Building strong health and career trajectories through translational research.

Translational research (TR) is the movement of fundamental scientific discoveries into healthcare settings and population health policy, and parallels the goals of DOHaD research. Unfortunately, there is little guidance on how to become a translational researcher. To understand the opinions of DOHaD trainees towards TR, we conducted a workshop at the DOHaD World Congress 2022. We found that trainees were enthusiastic for their work to have translational impact, and that they feel that holistic, multidisciplinary solutions may lead to more generalisable research. However, there lacks support for TR career pathways, which may stall the execution of the long-term vision of the DOHaD agenda. We put forward recommendations for trainees to clarify their purpose in pursuing TR and for seeking relevant people and patronages to support their training paths. For mentors, training institutions, and scientific societies, we recommend developing TR-specific programmes, and implementing training opportunities, networking events, and funding to support these endeavours.

COVID-19 vaccine safety in Scotland - background rates of adverse events of special interest.

OBJECTIVES: Mass COVID-19 vaccination commenced in December 2020 in Scotland. Monitoring vaccine safety relies on accurate background incidence rates (IRs) for health outcomes potentially associated with vaccination. This study aimed to quantify IRs in Scotland of adverse events of special interest (AESI) potentially associated with COVID-19 vaccination. STUDY DESIGN AND METHODS: IRs and 95% confidence intervals (CIs) for 36 AESI were calculated retrospectively for the pre-COVID-19 pandemic period (01 January 2015-31 December 2019) and the COVID-19 pandemic period (01 April 2020-30 November 2020), with age-sex stratification, and separately by calendar month and year. Incident cases were determined using International Classification of Diseases-10th Revision (ICD-10)-coded hospitalisations. RESULTS: Prepandemic population-wide IRs ranged from 0.4 (0.3-0.5 CIs) cases per 100,000 person-years (PYRS) for neuromyelitis optica to 478.4 (475.8-481.0 CIs) cases per 100,000 PYRS for acute renal failure. Pandemic population-wide IRs ranged from 0.3 (0.2-0.5 CIs) cases per 100,000 PYRS for Kawasaki disease to 483.4 (473.2-493.7 CIs) cases per 100,000 PYRS for acute coronary syndrome. All AESI IRs varied by age and sex. Ten AESI (acute coronary syndrome, acute myocardial infarction, angina pectoris, heart failure, multiple sclerosis, polyneuropathies and peripheral neuropathies, respiratory failure, rheumatoid arthritis and polyarthritis, seizures and vasculitis) had lower pandemic than prepandemic period IRs overall. Only deep vein thrombosis and pulmonary embolism had a higher pandemic IR. CONCLUSION: Lower pandemic IRs likely resulted from reduced health-seeking behaviours and healthcare provision. Higher IRs may be associated with SARS-CoV-2 infections. AESI IRs will facilitate future vaccine safety studies in Scotland.

An Overview of the Impact of the Covid-19 Pandemic on the Provision of Palliative Care.

The Sars-Cov-2 pandemic had an immeasurable impact on the provision of palliative care in Ireland, and continues to do so. Patients and families were affected by stringent infectious disease measures. Healthcare professionals were also impacted, with recent research demonstrating the psychological impact that the pandemic had on some of those working in palliative care during the pandemic. The services provided by palliative care services also shifted. Many patients opted to stay at home to receive end-of-life care or symptom management from their GP and community palliative homecare teams where possible. Palliative care services in the acute hospital setting were increasingly utilised to support teams to provide end-of-life care in a developing and challenging clinical environment. Communication technology was used to for multidisciplinary team meetings, to communicate with families and by community home care teams for some patient assessments. Our article outlines some of the major ways in which palliative care was impacted by the Sars-Cov-2 pandemic.

A comparative study of Western, high-carbohydrate, and standard lab diet consumption throughout adolescence on metabolic and anxiety-related outcomes in young adult male and female Long-Evans rats.

