Ongoing effects of preterm birth on the dopaminergic and noradrenergic pathways in the frontal cortex and hippocampus of guinea pigs.

Children born preterm have an increased likelihood of developing neurobehavioral disorders such as attention-deficit hyperactivity disorder (ADHD) and anxiety. These disorders have a sex bias, with males having a higher incidence of ADHD, whereas anxiety disorder tends to be more prevalent in females. Both disorders are underpinned by imbalances to key neurotransmitter systems, with dopamine and noradrenaline in particular having major roles in attention regulation and stress modulation. Preterm birth disturbances to neurodevelopment may affect this neurotransmission in a sexually dimorphic manner. Time-mated guinea pig dams were allocated to deliver by preterm induction of labor (gestational age 62 [GA62]) or spontaneously at term (GA69). The resultant offspring were randomized to endpoints as neonates (24 h after term-equivalence age) or juveniles (corrected postnatal day 40, childhood equivalence). Relative mRNA expressions of key dopamine and noradrenaline pathway genes were examined in the frontal cortex and hippocampus and quantified with real-time PCR. Myelin basic protein and neuronal nuclei immunostaining were performed to characterize the impact of preterm birth. Within the frontal cortex, there were persisting reductions in the expression of dopaminergic pathway components that occurred in preterm males only. Conversely, preterm-born females had increased expression of key noradrenergic receptors and a reduction of the noradrenergic transporter within the hippocampus. This study demonstrated that preterm birth results in major changes in dopaminergic and noradrenergic receptor, transporter, and synthesis enzyme gene expression in a sex- and region-based manner that may contribute to the sex differences in susceptibility to neurobehavioral disorders. These findings highlight the need for the development of sex-based treatments for improving these conditions.

Potential for a cerebellar role in moderate-late preterm associated behavioural disorders.

Preterm birth is known to cause impaired cerebellar development, and this is associated with the development of neurobehavioral disorders. This review aims to identify the mechanisms through which preterm birth impairs cerebellar development and consequently, increases the risk of developing neurobehavioral disorders. The severity of these disorders is directly related to the degree of prematurity, but it is also evident that even late preterm births are at significantly increased risk of developing serious neurobehavioral disorders. Preterm birth is associated with hypoxic events and increased glutamatergic tone within the neonatal brain which contribute to excitotoxic damage. The cerebellum is a dense glutamatergic region which undergoes relatively late neurodevelopment up to and beyond birth. Evidence indicates that the cerebellum forms reciprocal connections to regions important in behaviour regulation such as the limbic system and frontal cortex. Studies using fMRI (functional magnetic resonance Imaging), BOLD (blood oxygen level dependent) response and morphology studies in humans show the cerebellum is often involved in disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. The vulnerability of the cerebellum to preterm birth insult and its connections to behaviour associated brain regions implicates it in the development of neurobehavioral disorders. Protection against preterm associated insults on the cerebellum may provide a novel avenue through which ADHD and anxiety can be reduced in children born preterm.

Advancing mouse models for transplantation research.

Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field. They also discussed the generation of new models that incorporate environmental and genetic variables affecting clinical outcomes as potentially important. If implemented, these strategies are expected to improve the reproducibility of mouse studies and increase their translation to clinical trials and, ideally, new Food and Drug Administration-approved drugs.

A Hospital-Wide Open-Label Cluster Crossover Pragmatic Comparative Effectiveness Randomized Trial Comparing Normal Saline to Ringer's Lactate: Protocol and Statistical Analysis Plan of The FLUID Trial.

BACKGROUND: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids given to hospitalized patients. Despite concern about possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function, and death), few large multicenter randomized trials focused on critically ill patients have compared these fluids. Uncertainty exists about the effects of these fluids on clinically important outcomes across all hospitalized patients. OBJECTIVE: The FLUID trial is a pragmatic, multicenter, 2×2 cluster crossover comparative effectiveness randomized trial that aims to evaluate the effectiveness of a hospital-wide policy that stocks either NS or RL as the main crystalloid fluid in 16 hospitals across Ontario, Canada. METHODS: All hospitalized adult and pediatric patients (anticipated sample size 144,000 patients) with an incident admission to the hospital over the course of each study period will be included. Either NS or RL will be preferentially stocked throughout the hospital for 12 weeks before crossing to the alternate fluid for the subsequent 12 weeks. The primary outcome is a composite of death and hospital readmission within 90 days of hospitalization. Secondary outcomes include death, hospital readmission, dialysis, reoperation, postoperative reintubation, length of hospital stay, emergency department visits, and discharge to a facility other than home. All outcomes will be obtained from health administrative data, eliminating the need for individual case reports. The primary analysis will use cluster-level summaries to estimate cluster-average treatment effects. RESULTS: The statistical analysis plan has been prepared "a priori" in advance of receipt of the trial data set from ICES and any analyses. CONCLUSIONS: We describe the protocol and statistical analysis plan for the evaluation of primary and secondary outcomes for the FLUID trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04512950; https://classic.clinicaltrials.gov/ct2/show/NCT04512950. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51783.

