on an intention to treat basis. Crude and adjusted mean differences in the changes of RMDQ and NRS scores from baseline to Day 7 between tizanidine/tramadol and placebo were determined with 95% confidence intervals. RESULTS: Two hundred and ninety-one patients were analyzed with the mean age of 47.4 years and 57.7% were male. The primary outcome of mean difference in RMDQs on Day 7 (compared with baseline) was non-significant for tizanidine compared with placebo (adjusted mean difference - 0.56, 95% CI -2.48 to 1.37) and tramadol compared with placebo (adjusted mean difference - 0.85, 95% CI -2.80 to 1.10). Only 23.7% were fully compliant to the treatment allocated. Complier Average Causal Effect analysis also showed no difference in the primary outcome for the tizanidine and tramadol versus placebo. CONCLUSION: Among patients with acute LBP and sciatica presenting to the ED, adding tramadol or tizanidine to diclofenac did not improve functional recovery.

The TriAGe + score for vertigo or dizziness: A validation study in a university hospital emergency department in Hong Kong.

OBJECTIVE: Patients with dizziness commonly present to Emergency Departments (ED) and 6% of these patients will be diagnosed with acute stroke. The TriAGe+ score comprises of eight clinical parameters and stratifies patients into four risk groups. The Japanese authors reported that the tool performed well, so our aim was to validate this diagnostic tool in our ED in Hong Kong. MATERIALS AND METHODS: A single-center retrospective observational study was conducted in the ED of our university hospital in Hong Kong. The primary outcome was the diagnosis of an acute cerebrovascular event. Receiver operator characteristic (ROC) analysis was performed to determine the best cut-off score. Secondary outcomes included univariable and multivariable analyses of stroke predictors. RESULTS: 455 patients aged 18 years or above with dizziness or vertigo at ED triage were recruited between 19 July and 30 September 2021. The overall prevalence of stroke was 11.9%. The median TriAGe+ score was 7 (IQR = 4-9). The AUC was 0.9. At a cut-off >5, sensitivity was 96.4% (95%CI: 87.3-99.5) and the negative likelihood ratio was 0.09 (95%CI: 0.02-0.3). At a cut-off >10, specificity was 99.8% (95%CI: 98.6-100.0), and the positive likelihood ratio was 237.6 (95%CI: 33.1-1704). On multivariable analyses, atrial fibrillation, blood pressure, gender, dizziness (not vertigo) and no history of dizziness, vertigo or labyrinth/vestibular disease were found to be positively associated with stroke outcomes significantly. CONCLUSION: The TriAGe+ score is an efficient stroke prediction score for patients presenting to the ED with dizziness.

Impact of AIS 2015 versus 1998 on injury severity scoring and mortality prediction - single centre retrospective comparison study.

BACKGROUND: A key component of trauma system evaluation is the Injury Severity Score (ISS). The ISS is dependent on the AIS, and as AIS versions are updated this effects the number of patients within a health system which are considered severely injured (ISS >15). This study aims to analyse the changes comparing AIS1998 and AIS2015, and its impact on injury severity scoring and survival prediction model in a major trauma centre. METHODS: This retrospective study reviewed all blunt trauma admissions from 1 January 2020 to 31 December 2020 from the trauma registry of Prince of Wales Hospital, Hong Kong. Patients were manually double coded with AIS1998 and AIS2015 by the same experienced trauma nurse who have completed both AIS 1998 and AIS 2015 Courses. AIS patterns and Injury Severity Scores (ISS) derived from AIS 1998 and 2015 were compared using the Wilcoxon Signed Rank Test. The area under the receiving operator curve (AUROC) was compared based on the Trauma and Injury Severity Score (TRISS) model using AIS 1998 and AIS 2015. RESULTS: 739 patients were included. There were 34 deaths within 30 days (30-day mortality rate 4.6%). Patients coded with AIS2015 compared with AIS1998 had significant reductions in the classification of serious, severe and critical categories of AIS, with a substantial increase in the mild and moderate categories. The largest reduction was observed in the head and neck region (Z = -11.018, p < 0.001), followed by the chest (Z = -6.110, p < 0.001), abdomen (Z = -4.221, p < 0.001) and extremity regions (Z = -4.252, p < 0.001). There was a 27% reduction in number of cases with ISS >15 in AIS2015 compared with AIS1998. Rates of 30-day mortality, ICU admission, emergency operation and trauma team activation of ISS > 15 using AIS 1998 were similar to the cut off for New Injury Severity Score (NISS) >12 using AIS 2015. The AUROC from the TRISS (AIS2015) was 0.942, and not different from the AUROC for TRISS (AIS1998) of 0.936. The sensitivity and specificity were 93.9% and 82.1% for TRISS (AIS2015), and 93.9% and 76.0% for TRISS (AIS1998). CONCLUSION: Trauma centres should be aware of the impact of the AIS2015 update on the benchmarking of trauma care, and consider the need for updating the ISS cut off for major trauma definitions.

