Significant Inter-individual Variation Research Articles

The natural menstrual cycle revisited – can natural cycle be trusted

BackgroundThe serum progesterone (P4) level during the luteal phase (LP) plays a crucial role in the initiation and maintenance of pregnancy. However, it is unclear whether the natural cycle consistently provides the best endocrine profile and whether mid-luteal serum P4 levels are always sufficient to support implantation and early pregnancy. The question has become more relevant in relation to fertility treatment, as more frozen embryo transfer cycles are performed in the natural cycle. Moreover, can serum hormone levels and covariates measured during the follicular phase (FP), such as Follicle Stimulation Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2), Anti-Mullerian Hormone (AMH) and Antral Follicle Count (AFC), be used to predict P4 levels during the luteal phase (LP)?ResultsThis observational prospective cohort study analysed 26 healthy women with a cycle length between 21–35 days and a body mass index (BMI) < 30 kg/m2. Blood sampling started on the fifth day of the menstrual cycle and continued every fifth day until the next cycle. The procedure was repeated for a total of three cycles. The study found that only ten women had a P4 level greater than 30 nmol/L on cycle day 20 or 25 in all three cycles. In total, only 45 cycles out of 77 cycles had serum P4 levels ≥ 30 nmol/L.The E2 level ≥ 345 pmol/L on cycle day 10 proved to be predictive of a P4 level of ≥ 30 nmol/L on either day 20 or day 25 with a sensitivity of 57% and a specificity of 89%. No other covariates, including the FSH level cycle day 5, LH levels during the follicular phase, age, weight, AFC and AMH cycle day 5 correlated with LP P4 levels.ConclusionsA significant correlation between FP E2 levels cycle day 5 (> 131pmol/L) and cycle day 10 (> 345pmol/L) and a LP P4 level ≥ 30 nmol/l was found; thus, the FP E2 level is a predictor of corpus luteum competence. Our findings highlight the existence of suboptimal P4 levels during the LP and a significant inter-individual and intra-cycle variation in P4 levels during the LP in regular menstruating women.

Gut microbial factors predict disease severity in a mouse model of multiple sclerosis

Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation.

Vascularity evaluation of the equine tarsocrural and proximal intertarsal joint septum, and comparative analysis of two arthroscopic transection techniques.

To evaluate vascularity of the synovial membrane covered septum (SMS) separating the tarsocrural (TC) and proximal intertarsal (PIT) joints (Part 1) and compare two methods of transection, electrosurgical or Ferris Smith rongeur (FS rongeur) (Part 2). Experimental study. Part 1, 10 SMS (n = 5 horses). Part 2, six horses (n = 12 tarsi). In part 1, SMS harvested postmortem were each divided into eight regions of interest (ROIs), processed for histology, and immunostained with anti-α-actin antibody for blood vessel identification. Vascular density was calculated for each ROI. Data was compared within and between horses. In part 2, six horses underwent TC arthroscopy. Each limb was randomly assigned to undergo either electrosurgical or FS rongeur SMS transection. SMS transection and total operative time were recorded. Intraoperative hemorrhage was scored. Data was compared between both techniques. Significant interindividual variations in SMS vascular density were detected (p = .02), but there were no differences among ROIs. No differences in the transection time were detected between electrosurgery (4.83 ± 0.54 min) and FS rongeur (4.33 ± 0.67 min). No differences were found in intraoperative hemorrhage scores between techniques. Vascularity within the SMS varies among horses but not within its regions. Electrosurgical or FS rongeur transection of the medial SMS during tarsocrural arthroscopy is a rapid technique and improves surgical access to the dorsal compartment of the PIT.

The role of caffeine in headache disorders.

