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.

Evaluation of physical variables, thermal nociceptive threshold testing and pharmacokinetics during placement of transdermal buprenorphine matrix-type patch in healthy adult horses.

Background: Matrix type transdermal buprenorphine patches have not been investigated in horses and may provide an effective means of providing continuous pain control for extended period and eliminating venous catheterization. Objective: Assessment of the physiological variables (heart rate, respiratory rate, body temperature) and thermal nociceptive threshold testing, and describing the pharmacokinetic profile of transdermal buprenorphine matrix-type patch (20 µg h-1 and 40 µg h-1 dosing) in healthy adult horses. Study design: Randomised experimental study with a Latin-square design. Methods: Six adult healthy horses received each of the three treatments with a minimum 10 day washout period. BUP0 horses did not receive a patch (control). BUP20 horses received one patch (20 µg h-1) applied on the ventral aspect of the tail base resulting in a dose of 0.03-0.04 µg kg-1 h-1. BUP40 horses received two patches placed alongside each other (40 µg h-1) on the tail base resulting in a dose of 0.07-0.09 µg kg-1 h-1. Whole blood samples (for determination of buprenorphine concentration), physiological variables and thermal threshold testing were performed before (0 h) and at 2, 4, 8, 12, 16, 24, 32, 40, 48, 56, 64, 72, and 96 h after patch application. The patches were removed 72 h following placement and were analyzed for residual buprenorphine content. Results: Between the three groups, there was no change in physiological variables across timepoints as compared to baseline (p > 0.1). With the higher dose, there was a significant increase in thermal thresholds from baseline values from 2 h until 48 h and these values were significantly higher than the group receiving the lower patch dose for multiple timepoints up to 40 h. 40 µg h-1 patch led to consistent measurable plasma concentrations starting at 2 h up to 96 h, with the mean plasma concentrations of > 0.1 ng/ml from 4 h to 40 h. Conclusions: 20 µg h-1 and 40 µg h-1 patch doses were well tolerated by all horses. At higher dose, plasma buprenorphine concentrations were more consistently measurable and blunted thermal thresholds for 48 h vs. 32 h with 20 µg h-1 dosing as compared to control.

Evaluation of a rapid sequence induction technique in dogs with or without rocuronium.

OBJECTIVE: To determine, using a rapid sequence induction (RSI) technique, whether rocuronium improves the quality and speed of endotracheal intubation in healthy dogs. STUDY DESIGN: Randomized, crossover, experimental study. ANIMALS: Six adult intact male Beagles (12.3 ± 0.4 kg). METHODS: Dogs were premedicated with intravenous acepromazine (0.03 mg kg-1) and hydromorphone (0.1 mg kg-1). Ten minutes later, anesthesia was induced with intravenous propofol (2 mg kg-1 over 5 seconds), followed by saline (0.06 mL kg-1, CT group) or rocuronium (0.6 mg kg-1, RT group), with orotracheal intubation attempted after 45 seconds. Intubation time (IT) and conditions (IC) were assessed. PaO2, PaCO2, arterial blood pH and serum cortisol were obtained before and after RSI. After endotracheal intubation, saline (0.04 mL kg-1) or sugammadex (4 mg kg-1) were administered intravenously in CT or RT groups, respectively. Spontaneous ventilation restoration was noted. RESULTS: The IT was 54.3 ± 6.9 (mean ± SD) and 57.8 ± 5.2 seconds for CT and RT, respectively (p = 0.385). All laryngoscopies indicated good IC in both treatment groups. Heart rate was lower in CT group than in RT group (66 ± 16 versus 103 ± 39 beats minute-1, p = 0.016). PaCO2, pH, PaO2 and cortisol did not differ between treatments. Compared with baseline, PaCO2 increased from 47.7 ± 6.2 to 58.8 ± 5.8 (p < 0.001) and pH decreased from 7.35 ± 0.04 to 7.28 ± 0.04 (p = 0.003), independent of treatment. Dogs in both treatment groups returned to spontaneous ventilation within 30 seconds of RSI. CONCLUSIONS AND CLINICAL RELEVANCE: RSI resulted in respiratory acidosis without hypoxemia or increased cortisol. Rocuronium did not improve IT or IC. Spontaneous ventilation was observed immediately after administering saline or sugammadex. The co-administration of rocuronium showed no clinical benefits over propofol alone in RSI in healthy dogs.

Rocuronium-neuromuscular blockade does not influence the patient state index in anesthetized dogs.