Return to work after injury in Hong Kong: prospective multi-center cohort study.

PURPOSE: Trauma remains a major cause of morbidity and disability worldwide; however, reliable data on the health status of an urban Asian population after injury are scarce. The aim was to evaluate 1-year post-trauma return to work (RTW) status in Hong Kong. METHODS: This was a prospective, multi-center cohort study involving four regional trauma centers from 2017 to 2019 in Hong Kong. Participants included adult patients entered into the trauma registry who were working or seeking employment at the time of injury. The primary outcome was the RTW status up to 1 year. The Extended Glasgow Outcome Scale, 12-item Short Form (SF-12) survey and EQ5D were also obtained during 1-, 3-, 6-, 9-, and 12-month follow-ups. Multivariable Cox proportional hazards regression analysis was used for analysis. RESULTS: Six hundred and seven of the 1115 (54%) recruited patients had RTW during the first year after injury. Lower physical requirements (p = 0.003, HR 1.51) in pre-injury job nature, higher educational levels (p < 0.001, HR 1.95), non-work-related injuries (p < 0.001, HR 1.85), shorter hospital length of stay (p = 0.007, HR 0.98), no requirement for surgery (p = 0.006, HR 1.34), and patients who could be discharged home (p = 0.006, HR 1.43) were associated with RTW within 12 months post-injury. In addition, 1-month outcomes including extended Glasgow Outcome Scale ≥ 6 (p = 0.001, HR 7.34), higher mean SF-12 physical component summary (p = 0.002, HR 1.02) and mental component summary (p < 0.001, HR 1.03), and higher EQ5D health index (p = 0.018, HR 2.14) were strongly associated with RTW. CONCLUSIONS: We have identified factors associated with failure to RTW during the first year following in Hong Kong including socioeconomic factors, injury factors and treatment-related factors and 1-month outcomes. Future studies should focus on the interventions that can impact on RTW outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03219424.

RISC II is superior to TRISS in predicting 30-day mortality in blunt major trauma patients in Hong Kong.

PURPOSE: Hong Kong (HK) trauma registries have been using the Trauma and Injury Severity Score (TRISS) for audit and benchmarking since their introduction in 2000. We compare the mortality prediction model using TRISS and Revised Injury Severity Classification, version II (RISC II) for trauma centre patients in HK. METHODS: This was a retrospective cohort study with all five trauma centres in HK. Adult trauma patients with Injury Severity Score (ISS) > 15 suffering from blunt injuries from January 2013 to December 2015 were included. TRISS models using the US and local coefficients were compared with the RISC II model. The primary outcome was 30-day mortality and the area under the receiver operating characteristic curve (AUC) for tested models. RESULTS: 1840 patients were included, of whom 1236/1840 (67%) were male. Median age was 59 years and median ISS was 25. Low falls were the most common mechanism of injury. The 30-day mortality was 23%. RISC II yielded a superior AUC of 0.896, compared with the TRISS models (MTOS: 0.848; PATOS: 0.839; HK: 0.858). Prespecified subgroup analyses showed that all the models performed worse for age ≥ 70, ASA ≥ III, and low falls. RISC II had a higher AUC compared with the TRISS models in all subgroups, although not statistically significant. CONCLUSION: RISC II was superior to TRISS in predicting the 30-day mortality for Hong Kong adult blunt major trauma patients. RISC II may be useful when performing future audit or benchmarking exercises for trauma in Hong Kong.