Caffeine is known to have both beneficial and adverse effects in individuals with headache disorders. This review describes recent findings regarding caffeine that are relevant to headache disorders and puts these findings into the context of clinical management. Preclinical studies show that caffeine has complex effects on sleep, brain blood flow, and intracranial pressure that may depend on the timing of caffeine intake relative to the sleep-wake cycle. Caffeine metabolism may have significant inter-individual variation that influences its therapeutic and/or adverse effects. Caffeine has acute therapeutic benefit for some primary headache disorders. For migraine, this benefit is predominantly in milder headache without cutaneous allodynia. High levels of caffeine intake may contribute to progression of headache disorders. Caffeine-containing combination analgesics commonly cause medication overuse headache. Abrupt reduction in caffeine consumption is a trigger for migraine that may be important in situations including the hospital setting, religious and cultural fasting, and pregnancy. There is not sufficient evidence to support universal guidelines for the use of dietary and medicinal caffeine in headache disorders. A sensible approach based upon available evidence is to limit dietary caffeine intake to moderate amounts with consistent timing before noon, and to use caffeine-containing combination analgesics infrequently for milder headache.

Variations of the popliteal artery in human fetuses: preliminary study

IntroductionThis paper provides an in-depth analysis of the anatomical and morphometrical attributes of the popliteal artery (PA) in human fetuses. Additionally, it showcases significant interindividual variation in branching patterns, which are of great clinical importance in the context of vascular surgery and interventional radiology.AimThe purpose of this research was to systematically examine and categorize the anatomical and morphometrical diversities observed in the PA among a 166 sample of human fetuses at various gestational stages, spanning from 16 to 30 weeks of pregnancy.Material and methodsThe latex was injected into the 166 PA within the fetal specimens to visually analyze their anatomical features, and high-resolution digital images were captured at 24-bit color depth for detailed analysis.Results and DiscussionThe PAs were systematically classified into three distinct categories, further subcategorized into specific types. The classification system employed was based on the framework established initially by Lippert and Pabst, with modifications by Kim. The results of the analysis revealed the following distribution: Category I – it was mainly detected in the majority of specimens, comprising 144 cases (86.7%) of the sample population, and represented the most common anatomical configuration; Category II – it was found in 19 specimens (11.4%) of the total sample population (this category represented a less common anatomical variation within the PA); Category III – the rarest anatomical configuration observed in only 3 specimens (1.8%) from the sample population.ConclusionsThe frequent occurrence of short tibiofibular trunks in PA may be due to incidental lesions or postnatal developmental changes, highlighting the need for further research.

Fatigue risk assessment of a Helicopter Emergency Medical Service crew working a 24/7 shift pattern: results of a prospective service evaluation

BackgroundThe work of Helicopter Emergency Medical Services (HEMS) teams crosses the boundaries of several high-risk occupations including medicine, aviation, and transport. Working conditions can be challenging and operational demands requires a 24-h rota, resulting in disruption of the normal circadian rhythm. HEMS crews are therefore prone to both mental and physical fatigue. As fatigue in medical providers is linked to poor cognitive performance, degradation of psychomotor skills and error, this study aimed to explore the existence of predictable patterns of crew-fatigue in a HEMS service.MethodsHEMS medical crew members working a 3-on 3-off forward rotating rota with a 5-week shift cycle were asked to do psychomotor vigilance tests (PVT) as an objective measure of fatigue. PVT testing was undertaken at the start, mid- and at the end of every shift during a full 5-week shift cycle. In addition, they were asked to score subjective tiredness with the Samn-Perelli Fatigue Scale (SPFS), and to keep a Transport Fatigue Assessment shift log, wherein they noted shift characteristics potentially related to fatigue. Primary outcome of interest was defined as the change in PVT and SPFS scores over time.ResultsMean baseline resting PVT in milliseconds at the start of the study period was 427 [390–464]. There was an overall trend towards higher PVT-scores with shift progression mean [95% CI] PVT at the start of shifts 447 [433–460]; halfway through the shift 452 [440–463]; end of the shift 459 [444–475], p = 0.10), whereas SPFS scores remained constant. Within a 5 week forward-rotating cycle, an overall trend towards a gradual increase in both average PVT (from 436 [238–454] to 460 [371–527, p = 0.68] ms;) and SPFS (from 2.9 [2.6–3.2] to 3.6 [3.1–4.0], p = 0.38) was observed, although significant interindividual variation was present. Reported SPFS scores ≥ 4 (moderate fatigue) were mainly related to workload (number of jobs) and transport mode (car-based shifts).ConclusionAn overall trend towards a decline in psychomotor vigilance and an increase in self-reported tiredness was found for HEMS crew over a 5-week shift cycle. Using a bespoke predictive fatigue tool on a day-to-day basis could increase fatigue awareness and provide a framework to which relevant mitigating options can be applied.

