Exploring the impact of traumatic injury on mortality: An analysis of the certified cause of death within one year of serious injury in the Scottish population.

BACKGROUND: Few studies effectively quantify the long-term incidence of death following injury. The absence of detailed mortality and underlying cause of death data results in limited understanding and a potential underestimation of the consequences at a population level. This study takes a nationwide approach to identify the one-year mortality following injury in Scotland, evaluating survivorship in relation to pre-existing comorbidities and incidental causes of death. STUDY DESIGN: This retrospective cohort study assessed the one-year mortality of adult trauma patients with an Injury Severity Score ≥ 9 during 2020 using the Scottish Trauma Audit Group (STAG) registry linked to inpatient hospital data and death certificate records. Patients were divided into three groups: trauma death, trauma-contributed death, and non-trauma death. Kaplan-Meier curves were used for survival analysis to evaluate mortality, and cox proportional hazards regression analysed risk factors linked to death. RESULTS: 4056 patients were analysed with a median age 63 years (58-88) and male predominance (55.2 %). Falls accounted for 73.1 % of injuries followed by motor vehicle accidents (16.3 %) and blunt force (4.9 %). Extremity was the most commonly injured region overall followed by chest and head. However, head injury prevailed in those who died. The registry demonstrated a one-year mortality of 19.3 % with 55 % deaths occurring post-discharge. Of all deaths reported, 35.3 % were trauma deaths, and 47.7 % were trauma-contributed deaths. These groups accounted for over 70 % of mortality within 30 days of hospital admission and continued to represent the majority of deaths up to 6 months post-injury. Patients who died after 6 months were mainly the result of non-traumatic causes, frequently circulatory, neoplastic, and respiratory diseases (37.7 %, 12.3 %, 9.1 %, respectively). Independent risk factors for one-year mortality included a GCS ≤ 8, modified Charlson Comorbidity score >5, Injury Severity Score >25, serious head injury, age and sex. CONCLUSION: With a one-year mortality of 19.3 %, and post-discharge deaths higher than previously appreciated, patients can face an extended period of survival uncertainty. As mortality due to index trauma lasted up to 6 months post-admission, short-term outcomes fail to represent trauma burden and so cogent survival predictions should be avoided in clinical and patient settings.

Epidemiology of major trauma in older adults within Scotland: A national perspective from the Scottish Trauma Audit Group (STAG).

BACKGROUND: Major trauma in older adults (MTOA) poses distinctive health and social care challenges, further underlined by the unique socioeconomic and geographical environment of Scotland. This study provides epidemiological trends of MTOA, to provide insight into areas where further evaluation and research are required. MATERIALS AND METHODS: Pseudonymised aggregated demographic, injury and outcome data from 2011 to 2020 were obtained from the Scottish Trauma Audit Group (STAG) Database, covering 28 hospitals across Scotland. Only individuals age ≥ 70 with an Injury Severity Score (ISS) > 15 were included. RESULTS: There was an average of 216 annual cases of MTOA, with a 259 % rise in incidence from 2011 to 2020. This was predominantly driven by a rise in low velocity trauma (fall <2 m height; 287 % increase). The proportion of all major trauma attributable to those aged ≥70 rose from 18.5 % in 2011 to 34.6 % in 2020. Death censored median (IQR) acute hospital length of stay was 18 days (9-30). Overall, 30-day survival was 65.3 %, with no improvement seen between 2011 and 2020 (p = 0.50). Independent predictors of improved 30-day survival included Ages 70-79 & 80-89 [compared to reference ≥ 90] (OR 3.12; 95 %CI 2.24,4.31; p < 0.001 and OR 1.66; 95 %CI 1.21,2.29; p = 0.002 respectively), and Extremity injury (OR 1.89; 95 %CI 1.48,2.41; p < 0.001). Head injury (OR 0.72; 95 %CI 0.54,0.96; p = 0.027) and increasing ISS score (OR 0.88, 95 %CI 0.86,0.89; p < 0.001) were associated with lower likelihood of 30-day survival. A further model also including the admission ward (from eSTAG data November 2017 onwards) demonstrated an association with reduced 30-day survival with admission to General Surgery (OR 0.42; 95 %CI 0.19,0.93; p = 0.033), Intensive Care (OR 0.25; 95 %CI 0.10,0.60; p = 0.002) and Medical Specialities (OR 0.33; 95 %CI 0.15,0.73; p = 0.007) compared to the reference (Major Trauma). Exponential Smoothing predictions revealed a further potential 184 % rise in incidence of MTOA from 2021 to 2030 (3657 per 100,000 population at risk to 10,392 per 100,000 population at risk). CONCLUSION: MTOA is likely to be a rising health care burden, requiring larger quantities of health and social care resource. Urgent preventative strategies are required to reduce low velocity trauma (standing height falls), as well as the high mortality and morbidity of MTOA.