Seven-year excess mortality, functional outcome and health status after trauma in Hong Kong.

PURPOSE: The purpose was to investigate long-term health impacts of trauma and the aim was to describe the functional outcome and health status up to 7 years after trauma. METHODS: We conducted a prospective, multi-centre cohort study of adult trauma patients admitted to three regional trauma centres with moderate or major trauma (ISS ≥ 9) in Hong Kong (HK). Patients were followed up at regular time points (1, 6 months and 1, 2, 3, 4, 5, 6, and 7 years) by telephone using extended Glasgow Outcome Scale (GOSE) and the Short-Form 36 (SF36). Observed annual mortality rate was compared with the expected mortality rate estimated using the HK population cohort. Linear mixed model (LMM) analyses examined the changes in SF36 with subgroups of age ≥ 65 years, ISS > 15, and GOSE ≥ 5 over time. RESULTS: At 7 years, 115 patients had died and 48% (138/285) of the survivors responded. The annual mortality rate (AMR) of the trauma cohort was consistently higher than the expected mortality rate from the general population. Forty-one percent of respondents had upper good recovery (GOSE = 8) at 7 years. Seven-year mean PCS and MCS were 45.06 and 52.06, respectively. LMM showed PCS improved over time in patients aged < 65 years and with baseline GOSE ≥ 5, and the MCS improved over time with baseline GOSE ≥ 5. Higher mortality rate, limited functional recovery and worse physical health status persisted up to 7 years post-injury. CONCLUSION: Long-term mortality and morbidity should be monitored for Asian trauma centre patients to understand the impact of trauma beyond hospital discharge.

Understanding what matters most to patients in acute care in seven countries, using the flash mob study design.

BACKGROUND: Truly patient-centred care needs to be aligned with what patients consider important, and is highly desirable in the first 24 h of an acute admission, as many decisions are made during this period. However, there is limited knowledge on what matters most to patients in this phase of their hospital stay. The objective of this study was to identify what mattered most to patients in acute care and to assess the patient perspective as to whether their treating doctors were aware of this. METHODS: This was a large-scale, qualitative, flash mob study, conducted simultaneously in sixty-six hospitals in seven countries, starting November 14th 2018, ending 50 h later. One thousand eight hundred fifty adults in the first 24 h of an acute medical admission were interviewed on what mattered most to them, why this mattered and whether they felt the treating doctor was aware of this. RESULTS: The most reported answers to "what matters most (and why)?" were 'getting better or being in good health' (why: to be with family/friends or pick-up life again), 'getting home' (why: more comfortable at home or to take care of someone) and 'having a diagnosis' (why: to feel less anxious or insecure). Of all patients, 51.9% felt the treating doctor did not know what mattered most to them. CONCLUSIONS: The priorities for acutely admitted patients were ostensibly disease- and care-oriented and thus in line with the hospitals' own priorities. However, answers to why these were important were diverse, more personal, and often related to psychological well-being and relations. A large group of patients felt their treating doctor did not know what mattered most to them. Explicitly asking patients what is important and why, could help healthcare professionals to get to know the person behind the patient, which is essential in delivering patient-centred care. TRIAL REGISTRATION: NTR (Netherlands Trial Register) NTR7538 .

COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade.

Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins. We evaluated the prevalence of TIGIT and its cognate ligand, PVR (CD155), in human cancers by assessing their expression in a large set of solid tumors. TIGIT is expressed on CD4+ and CD8+ TILs and is upregulated in tumors compared to normal tissues. PVR is expressed on tumor cells and tumor-associated macrophages from multiple solid tumors. We explored the therapeutic potential of targeting TIGIT by generating COM902, a fully human anti-TIGIT hinge-stabilized IgG4 monoclonal antibody that binds specifically to human, cynomolgus monkey, and mouse TIGIT, and disrupts the binding of TIGIT with PVR. COM902, either alone or in combination with a PVRIG (COM701) or PD-1 inhibitor, enhances antigen-specific human T cell responses in-vitro. In-vivo, a mouse chimeric version of COM902 in combination with an anti-PVRIG or anti-PD-L1 antibody inhibited tumor growth and increased survival in two syngeneic mouse tumor models. In summary, COM902 enhances anti-tumor immune responses and is a promising candidate for the treatment of advanced malignancies.

Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial.

BACKGROUND: The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated. METHODS: A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18-75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118). FINDINGS: Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group. INTERPRETATION: Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects. FUNDING: Research Grants Council, Hong Kong.

Psychometric data on knowledge and fear of coronavirus disease 2019 and perceived stress among workers of filipino origin in Hong Kong.

Data on knowledge and fear of coronavirus disease 2019 (COVID-19) and perceived stress were collected in July 2020 from a convenience sample of Filipino domestic workers in Hong Kong by asking participants to take part in three questionnaires. First, twelve questions related to knowledge associated with the prevention and identification of COVID-19 were used to assess participants' knowledge regarding COVID-19. Second, the Fear of COVID-19 Scale (FCV-19S) was used to assess participants' perceived fear of infection. Third, the Short Form Perceived Stress Scale (PSS-4) was used to measure participants' perceived stress. Pearson product-moment correlation coefficients were obtained to assess the relationships between the total scores of the three questionnaires. The relationship between knowledge of COVID and fear of COVID was significant, r(108) = +0.23, p = .02; the relationship between fear of COVID and perceived stress was not statistically significant, r(108) = +0.17, p = .08; the relationship between knowledge of COVID and perceived stress was not statistically significant, r(108) = -0.11, p = .26. Cronbach's alpha coefficients were obtained for each of the three questionnaires to assess internal consistency reliability.

NEWS and qSIRS superior to qSOFA in the prediction of 30-day mortality in emergency department patients in Hong Kong.

BACKGROUND: We aim to compare the prognostic value of Quick Sepsis-Related Organ Failure Assessment (qSOFA) and the previous Systemic Inflammatory Response Syndrome (SIRS) criteria, the National Early Warning Score (NEWS) and along with their combinations in the emergency department (ED). METHODS: This single-centre prospective study recruited a convenience sample of unselected ED patients triaged as category 2 (Emergency) and 3 (Urgent). Receiver Operating Characteristic analyses were performed to determine the Area Under the Curve (AUC), along with sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios for the various scores. RESULTS: Of 1253 patients recruited, overall 30-day mortality was 5.7%. The prognostic value for prediction of 30-day mortality, with AUCs for qSOFA ≥2, SIRS ≥2, NEWS ≥5, qSIRS (qSOFA + SIRS) ≥2 and NSIRS (NEWS + SIRS) ≥5 of 0.56 (95%CI 0.53-0.58), 0.61 (95%CI 0.58-0.64), 0.61 (95%CI 0.58-0.64), 0.64 (95%CI 0.62-0.67) and 0.61 (95%CI 0.58-0.63), respectively. Using pairwise comparisons of ROC curves, NEWS ≥5 and qSIRS ≥2 were better than qSOFA ≥2 at predicting 30-day mortality. CONCLUSIONS: Among unselected emergency and urgent ED patients, the prognostic value for NEWS and qSIRS were greater than qSOFA, Combinations of qSOFA and SIRS could improve the predictive value for 30-day mortality for ED patients. Key messages NEWS ≥5 and qSIRS ≥2 were better than qSOFA ≥2 at predicting 30-day mortality in ED patients. Combinations of qSOFA and SIRS could improve the predictive value for 30-day mortality for ED patients.

Walking Route-Based Calculation is Recommended for Optimizing Deployment of Publicly Accessible Defibrillators in Urban Cities.