Human–machine cooperation meta-model for clinical diagnosis by adaptation to human expert’s diagnostic characteristics

Artificial intelligence (AI) using deep learning approaches the capabilities of human experts in medical image diagnosis. However, due to liability issues in medical decisions, AI is often relegated to an assistant role. Based on this responsibility constraint, the effective use of AI to assist human intelligence in real-world clinics remains a challenge. Given the significant inter-individual variations in clinical decisions among physicians based on their expertise, AI needs to adapt to individual experts, complementing weaknesses and enhancing strengths. For this adaptation, AI should not only acquire domain knowledge but also understand the specific human experts it assists. This study introduces a meta-model for human–machine cooperation that first evaluates each expert’s class-specific diagnostic tendencies using conditional probability, based on which the meta-model adjusts the AI’s predictions. This meta-model was applied to ear disease diagnosis using otoendoscopy, highlighting improved performance when incorporating individual diagnostic characteristics, even with limited evaluation data. The highest accuracy was achieved by combining each expert’s conditional probabilities with machine classification probability, using optimal weights specific to each individual’s overall classification accuracy. This tailored model aims to mitigate potential misjudgments due to psychological effects caused by machine suggestions and to capitalize on the unique expertise of individual clinicians.

Impact of Hypoxia-Hyperoxia Exposures on Cardiometabolic Risk Factors and TMAO Levels in Patients with Metabolic Syndrome.

Along with the known risk factors of cardiovascular diseases (CVDs) constituting metabolic syndrome (MS), the gut microbiome and some of its metabolites, in particular trimethylamine-N-oxide (TMAO), are actively discussed. A prolonged stay under natural hypoxic conditions significantly and multi-directionally changes the ratio of gut microbiome strains and their metabolites in feces and blood, which is the basis for using hypoxia preconditioning for targeted effects on potential risk factors of CVD. A prospective randomized study included 65 patients (32 females) with MS and optimal medical therapy. Thirty-three patients underwent a course of 15 intermittent hypoxic-hyperoxic exposures (IHHE group). The other 32 patients underwent sham procedures (placebo group). Before and after the IHHE course, patients underwent liver elastometry, biochemical blood tests, and blood and fecal sampling for TMAO analysis (tandem mass spectrometry). No significant dynamics of TMAO were detected in both the IHHE and sham groups. In the subgroup of IHHE patients with baseline TMAO values above the reference (TMAO ≥ 5 μmol/l), there was a significant reduction in TMAO plasma levels. But the degree of reduction in total cholesterol (TCh), low-density lipoprotein (LDL), and regression of liver steatosis index was more pronounced in patients with initially normal TMAO values. Despite significant interindividual variations, in the subgroup of IHHE patients with MS and high baseline TMAO values, there were more significant reductions in cardiometabolic and hepatic indicators of MS than in controls. More research is needed to objectify the prognostic role of TMAO and the possibilities of its correction using hypoxia adaptation techniques.

Remimazolam and serious adverse events: A scoping review.