Use of protracted CPAP as supportive treatment for COVID-19 pneumonitis and associated outcomes: a national cohort study.

BACKGROUND: Continuous positive airway pressure (CPAP) has been increasingly deployed to manage patients with COVID-19 and acute respiratory failure, often for protracted periods. However, concerns about protracted CPAP have been raised. This study aimed to examine the use of CPAP for patients with COVID-19 and the outcomes after protracted use. METHODS: This was a national cohort study of all adults admitted to Scottish critical care units with COVID-19 from March 1, 2020 to December 25, 2021 who received CPAP. Protracted CPAP was defined as ≥ 5 continuous days of CPAP. Outcomes included CPAP failure rate (institution of invasive mechanical ventilation [IMV] or death), mortality, and outcomes after institution of IMV. Multivariable logistic regression was performed to assess the impact of protracted CPAP on mortality after IMV. RESULTS: A total of 1961 patients with COVID-19 received CPAP for COVID-19 pneumonitis, with 733 patients (37.4%) receiving protracted CPAP. CPAP failure occurred in 891 (45.4%): 544 patients (27.7%) received IMV and 347 patients (17.7%) died in critical care without IMV. Hospital mortality rate was 41.3% for the population. For patients who subsequently commenced IMV, hospital mortality was 58.7% for the standard duration CPAP group and 73.9% for the protracted duration CPAP group (P=0.003); however, there was no statistical difference in hospital mortality after adjustment for confounders (odds ratio 1.4, 95% confidence interval 0.84-2.33, P=0.195). CONCLUSIONS: Protracted CPAP was used frequently for managing patients with COVID-19. Whilst it was not associated with worse outcomes for those patients who subsequently required IMV, this might be due to residual confounding and differences in processes of care.

Prevalence, characteristics, and longer-term outcomes of patients with persistent critical illness attributable to COVID-19 in Scotland: a national cohort study.

BACKGROUND: Patients with COVID-19 can require critical care for prolonged periods. Patients with persistent critical Illness can have complex recovery trajectories, but this has not been studied for patients with COVID-19. We examined the prevalence, risk factors, and long-term outcomes of critically ill patients with COVID-19 and persistent critical illness. METHODS: This was a national cohort study of all adults admitted to Scottish critical care units with COVID-19 from March 1, 2020 to September 4, 20. Persistent critical illness was defined as a critical care length of stay (LOS) of ≥10 days. Outcomes included 1-yr mortality and hospital readmission after critical care discharge. Fine and Gray competing risk analysis was used to identify factors associated with persistent critical Illness with death as a competing risk. RESULTS: A total of 2236 patients with COVID-19 were admitted to critical care; 1045 patients were identified as developing persistent critical Illness, comprising 46.7% of the cohort but using 80.6% of bed-days. Patients with persistent critical illness used more organ support, had longer post-critical care LOS, and longer total hospital LOS. Persistent critical illness was not significantly associated with long-term mortality or hospital readmission. Risk factors associated with increased hazard of persistent critical illness included age, illness severity, organ support on admission, and fewer comorbidities. CONCLUSIONS: Almost half of all patients with COVID-19 admitted to critical care developed persistent critical illness, with high resource use in critical care and beyond. However, persistent critical illness was not associated with significantly worse long-term outcomes compared with patients who were critically ill for shorter periods.

Low-input Nucleus Isolation and Multiplexing with Barcoded Antibodies of Mouse Sympathetic Ganglia for Single-nucleus RNA Sequencing.