Anxiety and obesity are prevalent health concerns that are affected by diet in rodents and humans. How diet influences the development and maintenance of anxiety and obesity has been challenging to characterize, in part, due to methodological differences in chosen experimental and control diets. Within the same experiment, anxiety- and obesity-related effects were characterized in rats fed a Western diet (WD) relative to two control diets. Sixty Long-Evans rats split equally by sex were given standard diet (SD), control (i.e., high-carbohydrate) diet (HCD), or WD from weaning until sacrifice in early adulthood. Anxiety-related behavior was characterized in a modified open field test (mOFT) that allowed for the measurement of defensive behaviors (e.g., hiding within a refuge area), in addition to traditional OF measures (e.g., time in center). Both anxiety-related behaviors and hippocampal CA3 BDNF revealed specific sex differences. Neither adolescent weight gain of male and female rats, nor total body weight in early adulthood, were dependent on administration of HCD or WD, although the WD group consumed the most calories. In males only, administration of either WD or HCD resulted in elevated leptin levels relative to administration of the SD. Results indicate that SDs and HCDs are two distinct types of control diets that can affect comparability of studies and that using an SD might reveal more subtle metabolic changes. Control diet choice should be strongly considered during study design and interpretation, depending on specific research goals. Such studies should include both males and females as these effects are sex-specific.

Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. Methods: We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31st of December 2018. A retrospective electronic chart review was performed. Results: The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, P = .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (P = 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, P = 0.02). Conclusions: ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.

First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.

Reports of ChAdOx1 vaccine-associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0-27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41-13.83), with an estimated incidence of 1.13 (0.62-1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29-3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12-1.34) 0-27 d after vaccination, with an SCCS RR of 0.97 (0.93-1.02). For hemorrhagic events 0-27 d after vaccination, the aRR was 1.48 (1.12-1.96), with an SCCS RR of 0.95 (0.82-1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.

The impact of depressed mood and coping motives on cannabis use quantity across the menstrual cycle in those with and without pre-menstrual dysphoric disorder.

BACKGROUND AND AIMS: Reported rates of cannabis use among Canadian females are increasing. Female cannabis users progress to cannabis use disorder more rapidly than males (telescoping) and have higher rates of emotional disorder comorbidity. Addictive behaviors may change, along with mood and motivations, across the menstrual cycle (MC), particularly for females with pre-menstrual dysphoric disorder (PMDD). This study aimed to determine whether increases in depressed mood and coping motives would predict increased cannabis use pre-menstrually/menstrually, particularly among females with PMDD. We also assessed positive mood and enhancement motive ratings to establish specificity of predicted depressed mood and coping motive results. DESIGN: Observational study using data collected across 32 days using electronic daily diary methods. SETTING: Nova Scotia, Canada. PARTICIPANTS: Sixty-nine naturally cycling female cannabis users (Mean (M) age = 29.25, Standard Deviation  (SD) = 5.66) with and without retrospectively identified PMDD (via structured clinical interview) and prospectively identified PMDD (via elevated pre-menstrual depressed mood). Self-reported MC phase was validated using salivary progesterone concentrations. MEASUREMENTS: Depressed/positive mood, coping-/enhancement-motivated cannabis use, and cannabis use quantity. FINDINGS: Coping motives explained heightened cannabis use pre-menstrually/menstrually in those with retrospectively identified PMDD. Depressed mood explained increased cannabis use menstrually in those with retrospectively/prospectively identified PMDD. Moreover, prospectively identified PMDD significantly moderated the relationship between depressed mood and cannabis use quantity menstrually. In those with prospectively identified PMDD, positive mood and enhancement motives were associated with decreased cannabis use during the follicular/ovulatory phases. Females with versus without retrospectively identified PMDD also displayed greater overall cannabis use quantity (M [SD] = 3.44[2.84] standard joint equivalents versus 1.85[1.82], respectively; U = 277.50, P = 0.008). CONCLUSIONS: Depressed mood may explain heightened cannabis use menstrually in females with pre-menstrual dysphoric disorder. Coping motives may explain heightened cannabis use pre-menstrually/menstrually in females with retrospectively identified with pre-menstrual dysphoric disorder.

Supplementation with Combined Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 Across Development Reveals Sex Differences in Physiological and Behavioural Effects of Western Diet in Long-Evans Rats.

The gut microbiome affects various physiological and psychological processes in animals and humans, and environmental influences profoundly impact its composition. Disorders such as anxiety, obesity, and inflammation have been associated with certain microbiome compositions, which may be modulated in early life. In 62 Long-Evans rats, we characterised the effects of lifelong Bifidobacterium longum R0175 and Lactobacillus helveticus R0052 administration-along with Western diet exposure-on later anxiety, metabolic consequences, and inflammation. We found that the probiotic formulation altered specific anxiety-like behaviours in adulthood. We further show distinct sex differences in metabolic measures. In females, probiotic treatment increased calorie intake and leptin levels without affecting body weight. In males, the probiotic seemed to mitigate the effects of Western diet on adult weight gain and calorie intake, without altering leptin levels. The greatest inflammatory response was seen in male, Western-diet-exposed, and probiotic-treated rats, which may be related to levels of specific steroid hormones in these groups. These results suggest that early-life probiotic supplementation and diet exposure can have particular implications on adult health in a sex-dependent manner, and highlight the need for further studies to examine the health outcomes of probiotic treatment in both sexes.