Remimazolam is anticipated to be an interesting anaesthetic and sedative. It combines the pharmacodynamic properties of midazolam with pharmacokinetic properties similar to remifentanil. However, worrisome case reports of anaphylaxis, delayed emergence and re-sedation have emerged recently and necessitate further investigation. PubMed (including MEDLINE) and EMBASE were searched for all studies reporting serious adverse events where remimazolam was administered for sedation or anaesthesia. Thirty-six case reports and 73 trials were identified, involving a total of 6740 patients who received remimazolam. Hypotension was reported in 911 cases, delayed emergence in 68 cases, anaphylaxis in 10 cases and re-sedation in 8 cases. The incidence of hypotension seems to be lower compared with other anaesthetics, even in high-risk patients. Delayed emergence might be related to the metabolism of remimazolam through carboxylesterase 1 (CES1), a tissue esterase predominant in the liver. There is significant interindividual variation, and it is inhibited by flavonoids, fatty acids and alcohol. Individual benzodiazepine sensitivity has also been reported. A higher BMI, older age and low plasma albumin concentration are risk factors for delayed emergence. Anaphylaxis might be related to a non-IgE-mediated effect of the excipient dextran-40 or a partially IgE-mediated reaction to remimazolam itself. Resedation has been reported after flumazenil reversal and is explained by the specific pharmacokinetic properties of flumazenil and remimazolam. Reversal by flumazenil should be reserved for and used carefully in patients with delayed emergence. Visual Abstract http://links.lww.com/EJA/A864.

At last, empirical elicitations of the magnitudes of those risks (and costs!) too small to matter and those too large to abide

Scholars, decision-makers, and pundits have long tossed around words and numbers meant to demarcate those health/safety risks that are too small to matter at all (called, variously, “trivial” or “de minimis” or “insignificant”), or risks that are so large as to be abhorrent (“unacceptable,” “intolerable,” and the like). But there has been nothing approaching a consensus about how large or small these important probabilities are, and worse, there have been no serious attempts to explore these concepts via any carefully-elicited preferences from laypeople themselves. Perhaps even more concerning, the dominant paradigm—cost-benefit analysis (CBA)—requires balancing of (monetized) risks against the costs of controlling them, but the parallel concepts of de minimis costs and intolerable costs have never been formally considered. As a result of these lapses, all attempts to consider equity or justice in the distribution of how risks and costs are borne are an absurdity, despite claims to the contrary. This article reports on a pair of elicitations involving 1350 laypeople. In one elicitation, a careful set of background and contextual explanations and a structured series of questions probed where each subject perceived lifetime excess mortality risk (from involuntary exposure) to become “so small you would not spend a moment thinking about it,” and where it becomes so large that “you would strongly object, as an ethical matter, to ever having to face it.” With a separate sample, we asked the parallel questions with regard to regulatory costs imposed by the government in the name of risk reduction. Although there was significant interindividual variation in responses, the central tendency of each of these four science-policy-values “goalposts” was as follows: (1) de minimis risk—a lifetime excess chance of premature death of 1 in 770,000; (2) intolerable risk—1 chance in 570; (3) de minimis cost—$25 per year; and (4) intolerable cost—$775 per year. These results offer, for the first time, a principled and evidence-based starting point for further refinement of which risks or costs to individuals can/should be disregarded in setting policy, and which must dominate policies regardless of how total “monetized lives saved” and total dollar costs compare to each other when viewed simplistically. We offer several prescriptions for how CBA might change, and how environmental/health/safety policy might improve, to take account of these fundamental thresholds in how risks and costs actually impose burdens on citizens. Both those interventions that impose intolerable costs while only reducing diffuse and trivially small risks, and those failures to intervene (sufficiently) that perpetuate intolerable risks for the sake of avoiding trivial and eminently manageable costs, are inefficient, unjust, and are thus unethical.

The normal distribution of the hypoxic ventilatory response and methodological impacts: a meta-analysis and computational investigation.