Background A straight line-based model is often used to calculate the distance between an out-of-hospital cardiac arrest (OHCA) and the location of an automated external defibrillator (AED). This model may be inaccurate as it overlooks any obstacles between the OHCA and AED. This study aimed to elucidate the effect of the straight line-based and walking route-based calculation on the average distance between an historical OHCA and the closest AED and the coverage rate of AEDs, ie, the proportion of historical OHCAs that were within 100 meters of an AED. It is hoped that the findings will help policy makers in deploying AEDs in optimal urban settings. Methods and Results This was an observational study conducted in Hong Kong. The average distance between an historical OHCA and its closest AED and the coverage rate of AEDs were calculated with both the straight line-based and walking route-based model. A total of 1637 AEDs and 5119 cases of OHCA were included for analysis. The average distances calculated by the straight line-based and walking route-based model were 230.8 and 545.3 meters, respectively. The coverage rate calculated by the straight line-based model was 30.04%, while that by the walking route-based model was 11.17%. Conclusions The straight line-based model may underestimate the average distances and overestimate the coverage rate in an urban setting. The walking route-based model may be more useful for studies of AED deployment in urban cities.

Agreement between capillary and venous lactate in emergency department patients: prospective observational study.

OBJECTIVES: Capillary blood lactate testing with handheld analysers has great advantages to reduce the time needed for clinical decisions, and for extended use in the prehospital setting. We investigated the agreement of capillary lactate measured using handheld analysers (CL-Nova and CL-Scout+ measured by Nova and Lactate Scout+ analyzers) and the reference venous level assessed using a point-of-care testing (POCT) blood gas analyser (VL-Ref). DESIGN: A prospective observational study. SETTING: A university teaching hospital emergency department in Hong Kong. PARTICIPANTS: Patients triaged as 'urgent' (Category 3 of a 5-point scale), aged ≥18 years during 2016 were eligible. 240 patients (mean age 69.9 years) were recruited. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the agreement of the capillary blood lactate level measured by handheld lactate analyser when compared with the reference standard technique, namely venous blood samples obtained by venepuncture and analysed using the blood gas analyser. The secondary outcome measure was the difference in values of venous lactate using blood gas analysers and handheld lactate analysers. RESULTS: The results of VL-Ref ranged from 0.70 to 5.38 mmol/L (mean of 1.96 mmol/L). Regarding capillary lactate measurements, the bias (mean difference) between VL-Ref and CL-Scout+ was -0.22 with 95% limits of agreement (LOA) of -2.17 to 1.73 mmol/L and the bias between VL-Ref and CL-Nova was 0.46, with LOA of -1.08 to 2.00 mmol/L. For venous lactate, results showed the bias between VL-Ref and VL-Scout+ was 0.22 with LOA being -0.46 to 0.90 mmol/L, and the bias between VL-Ref and VL-Nova was 0.83 mmol/L with LOA -0.01 to 1.66 mmol/L. CONCLUSION: Our study shows poor agreement between capillary lactate and reference values. The study does not support the clinical utility of capillary lactate POCT. However, venous lactate measured by Scout+ handheld analyser may have potential for screening patients who may need further testing. TRIAL REGISTRATION NUMBER: NCT02694887.

PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function.

Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8+ T-cell cytokine production and cytotoxic activity. The inhibitory effect of PVRL2 was mediated by PVRIG and not TIGIT, demonstrating that the PVRIG-PVRL2 pathway is a nonredundant signaling node. A combination of PVRIG blockade with TIGIT or PD-1 blockade further increased T-cell activation. In human tumors, PVRIG expression on T cells was increased relative to normal tissue and trended with TIGIT and PD-1 expression. Tumor cells coexpressing PVR and PVRL2 were observed in multiple tumor types, with highest coexpression in endometrial cancers. Tumor cells expressing either PVR or PVRL2 were also present in numbers that varied with the cancer type, with ovarian cancers having the highest percentage of PVR-PVRL2+ tumor cells and colorectal cancers having the highest percentage of PVR+PVRL2- cells. To demonstrate a role of PVRIG and TIGIT on tumor-derived T cells, we examined the effect of PVRIG and TIGIT blockade on human tumor-infiltrating lymphocytes. For some donors, blockade of PVRIG increased T-cell function, an effect enhanced by combination with TIGIT or PD-1 blockade. In summary, we demonstrate that PVRIG and PVRL2 are expressed in human cancers and the PVRIG-PVRL2 and TIGIT-PVR pathways are nonredundant inhibitory signaling pathways.See related article on p. 244.