OBJECTIVE: To evaluate the effects of rocuronium and sugammadex on the patient state index (PSI) in dogs anesthetized with propofol. ANIMALS: 6 intact healthy male Beagles. PROCEDURES: Anesthesia was induced with and maintained on a propofol infusion. The estimated plasma propofol concentration (ePC) was recorded. Baseline PSI and train-of-four ratio (TOFR) readings were collected for 2 minutes in stable general anesthesia. Neuromuscular blockade (NMB) was induced with 0.6 mg/kg, IV, rocuronium, and full NMB was confirmed with a TOFR of 0. After 5 minutes, the neuromuscular function was restored with 4 mg/kg sugammadex, IV (reversal), and monitored for 5 minutes. Throughout the data collection, ePC, PSI, and TOFR were recorded every 15 seconds and compared with mixed-effect ANOVA. RESULTS: Baseline ePC, PSI, and TOFR were 3.63 ± 0.38, 41 ± 6, and 0.97 ± 0.08 µg/mL, respectively. There was no difference between the baseline of ePC and PSI from NMB or reversal. Compared to the baseline, the TOFR decreased to 0 with NMB (P < .001) and returned to 0.96 ± 0.08 (P = .721) on reversal. After 5 minutes, sugammadex fully reversed 5 out of 6 dogs to TOFR > 0.90 and partially reversed 1 animal to TOFR = 0.80. CLINICAL RELEVANCE: There was no evidence that NMB with rocuronium and sugammadex-induced reversal interfered with PSI readings under steady-state total intravenous anesthesia with propofol. Further evaluation of PSI is warranted to assess its utility in a clinical population to detect changes in levels of consciousness during NMB.

Evaluation of the electroencephalogram in awake, sedated, and anesthetized dogs.

Sedation and anesthesia alter the raw electroencephalogram (EEG). Interpretation of the EEG is facilitated by measuring the patient state index (PSI), visual inspection of density spectral arrays (DSA), and power density analysis of the delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta plus gamma (12-40 Hz) frequency bands. Baseline data were recorded in six male intact Beagles before sedation with intravenous acepromazine (0.03 mg/kg) and hydromorphone (0.1 mg/kg). Anesthesia was induced and maintained for five minutes with intravenous propofol (1.5 mg/kg over five seconds followed by 12 mg/kg/h). Additional propofol (0.5-1.0 mg/kg and up to 16.7 mg/kg/h) was administered within this time frame if the PSI was above 50. The effects of sedation and anesthesia were evaluated with a mixed-effect model followed by Dunnett's test (alpha = 0.05). The average baseline PSI (95% confidence interval) was 93.0 (91.4-94.6) and decreased on sedation [88.7 (86.0-91.3); p = 0.039] and anesthesia [44.5 (40.8-48.2); p < 0.001]. The awake DSA showed dense power in all bands. The power density decreased with sedation. During anesthesia, the power density was reduced in frequencies above 12 Hz. The baseline power density on the delta, theta, alpha, and beta plus gamma bands was higher than sedation (p < 0.007). Compared to baseline, anesthesia had lower power on delta, and beta plus gamma bands (p < 0.002). The interpretation in awake, sedated, and anesthetized dogs of the EEG can be facilitated by processing and generating PSI and DSA.

Proline-specific aminopeptidase P prevents replication-associated genome instability.

Genotoxic stress during DNA replication constitutes a serious threat to genome integrity and causes human diseases. Defects at different steps of DNA metabolism are known to induce replication stress, but the contribution of other aspects of cellular metabolism is less understood. We show that aminopeptidase P (APP1), a metalloprotease involved in the catabolism of peptides containing proline residues near their N-terminus, prevents replication-associated genome instability. Functional analysis of C. elegans mutants lacking APP-1 demonstrates that germ cells display replication defects including reduced proliferation, cell cycle arrest, and accumulation of mitotic DSBs. Despite these defects, app-1 mutants are competent in repairing DSBs induced by gamma irradiation, as well as SPO-11-dependent DSBs that initiate meiotic recombination. Moreover, in the absence of SPO-11, spontaneous DSBs arising in app-1 mutants are repaired as inter-homologue crossover events during meiosis, confirming that APP-1 is not required for homologous recombination. Thus, APP-1 prevents replication stress without having an apparent role in DSB repair. Depletion of APP1 (XPNPEP1) also causes DSB accumulation in mitotically-proliferating human cells, suggesting that APP1's role in genome stability is evolutionarily conserved. Our findings uncover an unexpected role for APP1 in genome stability, suggesting functional connections between aminopeptidase-mediated protein catabolism and DNA replication.

Comparing singlet and duplicate immunogenicity assay in human plasma for pembrolizumab using Gyrolab®.

Aim: For decades, the traditional approach for ligand-binding assays has been to generate two measurements from adjacent wells on the plate. In recent years, scientists have investigated the true benefit of this 'duplicate analysis' by looking back at previously generated bioanalytical data with the conclusion that the benefits are negligible. Materials & methods: We demonstrated a method development approach to determine the best number of replicate measurements of an immunogenicity assay. We used an anti-pembrolizumab immunogenicity assay on Gyrolab® to challenge the traditional use of duplicate measurements as we compare it to singlet measurement and show a balanced design for assessing the cut-point in singlet. Results & conclusion: We introduced the concept of calculating the maximum drug tolerance during method development. In this method, we found no practical benefit for duplicate analysis and go further in recommending that singlet analysis should be considered the default for all ligand-binding assays.