The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental conditions. In the final analysis, 72 datasets reported mean HVR values and 60 datasets provided raw HVR datasets. Of the 60 datasets reporting raw HVR values, 35 (58.3%) were at least moderately positively skewed (skew > 0.5), and 21 (35%) were significantly positively skewed (skew > 1), indicating that lower HVR values are common. The skewness of HVR distributions does not appear to be an artifact of methodology or the unit with which the HVR is reported. Further analysis demonstrated that the use of step-down hypoxia versus progressive hypoxia methods did not have a significant impact on average HVR values, but that isocapnic protocols produced higher HVRs than poikilocapnic protocols. This work provides a reference for expected HVR values and illustrates substantial inter-individual variation in this key reflex. Finally, the prevalence of low HVRs in the general population provides insight into our understanding of blunted HVRs in high-altitude adapted groups. KEY POINTS: The hypoxic ventilatory response (HVR) plays a crucial role in determining an individual's predisposition to hypoxia-related pathologies. There is notable variability in HVR sensitivity across individuals as well as significant population-level differences. We report that the normal distribution of the HVR is positively skewed, with a significant prevalence of low HVR values amongst the general healthy population. We also find no significant impact of the experimental protocol used to induce hypoxia, although HVR is greater with isocapnic versus poikilocapnic methods. These results provide insight into the normal distribution of the HVR, which could be useful in clinical decisions of diseases related to hypoxaemia. Additionally, the low HVR values found within the general population provide insight into the genetic adaptations found in populations residing in high altitudes.

A review of pediatric fasting guidelines and strategies to help children manage preoperative fasting.

Fasting for surgery is a routine step in the preoperative preparation for surgery. There have however been increasing concerns with regard to the high incidence of prolonged fasting in children, and the subsequent psycho-social distress and physiological consequences that this poses. Additionally, the past few years have yielded new research that has shown significant inter-individual variation in gastric emptying regardless of the length of the fast, with some patients still having residual gastric contents even after prolonged fasts. Additionally, multiple large-scale studies have shown no long-term sequalae from clear fluid aspiration, although two deaths from aspiration have been reported within the large Wake Up Safe cohort. This has led to a change in the recommended clear fluid fasting times in multiple international pediatric societies; similarly, many societies continue to recommend traditional fasting times. Multiple fasting strategies exist in the literature, though these have mostly been studied and implemented in the adult population. This review hopes to summarize the recent updates in fasting guidelines, discuss the issues surrounding prolonged fasting, and explore potential tolerance strategies for children.

Pearls and Pitfalls of Adaptive Optics Ophthalmoscopy in Inherited Retinal Diseases.

Adaptive optics (AO) retinal imaging enables individual photoreceptors to be visualized in the clinical setting. AO imaging can be a powerful clinical tool for detecting photoreceptor degeneration at a cellular level that might be overlooked through conventional structural assessments, such as spectral-domain optical coherence tomography (SD-OCT). Therefore, AO imaging has gained significant interest in the study of photoreceptor degeneration, one of the most common causes of inherited blindness. Growing evidence supports that AO imaging may be useful for diagnosing early-stage retinal dystrophy before it becomes apparent on fundus examination or conventional retinal imaging. In addition, serial AO imaging may detect structural disease progression in early-stage disease over a shorter period compared to SD-OCT. Although AO imaging is gaining popularity as a structural endpoint in clinical trials, the results should be interpreted with caution due to several pitfalls, including the lack of standardized imaging and image analysis protocols, frequent ocular comorbidities that affect image quality, and significant interindividual variation of normal values. Herein, we summarize the current state-of-the-art AO imaging and review its potential applications, limitations, and pitfalls in patients with inherited retinal diseases.

Effects of an Extract of the Brown Seaweed Ascophylum nodosum on Postprandial Glycaemic Control in Healthy Subjects: A Randomized Controlled Study.

The effects of the consumption of an extract of the brown seaweed Ascophyllum nodosum (BSW) on postprandial glucose and insulin responses to white bread were investigated in an acute, randomized, double-blind, three-arm, crossover, controlled trial in healthy, normoglycemic subjects. Sixteen subjects were administered either control white bread (50 g total digestible carbohydrates) or white bread with 500 mg or 1000 mg of BSW extract. Biochemical parameters were measured in venous blood over 3 h. Significant inter-individual variation in the glycaemic response to white bread was observed. Analysis of the responses of all subjects to either 500 mg or 1000 mg of BSW extract versus control revealed no significant effects of treatments. The variation in response to the control was used to classify individuals into glycaemic responders and non-responders. In the sub-cohort of 10 subjects with peak glucose levels after white bread above 1 mmol/L, we observed a significant decrease in maximum levels of plasma glucose after the intervention meal with 1000 mg of extract compared with the control. No adverse effects were reported. Further work is warranted to define all factors that determine "responders" to the effects of brown seaweed extracts and identify the cohort that would benefit the most from their consumption.