The cardiac autonomic nervous system is crucial in controlling cardiac function, such as heart rate and cardiac contractility, and is divided into sympathetic and parasympathetic branches. Normally, there is a balance between these two branches to maintain homeostasis. However, cardiac disease states such as myocardial infarction, heart failure, and hypertension can induce the remodeling of cells involved in cardiac innervation, which is associated with an adverse clinical outcome. Although there are vast amounts of data for the histological structure and function of the cardiac autonomic nervous system, its molecular biological architecture in health and disease is still enigmatic in many aspects. Novel technologies such as single-cell RNA sequencing (scRNA-seq) hold promise for the genetic characterization of tissues at single-cell resolution. However, the relatively large size of neurons may impede the standardized use of these techniques. Here, this protocol exploits droplet-based single-nucleus RNA sequencing (snRNA-seq), a method to characterize the biological architecture of cardiac sympathetic neurons in health and disease. A stepwise approach is demonstrated to perform snRNA-seq of the bilateral superior cervical (SCG) and stellate ganglia (StG) dissected from adult mice. This method enables long-term sample preservation, maintaining an adequate RNA quality when samples from multiple individuals/experiments cannot be collected all at once within a short period of time. Barcoding the nuclei with hashtag oligos (HTOs) enables demultiplexing and the trace-back of distinct ganglionic samples post sequencing. Subsequent analyses revealed successful nuclei capture of neuronal, satellite glial, and endothelial cells of the sympathetic ganglia, as validated by snRNA-seq. In summary, this protocol provides a stepwise approach for snRNA-seq of sympathetic extrinsic cardiac ganglia, a method that has the potential for broader application in studies of the innervation of other organs and tissues.

Influence of socioeconomic deprivation on interventions and outcomes for patients admitted with COVID-19 to critical care units in Scotland: A national cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to significant respiratory failure with between 14% and 18% of hospitalised patients requiring critical care admission. This study describes the impact of socioeconomic deprivation on 30-day survival following critical care admission for COVID-19, and the impact of the COVID-19 pandemic on critical care capacity in Scotland. METHODS: This cohort study used linked national hospital records including ICU, virology testing and national death records to identify and describe patients with COVID-19 admitted to critical care units in Scotland. Multivariable logistic regression was used to assess the impact of deprivation on 30-day mortality. Critical care capacity was described by reporting the percentage of baseline ICU bed utilisation required. FINDINGS: There were 735 patients with COVID-19 admitted to critical care units across Scotland from 1/3/2020 to 20/6/2020. There was a higher proportion of patients from more deprived areas, with 183 admissions (24.9%) from the most deprived quintile and 100 (13.6%) from the least deprived quintile. Overall, 30-day mortality was 34.8%. After adjusting for age, sex and ethnicity, mortality was significantly higher in patients from the most deprived quintile (OR 1.97, 95%CI 1.13, 3.41, p=0.016). ICUs serving populations with higher levels of deprivation spent a greater amount of time over their baseline ICU bed capacity. INTERPRETATION: Patients with COVID-19 living in areas with greatest socioeconomic deprivation had a higher frequency of critical care admission and a higher adjusted 30-day mortality. ICUs in health boards with higher levels of socioeconomic deprivation had both higher peak occupancy and longer duration of occupancy over normal maximum capacity. FUNDING: None.

The effectiveness of quality control samples in pharmaceutical bioanalysis.

The use of quality control (QC) samples in bioanalysis is well established and consistent with regulatory guidance. However, a systematic evaluation of whether QC samples serve the intended purpose of improving data quality has not been undertaken. The Translational and ADME Sciences Leadership Group (TALG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) conducted an evaluation to assess whether closer agreement is observed when comparing pharmacokinetic data from two passed runs, than when comparing data from failed and passed (retest) runs. Analysis of data collected across organizations, molecular types and analytical platforms, revealed that bioanalytical methods are very reproducible; and that QC samples improve the overall quality of pharmacokinetic concentration data and justifies their continued use.

Regional variation in the incidence rate and sex ratio of multiple sclerosis in Scotland 2010-2017: findings from the Scottish Multiple Sclerosis Register.

BACKGROUND: Fifteen regional studies published over the last six decades surveying prevalence, mortality and hospital admissions have suggested that Scotland is amongst the highest risk nations for multiple sclerosis (MS) in the world. However, substantial intranational variation in rates (between regions) has been described in numerous countries, including in the only previous Scottish national survey, which used hospital admission data, to address this issue. Against this backdrop, the Scottish Multiple Sclerosis Register (SMSR) was established in 2010 to prospectively collect nationally comprehensive incidence data and to allow for regional comparisons. METHODS: Here, we present the SMSR and analyse the variation in crude and age-sex standardized incidence rates, lifetime risk (cumulative incidence), and the sex distribution of cases and rates, between the 14 administrative Health Boards or regions of Scotland: 01 January 2010 to 31 December 2017. RESULTS: The overall incidence rate for Scotland was 8.76/100,000 person-years (standardized: 8.54). Regional incidence rates varied significantly-up to threefold-between Health Boards (p < 1 × 10-13). The national female-to-male sex ratio was 2.3:1, but this too varied regionally (outlier regions result in a range from 1.0 to 4.2:1). Lifetime risk ranged from 19.9/1000 for females in Orkney (58.98°N) to 1.6/1000 for males in the Borders (55.60°N). Comparison with a previous national survey suggests that these differences are longstanding. In 6 of 14 regions the lifetime risk for women exceeds 1%. CONCLUSIONS: This study introduces a national incidence register: a valuable research tool and the result of substantial public investment. The wide variation in incidence rates and sex ratios between regions, in a relatively homogenous population, raises questions for future study.

Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury.

Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas.

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor.

Automated non-stepwise preparation of bioanalytical calibration standards and quality controls using an ultra-low volume digitizing liquid dispenser.

RATIONALE: Stepwise preparation of calibration standards and quality controls (QCs) is one of the most routine and laborious steps in bioanalysis. An alternative non-contact dispenser using low picoliter digitized dispensing technology is evaluated for its application in non-stepwise preparation of calibration curve and QCs in bioanalysis. METHODS: Fluorescein was initially used to assess the accuracy and precision of dispense volumes with fluorescent measurement. Various concentrations of MX-1, an in-house proprietary small molecule compound, in neat solution and in dog plasma were prepared manually with calibrated pipettors and digitally by the digital dispenser. The plasma samples were extracted by protein precipitation. The resultant extracted samples and neat solutions of MX-1 were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) using an electrospray ionization (ESI) source in positive ion mode with selected reaction monitoring (SRM) of the mass transitions. RESULTS: In the three-day precision and accuracy assessment of dispensing volumes between 13 pL to 411.2 nL, the intra-day precision and accuracy ranged from 1.4% to 10.3% and -12.7% to 12.8%, respectively. The inter-day precision and accuracy ranged from 3.5% to 7.8% and -6.6% to 10.4%, respectively. For real analysis of in vivo study samples, all 49 samples analyzed showed a less than 5% difference between calibrations with digital and manual curve preparations. The resultant pharmacokinetic (PK) parameters were physiologically comparable as well. CONCLUSIONS: Using the digitized picoliter dispensing technology, high-speed automated precise and accurate dispense of a wide range of volumes can be achieved and tests for bioanalytical standards and QC preparations passed the stringent criteria set forth for regulated bioanalysis using LC/MS/MS-based technology. The digital dispenser has been found to be a useful tool in drug discovery for automatically preparing standards and QCs in seconds with low consumption of stock solutions and blank matrices.

A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children's Oncology Group study.

PURPOSE: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia. EXPERIMENTAL DESIGN: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor kappaB (NF-kappaB) binding activity were evaluated during the first treatment cycle. RESULTS: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m(2) dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis at 1.3 mg/m(2) revealed a clearance of 11 mL/h/m(2), a central volume of distribution of 6.7 L/m(2), and a terminal half-life of 12.6 h. NF-kappaB activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6-fold by 24 h following bortezomib in two patients. There were no objective clinical responses. CONCLUSIONS: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m(2)/dose. Although bortezomib treatment inhibited NF-kappaB activity, bortezomib had little activity as a single agent in this population.

Impact of differential recovery in bioanalysis: the example of bortezomib in whole blood.

A key assumption in pharmaceutical bioanalysis is that spiked standards mimic incurred samples in every analytical aspect. Although deviations from this assumption have been reported in terms of the difference in ion suppression or metabolite interference, the difference of extraction recovery and its impact has been rarely reported and is often characterized as unlikely. In this work, we demonstrated the presence and significance of differential recovery using a real-world example: the assay of bortezomib in whole blood. Recovery differences of up to 10-fold were observed between the spiked standards and the incurred samples when different extraction methods were used. Because of its high impact, it is important that the potential of differential recovery between standards and incurred samples be evaluated during method validation. A simple time course incubation experiment was proposed to screen compounds for potential differential recovery during method validation in heterogeneous matrixes, such as whole blood and tissue. The use of this approach and the interpretation of the results from this experiment were demonstrated using bortezomib in whole blood as an example. The differential recovery of bortezomib is likely to be driven by slow binding to the proteosome present in red blood cells. Spiked samples, however, do not have sufficient time for binding to occur.