An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression.

The immunosuppressive tumor microenvironment constitutes a significant hurdle to immune checkpoint inhibitor responses. Both soluble factors and specialized immune cells, such as regulatory T cells (Treg), are key components of active intratumoral immunosuppression. Inducible costimulatory receptor (ICOS) can be highly expressed in the tumor microenvironment, especially on immunosuppressive Treg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we performed immune profiling of samples from tumor-bearing mice and patients with cancer to demonstrate differential expression of ICOS in immune T-cell subsets in different tissues. ICOS expression was higher on intratumoral Treg than on effector CD8 T cells. In addition, by immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that bound ICOS from different species. We showed that KY1044 induced sustained depletion of ICOShigh T cells but was also associated with increased secretion of proinflammatory cytokines from ICOSlow effector T cells (Teff). In syngeneic mouse tumor models, KY1044 depleted ICOShigh Treg and increased the intratumoral TEff:Treg ratio, resulting in increased secretion of IFNγ and TNFα by TEff cells. KY1044 demonstrated monotherapy antitumor efficacy and improved anti-PD-L1 efficacy. In summary, we demonstrated that using KY1044, one can exploit the differential expression of ICOS on T-cell subtypes to improve the intratumoral immune contexture and restore an antitumor immune response.

using photovoice to foster a student vision for natural spaces on a college campus in the Pacific Northwest United States.

Undergraduate students face a host of stressors and may be particularly susceptible to encountering health-related challenges throughout college life. Seventy-two (N = 72) undergraduate students enrolled at a newly developed university campus located in the pacific northwest United States used the photovoice research method in crafting a vision for how natural spaces on campus might be maintained and minimally developed to promote student health. Five student-created themes emerged: 1) mental and physical health, 2) developing community spaces, 3) sustainable infrastructure design, 4) preserving natural habitat and history of the region, and 5) addressing issues related to homelessness. Initial evidence suggests that many aspects of the student vision may be incorporated into future campus environmental planning efforts. Additional research is needed in determining whether community-based greenspace planning on college campuses can positively impact the extent to which students access natural spaces for the purposes of alleviating stress and promoting health.

The significance of alternative transcripts for Caenorhabditis elegans transcription factor genes, based on expression pattern analysis.

BACKGROUND: Sequence-specific DNA-binding proteins, with their paramount importance in the regulation of expression of the genetic material, are encoded by approximately 5% of the genes in an animal's genome. But it is unclear to what extent alternative transcripts from these genes may further increase the complexity of the transcription factor complement. RESULTS: Of the 938 potential C. elegans transcription factor genes, 197 were annotated in WormBase as encoding at least two distinct isoforms. Evaluation of prior evidence identified, with different levels of confidence, 50 genes with alternative transcript starts, 23 with alternative transcript ends, 35 with alternative splicing and 34 with alternative transcripts generated by a combination of mechanisms, leaving 55 that were discounted. Expression patterns were determined for transcripts for a sample of 29 transcription factor genes, concentrating on those with alternative transcript starts for which the evidence was strongest. Seamless fosmid recombineering was used to generate reporter gene fusions with minimal modification to assay expression of specific transcripts while maintaining the broad genomic DNA context and alternative transcript production. Alternative transcription factor gene transcripts were typically expressed with identical or substantially overlapping distributions rather than in distinct domains. CONCLUSIONS: Increasingly sensitive sequencing technologies will reveal rare transcripts but many of these are clearly non-productive. The majority of the transcription factor gene alternative transcripts that are productive may represent tolerable noise rather than encoding functionally distinct isoforms.

Expression pattern analysis of regulatory transcription factors in Caenorhabditis elegans.

Expression pattern data are fundamental to understanding transcriptional regulatory networks and the biological significance of such networks. For Caenorhabditis elegans, expression pattern analysis of transcription factor genes, with cellular resolution, typically involves generation of transcription factor gene/reporter gene fusions. This is followed by the creation of C. elegans strains transgenic for, and determination of expression patterns driven by, these fusions. Physiologically relevant regulatory relationships between transcription factors are both inferred from their expression patterns, in combination with protein-DNA interaction data, and evidenced from alterations of expression patterns when networks are disturbed.

Unravelling the moulting degradome: new opportunities for chemotherapy?

Replacement of the nematode cuticle with a newly synthesized cuticle (a process known as moulting) occurs four times during larval development. Therefore, the key components of this essential developmental process represent attractive targets for new chemotherapeutic strategies. Recent advances in understanding the molecular genetics of nematode moulting should stimulate and facilitate development of novel drugs that target the essential molecules of the moulting cycle. In particular, we argue that further understanding of the moulting degradome and its key peptidase members offers an important opportunity for the development of novel antinematode agents.