Transposable elements are associated with the variable response to influenza infection

Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factorsin variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity.

Application of symmetry evaluation to deep learning algorithm in detection of mastoiditis on mastoid radiographs

As many human organs exist in pairs or have symmetric appearance and loss of symmetry may indicate pathology, symmetry evaluation on medical images is very important and has been routinely performed in diagnosis of diseases and pretreatment evaluation. Therefore, applying symmetry evaluation function to deep learning algorithms in interpreting medical images is essential, especially for the organs that have significant inter-individual variation but bilateral symmetry in a person, such as mastoid air cells. In this study, we developed a deep learning algorithm to detect bilateral mastoid abnormalities simultaneously on mastoid anterior–posterior (AP) views with symmetry evaluation. The developed algorithm showed better diagnostic performance in diagnosing mastoiditis on mastoid AP views than the algorithm trained by single-side mastoid radiographs without symmetry evaluation and similar to superior diagnostic performance to head and neck radiologists. The results of this study show the possibility of evaluating symmetry in medical images with deep learning algorithms.

Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes.

Significant interindividual and intraindividual variations on cytochrome P450 (CYP)-mediated drug metabolism exist in the general population globally. Genetic polymorphisms are one of the major contribution factors for interindividual variations, but epigenetic mechanisms mainly contribute to intraindividual variations, including DNA methylation, histone modifications, microRNAs, and long non-coding RNAs. The current review provides analysis of advanced knowledge in the last decade on contributions of epigenetic mechanisms to intraindividual variations on CYP-mediated drug metabolism in several situations, including (1) ontogeny, the developmental changes of CYP expression in individuals from neonates to adults; (2) increased activities of CYP enzymes induced by drug treatment; (3) increased activities of CYP enzymes in adult ages induced by drug treatment at neonate ages; and (4) decreased activities of CYP enzymes in individuals with drug-induced liver injury (DILI). Furthermore, current challenges, knowledge gaps, and future perspective of the epigenetic mechanisms in development of CYP pharmacoepigenetics are discussed. In conclusion, epigenetic mechanisms have been proven to contribute to intraindividual variations of drug metabolism mediated by CYP enzymes in age development, drug induction, and DILI conditions. The knowledge has helped understanding how intraindividual variation are generated. Future studies are needed to develop CYP-based pharmacoepigenetics to guide clinical applications for precision medicine with improved therapeutic efficacy and reduced risk of adverse drug reactions and toxicity. SIGNIFICANCE STATEMENT: Understanding epigenetic mechanisms in contribution to intraindividual variations of CYP-mediated drug metabolism may help to develop CYP-based pharmacoepigenetics for precision medicine to improve therapeutic efficacy and reduce adverse drug reactions and toxicity for drugs metabolized by CYP enzymes.

The Role of The Predominant Polarity on Neurocognitive and Social Cognitive Dysfunctions in Patients with Bipolar Disorder