A model to predict level of adherence to prehabilitation in older adults with frailty having cancer surgery.

PURPOSE: Preoperative exercise could improve postoperative outcomes for people with frailty; however, little is known about how to predict older people's adherence to exercise before surgery (i.e., prehabilitation) programs. Our objective was to derive and validate a model to predict prehabilitation adherence in older adults living with frailty before cancer surgery. METHODS: This was a nested prospective cohort study of older adults with frailty having cancer surgery who participated in a randomized controlled trial of home-based prehabilitation compared with standard perioperative care. We constructed a multivariable ordinary least squares linear regression model to predict adherence. Covariates were selected a priori based on clinical expertise and systematic review. Optimism was estimated through internal validation using bootstrap resampling. RESULTS: The derivation cohort consisted of 95 participants in the intervention arm of the trial. Percent adherence ranged from 0% to 100%, with a mean (standard deviation) of 61 (34)%. Previous physical activity and age were the only predictors significant at the 5% level. CONCLUSION: A prespecified multivariable model may help to explain a modest degree of variation in prehabilitation adherence in older people with frailty. While this model is an important step toward personalizing prehabilitation support, this study was limited by a small sample size and future research is needed to better understand personalized prediction of prehabilitation adherence in older people with frailty.

RéSUMé: OBJECTIF: L'exercice préopératoire pourrait améliorer les issues postopératoires pour les personnes fragilisées; cependant, on ne sait que peu de choses sur la façon de prédire l'observance des personnes âgées à faire de l'exercice avant leur chirurgie (c.-à-d. à suivre des programmes de préadaptation). Notre objectif était de définir et de valider un modèle pour prédire l'observance de la préadaptation chez les personnes âgées fragilisées avant une chirurgie oncologique. MéTHODE: Il s'agissait d'une étude de cohorte prospective imbriquée auprès de personnes âgées fragilisées subissant une chirurgie oncologique qui ont participé à une étude randomisée contrôlée sur la préadaptation à domicile par rapport aux soins périopératoires standard. Nous avons construit un modèle de régression linéaire des moindres carrés ordinaires multivariés pour prédire l'observance. Les covariables ont été sélectionnées a priori sur la base de notre expertise clinique et d'une revue systématique. L'optimisme a été estimé par validation interne à l'aide d'une méthode de rééchantillonnage type « bootstrap ¼. RéSULTATS: La cohorte de dérivation comprenait 95 participant·es dans le volet intervention de l'étude. Le pourcentage d'observance variait de 0 % à 100 %, avec une moyenne (écart type) de 61 (34) %. L'activité physique antérieure et l'âge étaient les seuls prédicteurs significatifs au seuil de 5 %. CONCLUSION: Un modèle multivarié prédéfini peut aider à expliquer un degré modeste de variation dans l'observance de la préadaptation chez les personnes âgées fragilisées. Bien que ce modèle soit une étape importante vers la personnalisation du soutien à la préadaptation, cette étude a été limitée par un échantillon de petite taille; des recherches futures sont nécessaires pour mieux comprendre la prédiction personnalisée de l'observance de la préadaptation chez les personnes âgées fragilisées.

"My Biggest Fear Is She'll Die Alone": Care Partner Perspectives of Institutional COVID-19 Visitor Restrictions in Ontario, Canada.

In March 2020, the Government of Ontario, Canada implemented public health measures, including visitor restrictions in institutional care settings, to protect vulnerable populations, including older adults (> 65 years), against COVID-19 infection. Prior research has shown that visitor restrictions can negatively influence older adults' physical and mental health and can cause increased stress and anxiety for care partners. This study explores the experiences of care partners separated from the person they care for because of institutional visitor restrictions during the COVID-19 pandemic. We interviewed 14 care partners between the ages of 50 and 89; 11 were female. The main themes that emerged were changing public health and infection prevention and control policies, shifting care partner roles as a result of visitor restrictions, resident isolation and deterioration from the care partner perspective, communication challenges, and reflections on the impacts of visitor restrictions. Findings may be used to inform future health policy and system reforms.