Guidelines for best practice in placebo-controlled experimental studies on probiotics in rodent animal models.

In the absence of established best practice standards in the probiotic field for reducing the risk of bacterial transfer between experimental groups, we developed protocols and methods to ensure the highest quality and interpretability of results from animal studies, even when performed in non-conventional animal care facilities. We describe easily implementable methods for reducing cross-contamination during animal housing, behavioural testing, and euthanasia, along with highlighting protocols for contamination detection in experimental subjects and laboratory areas using qPCR. In light of the high cross-contamination risks between animals during experiments involving probiotics, constant vigilance in animal care and research protocols is critical to ensure valid and reliable research findings.

Whole Genome Sequence of Xylella fastidiosa ATCC 35879T and Detection of Genome Rearrangements Within Subsp. fastidiosa.

Xylella fastidiosa is a Gram-negative and nutritionally fastidious bacterial pathogen causing Pierce's disease (PD) of grapevine and other plant diseases. X. fastidiosa strain ATCC 35879T which originated from Florida is the designated type strain for the species and for subsp. fastidiosa. In bacterial taxonomy, type strains preserve the characters of the original descriptions. Whole genome sequence of a type strain not only provides a standard reference for bacterial taxonomy, but also facilitates research in other fields such as population diversity and genome evolution. In this study, the whole genome sequence of strain ATCC 35879T was determined using PacBio RSII format. The ATCC 35879T genome has a circular chromosome of 2,565,504 bp with 2,904 predicted protein coding genes and 55 RNA genes, and a circular plasmid of 41,753 bp. The chromosomal sequence of strain ATCC 35879T was compared to that of X. fastidosa subsp. fastidiosa strain M23 from California which causes both PD and almond leaf scorch disease. Genome rearrangements involving a ~ 1,200 K bp region were detected. Genome annotations showed clusters of phage-related genes around the rearrangement junctions, suggesting the likely involvement of phage activities. This is the first report on genome structure variations within strains of X. fastidiosa subsp. fastidiosa.

Mechanisms of Drug Binding to Voltage-Gated Sodium Channels.

Voltage-gated sodium (Na+) channels are expressed in virtually all electrically excitable tissues and are essential for muscle contraction and the conduction of impulses within the peripheral and central nervous systems. Genetic disorders that disrupt the function of these channels produce an array of Na+ channelopathies resulting in neuronal impairment, chronic pain, neuromuscular pathologies, and cardiac arrhythmias. Because of their importance to the conduction of electrical signals, Na+ channels are the target of a wide variety of local anesthetic, antiarrhythmic, anticonvulsant, and antidepressant drugs. The voltage-gated family of Na+ channels is composed of α-subunits that encode for the voltage sensor domains and the Na+-selective permeation pore. In vivo, Na+ channel α-subunits are associated with one or more accessory ß-subunits (ß1-ß4) that regulate gating properties, trafficking, and cell-surface expression of the channels. The permeation pore of Na+ channels is divided in two parts: the outer mouth of the pore is the site of the ion selectivity filter, while the inner cytoplasmic pore serves as the channel activation gate. The cytoplasmic lining of the permeation pore is formed by the S6 segments that include highly conserved aromatic amino acids important for drug binding. These residues are believed to undergo voltage-dependent conformational changes that alter drug binding as the channels cycle through the closed, open, and inactivated states. The purpose of this chapter is to broadly review the mechanisms of Na+ channel gating and the models used to describe drug binding and Na+ channel inhibition.

High risk HPV testing following treatment for cervical intraepithelial neoplasia.

AIM: To determine the results of combined cytology and high-risk human papilloma virus (HR HPV) tests at 6 and 18 months postcolposcopy treatment at one Irish colposcopy centre. METHODS: All women who attended the centre's colposcopy smear clinic for a co-test 6 months (initial test) posttreatment were included in the audit (n = 251). RESULTS: The results revealed negative HR HPV for 79 % (n = 198) of women tested 6 months after treatment and positive results for 21 % (n = 53). HR HPV testing was more sensitive than cytology and led to early detection of residual disease. No women with negative HR HPV had high-grade cytology. CONCLUSION: HR HPV is more sensitive than cytology for detection of persistent CIN. However, 19 women with positive HR HPV had normal colposcopy with no persistent CIN detected. A national cost-benefit analysis is recommended to determine the value of the second co-test.

Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat.

CONTEXT: Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics). OBJECTIVE: The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom. MATERIALS AND METHODS: Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5-100 µg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK versus time were made and the area under the curve (AUC) was calculated. RESULTS: There was a significant dose-dependent increase in CK concentration after administration of P. australis venom, which was greatest for i.v. administration. Timed measurement of venom concentrations showed a rapid absorption through s.d. and i.m. routes and a delayed rise in CK concentrations following any route. Antivenom prevented myotoxicity shown by a decrease in the CK AUC, which was most effective if given earliest. There was a rise in creatinine following i.v. venom administration. CONCLUSION: The study shows the delayed relationship between venom absorption and the rise in CK, consistent with the delayed onset of myotoxicity in human envenoming. Antivenom prevented myotoxicity more effectively if given earlier.

Detection of venom-antivenom (VAV) immunocomplexes in vitro as a measure of antivenom efficacy.

The measurement of free venom with enzyme immunoassay in serum of patients with snake envenoming is used to confirm snake identification and to determine if sufficient antivenom has been given. Recent studies with Russell's viper (RV; Daboia russelii) envenoming have detected free venom post-antivenom despite recovery of coagulopathy. This raises the question as to whether this assay also measures venom-antivenom (VAV) complexes. In this study we developed an assay to measure VAV complexes and investigate the binding of venom and antivenom in vitro. The assay consisted of rabbit anti-snake venom IgG attached to a microplate which binds the venom component of VAV and anti-horse IgG antibodies conjugated to horseradish peroxidase to detect the antivenom portion of VAV. A known amount of venom or toxin was incubated with increasing antivenom concentrations and VAV was detected as absorbance at 450 nm and plotted against AV concentration. Pseudonaja textilis (brown snake), Notechis scutatus (tiger snake), Oxyuranus scutellatus (taipan), Tropidechis carinatus (rough-scaled snake), Pseudechis porphyriacus (red-bellied black snake) and D. russelii mixtures with appropriate antivenoms were assayed. Measured VAV initially increased with increasing antivenom concentration until it reached a maximum after which the VAV concentration decreased with further increasing antivenom concentrations. The VAV curves for two Australian snake venom-antivenom mixtures, Hoplocephalus stephensii and Ancanthophis antarcticus, had broad VAV peaks with two maxima. Two fractions isolated from N. scutatus venom and Russell's viper factor X activator toxin produced similar VAV curves to their whole venoms. The antivenom concentration for which the maximum VAV occurred was linearly related to the venom concentration, and this slope or ratio was consistent with that used to define the neutralisation units for Australian antivenoms. The maximal VAV point appears to represent the antivenom concentration where every venom molecule (toxin) is attached to at least one antivenom molecule (antibody) on average and may be a useful measure of antivenom efficacy. In vivo this would mean that for a defined antivenom concentration, venom components will be eliminated and are trapped in the central compartment.

Fertility preservation in young females with non-gynaecologic malignancy: an emerging speciality.

BACKGROUND: As new treatment and research advances continue to improve the prognosis of cancer patients, oncologists and surgeons are increasingly faced with the issue of fertility protection and preservation. Cancer patients are frequently exposed to gonadotoxic chemotherapy and radiation therapy as a component of their treatment regimens. There are currently various anticipatory techniques available to women who wish to retain future reproductive ability, the most successful of which involves oocyte retrieval followed by in vitro fertilisation and embryo cryopreservation. Innovative methods include oocyte cryopreservation, ovarian follicle cryopreservation and oophoropexy. AIM: The aim of this study was to examine our combined experiences at Mayo General Hospital of treating female patients (<30 years) with non-gynaecologic malignancy and requiring referral to the HARI Unit during a 6-year period (2007-2012). Emphasis was placed on reviewing the fertility-preservation options available. METHODS: The hospital inpatient enquiry system was inspected for all cases of non-gynaecologic malignancy referred for fertility preservation from 2007 to 2012. RESULTS: Three cases of non-gynaecologic malignancy in young females, with an intention to protect and preserve future fertility were identified. The primary treatment plan did not initially incorporate input from a gynaecology or fertility specialist. It was after concerted inquiry and reflection by both physician and patient that oncofertility consultation was sought. CONCLUSION: The responsibility is on both physicians and surgeons to consider a more holistic approach to cancer care in young female patients, which focuses not only on the elimination of malignancy but also on preservation of fertility and quality of life.