IntroductionBipolar disorder (BD) is characterized by significant inter-individual variation in terms of course and outcome. The most important factors associated with the outcome are subsyndromal depression and cognitive disability. Predominant polarity (PP), which is a proposed course specifier for BD, can be associated with various clinical differences such as psychotic feature, suicidality, hospitalization, while it is thought to be associated with the severity of cognitive impairment.ObjectivesTo elucidate the role of the predominant polarity on cognitive dysfunction in patients with BD.MethodsPatients with BD in remission (n=84) and healthy control volunteers (HC, n=27) participated in the study. Patients were divided into 3 subgroups according to their PP characteristics: manic (MPP, n=31), depressive (DPP, n=25), and undetermined (UPP, n=28). Structured Clinical Interview for DSM-5 Disorders-Clinician Version (SCID-5/CV), WAIS-R-Vocabulary Subtest, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Young Mania Rating Scale, Rey’s Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT), Stroop Test (ST), WMS-R Visual Reproduction Subtest, Controlled Oral Word Association Test (COWAT), Auditory Consonant Trigrams Test (ACT), Reading the Mind in the Eyes Test (RMET), Hinting Test (HT), Wisconsin Card Sorting Test (WCST), and Conners Continuous Performance Test (CCPT) were administered. Scores that do not show normal distribution were transformed using the two-step normalization method. Principal component analysis (PCA) with direct oblimin rotation was applied as a dimension reduction technique to identify different neurocognitive domains. Single-factorial PCA was also applied to calculate global cognition scores.ResultsIn MPP group compared to HC, worse performance was observed in ACT (d=1.24), COWAT (d=1.16), RMET (d=1.03), HT (d=1.78), WCST correct answers (d=0.99), CCPT correct target section (d=0.99) and a prolongation in TMT-A (d=1.00). Compared to DPP, MPP had a weak performance in COWAT (d=0.89), RMET (d=0.86) and HT (d=1.00). MPP (d=1.18) and UPP (d=1.03) groups showed deterioration in processing speed compared to HC. MPP group showed impairment in working memory (d=1.17) and attention (d=0.70) compared to HC. In problem-solving and reasoning, deterioration was found in MPP compared to HC (d=1.16) and UPP (d=0.67), also in DPP compared to HC (d=0.74).ConclusionsThe MPP group yielded more severe cognitive impairment in verbal fluency and social cognition tests compared to DPP. Predominant polarity may also be related to cognitive impairment patterns seen in BD.Disclosure of InterestNone Declared

Cardiovascular Toxicity Induced by Vascular Endothelial Growth Factor Inhibitors.

Cardiotoxicity is an important side effect of vascular endothelial growth factor (VEGF) inhibitors therapy used in the treatment of various malignancies, leading to increased morbidity and mortality. Arterial hypertension, cardiac ischemia with the acceleration of atherosclerosis, arrhythmias, myocardial dysfunction and thromboembolic disease are the most feared cardiovascular adverse reactions due to VEGF inhibitors. Susceptibility for the occurrence of VEGF inhibitors-induced cardiotoxicity has multifactorial determinants, with a significant inter-individual variation. Baseline cardiovascular risk assessment of the patient, type and stage of cancer, dose and duration of VEGF inhibitors treatment and adjuvant chemotherapy or radiotherapy are the main predictors for cardiotoxicity. The role of the cardio-oncology team becomes essential for achieving maximum therapeutic anti-angiogenic effects with minimum cardiovascular side effects. This review will summarize the incidence, risk factors, mechanisms, management and treatment of VEGF inhibitors-induced cardiovascular toxicity.

Quantifying faecal cortisol metabolites in rescued orphaned koala joeys undergoing rehabilitation†

Mortality is prevalent in koala joeys being hand reared/rehabilitated, with little knowledge about the causes of such high rates of mortality. Wildlife hospitals/rehabilitation expose koala joeys to novel husbandry environments that create stressful stimulus for these animals. Furthermore, loss of the mother and/or being raised by a human can be threatening and/or stressful. The hypothalamic–pituitary–adrenal axis plays a vital role in mediating the stress endocrine response of vertebrate species including marsupials (by adrenocortical release of glucocorticoids such as cortisol), however, there are no studies that quantify cortisol metabolites in koala joeys. To contribute to this dearth of knowledge, the primary aim of this study was to quantify the levels of faecal cortisol metabolites (as an index of physiological stress) in koala joeys undergoing rehabilitation. A total of 39 faecal samples were collected from four koala joeys admitted at a wildlife hospital in New South Wales, Australia. The samples were processed and analysed for faecal cortisol metabolites (FCM) using a polyclonal R4866 cortisol enzyme-immunoassay which has been previously biologically validated in adult koalas. The results indicated that there was significant inter-individual variation in FCM concentrations among the joeys, however, these differences were not based on the sex of the joeys. The average FCM concentration among joeys varied from 18.34 to 44.18 ng/g. Our study provides the first record of physiological stress in male and female rescued koala joeys by indexing FCM concentrations during rehabilitation.