Prenatal Stress Induces Translational Disruption Associated with Myelination Deficits.

Disruptions to neurodevelopment are known to be linked to behavioral disorders in childhood and into adulthood. The fetal brain is extremely vulnerable to stimuli that alter inhibitory GABAergic pathways and critical myelination processes, programing long-term neurobehavioral disruption. The maturation of the GABAergic system into the major inhibitory pathway in the brain and the development of oligodendrocytes into mature cells capable of producing myelin are integral components of optimal neurodevelopment. The current study aimed to elucidate prenatal stress-induced mechanisms that disrupt these processes and to delineate the role of placental pathways in these adverse outcomes. Pregnant guinea pig dams were exposed to prenatal stress with strobe light exposure for 2 h/day on gestational age (GA) 35, 40, 45, 50, 55, 60, and 65, and groups of fetuses and placentae were collected after the stress exposure on GA40, GA50, GA60, and GA69 (term). Fetal plasma, placental, and brain tissue were collected for allopregnanolone and cortisol quantification with ELISA. Relative mRNA expression of genes of specific pathways of interest was examined with real-time PCR in placental and hippocampal tissue, and myelin basic protein (MBP) was quantified immunohistochemically in the hippocampus and surrounding regions for assessment of mature myelin. Prenatal stress in mid-late gestation resulted in disruptions to the translational machinery responsible for the production of myelin and decreased myelin coverage in the hippocampus and surrounding regions. The male placenta showed an initial protective increase in allopregnanolone concentrations in response to maternal psychosocial stress. The male and female placentae had a sex-dependent increase in neurosteroidogenic enzymes at term following prenatal stress. Independent from exposure to prenatal stress, at gestational day 60 - a critical period for myelin development, the placentae of female fetuses had increased capability of preventing cortisol transfer to the fetus through expression of 11-beta-hydroxysteroid dehydrogenase types 1 and 2. The deficits early in the process of maturation of myelination indicate that the reduced myelination observed at childhood equivalence in previous studies begins in fetal life. This negative programing persists into childhood, potentially due to dysregulation of MBP translation processes. Expression patterns of neurosteroidogenic enzymes in the placenta at term following stress may identify at-risk fetuses that have been exposed to a stressful in utero environment.

Dual isolation of primary neurons and oligodendrocytes from guinea pig frontal cortex.

Primary cell culture is a technique that is widely used in neuroscience research to investigate mechanisms that underlie pathologies at a cellular level. Typically, mouse or rat tissue is used for this process; however, altricial rodent species have markedly different neurodevelopmental trajectories comparatively to humans. The use of guinea pig brain tissue presents a novel aspect to this routinely used cell culture method whilst also allowing for dual isolation of two major cell types from a physiologically relevant animal model for studying perinatal neurodevelopment. Primary neuronal and oligodendrocyte cell cultures were derived from fetal guinea pig's frontal cortex brain tissue collected at a gestational age of 62 days (GA62), which is a key time in the neuronal and oligodendrocyte development. The major advantage of this protocol is the ability to acquire both neuronal and oligodendrocyte cellular cultures from the frontal cortex of one fetal brain. Briefly, neuronal cells were grown in 12-well plates initially in a 24-h serum-rich medium to enhance neuronal survival before switching to a serum-free media formulation. Oligodendrocytes were first grown in cell culture flasks using a serum-rich medium that enabled the growth of oligodendrocyte progenitor cells (OPCs) on an astrocyte bed. Following confluency, the shake method of differential adhesion and separation was utilized via horizontally shaking the OPCs off the astrocyte bed overnight. Therefore, OPCs were plated in 12-well plates and were initially expanded in media supplemented with growth hormones, before switching to maturation media to progress the lineage to a mature phenotype. Reverse transcription-polymerase chain reaction (RT-PCR) was performed on both cell culture types to analyze key population markers, and the results were further validated using immunocytochemistry. Primary neurons displayed the mRNA expression of multiple neuronal markers, including those specific to GABAergic populations. These cells also positively stained for microtubule-associated protein 2 (MAP2; a dendritic marker specific to neurons) and NeuN (a marker of neuronal cell bodies). Primary oligodendrocytes expressed all investigated markers of the oligodendrocyte lineage, with a majority of the cells displaying an immature oligodendrocyte phenotype. This finding was further confirmed with positive oligodendrocyte transcription factor (OLIG2) staining, which serves as a marker for the overall oligodendrocyte population. This study demonstrates a novel method for isolating both neurons and oligodendrocytes from the guinea pig brain tissue. These isolated cells display key markers and gene expression that will allow for functional experiments to occur and may be particularly useful in studying neurodevelopmental conditions with perinatal origins.

Identifying relative efficacy of components of prehabilitation in adult surgical patients: protocol for a systematic review and component network meta-analysis.

INTRODUCTION: Prehabilitation is a high-priority intervention for patients, the public, clinicians and health systems. However, existing knowledge syntheses are generally low quality and do not provide insights regarding the relative efficacy of different prehabilitation components (eg, exercise, nutrition, psychosocial or cognitive interventions). The objective of the planned review is to evaluate the relative efficacy of different prehabilitation components to inform current care, implementation and future research. METHODS AND ANALYSIS: We will perform a systematic review and component network meta-analysis (CNMA). We will use a peer-reviewed search strategy to identify all randomised trials of prehabilitation in adult surgical patients from Ovid Medline, Embase, the CINAHL, PsycINFO, Web of Science and the Cochrane Central Register of Controlled Trials, along with grey literature. All stages of the review and data extraction process will be performed in duplicate, following recommended best practices. To compare the relative efficacy of different prehabilitation components (prespecified as exercise, nutrition, psychosocial or cognitive interventions), we will use CNMA, an extension of network meta-analysis that allows estimation of the contributions to efficacy of each component of a multicomponent intervention through direct and indirect comparisons. We will use additive CNMA models for critical outcomes (postoperative complications, patient-reported recovery, physical recovery and length of stay); standard care will be the common reference condition. Pre-specified sensitivity and subgroup analyses will be conducted. ETHICS AND DISSEMINATION: This review of published data does not require ethical review. Results will be disseminated via scientific conferences, peer-reviewed publications, social and traditional media and via our research network to target partners and organisations.

Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment.

Background: Preterm birth can lead to brain injury and currently there are no targeted therapies to promote postnatal brain development and protect these vulnerable neonates. We have previously shown that the neurosteroid-analogue ganaxolone promotes white matter development and improves behavioural outcomes in male juvenile guinea pigs born preterm. Adverse side effects in this previous study necessitated this current follow-up dosing study, where a focus was placed upon physical wellbeing during the treatment administration and markers of neurodevelopment at the completion of the treatment period. Methods: Time-mated guinea pigs delivered preterm (d62) by induction of labour or spontaneously at term (d69). Preterm pups were randomized to receive no treatment (Prem-CON) or ganaxolone at one of three doses [0.5 mg/kg ganaxolone (low dose; LOW-GNX), 1.0 mg/kg ganaxolone (mid dose; MID-GNX), or 2.5 mg/kg ganaxolone (high dose; HIGH-GNX) in vehicle (45% ß-cyclodextrin)] daily until term equivalence age. Physical parameters including weight gain, ponderal index, supplemental feeding, and wellbeing (a score based on respiration, activity, and posture) were recorded throughout the preterm period. At term equivalence, brain tissue was collected, and analysis of hippocampal neurodevelopment was undertaken by immunohistochemistry and RT-PCR. Results: Low and mid dose ganaxolone had some impacts on early weight gain, supplemental feeding, and wellbeing, whereas high dose ganaxolone significantly affected all physical parameters for multiple days during the postnatal period when compared to the preterm control neonates. Deficits in the preterm hippocampus were identified using neurodevelopmental markers including mRNA expression of oligodendrocyte lineage cells (CSPG4, MBP), neuronal growth (INA, VEGFA), and the GABAergic/glutamatergic system (SLC32A1, SLC1A2, GRIN1, GRIN2C, DLG4). These deficits were not affected by ganaxolone at the doses used at the equivalent of normal term. Conclusion: This is the first study to investigate the effects of a range of doses of ganaxolone to improve preterm brain development. We found that of the three doses, only the highest dose of ganaxolone (2.5 mg/kg) impaired key indicators of physical health and wellbeing over extended periods of time. Whilst it may be too early to see improvements in markers of neurodevelopment, further long-term study utilising the lower doses are warranted to assess functional outcomes at ages when preterm birth associated behavioural disorders are observed.

Predictors of adherence to prescribed exercise programs for older adults with medical or surgical indications for exercise: a systematic review.

BACKGROUND AND OBJECTIVES: Prescribed exercise to treat medical conditions and to prepare for surgery is a promising intervention to prevent adverse health outcomes for older adults; however, adherence to exercise programs may be low. Our objective was to identify and grade the quality of predictors of adherence to prescribed exercise in older adults. METHODS: Prospective observational and experimental studies were identified using a peer-reviewed search strategy applied to MEDLINE, EMBASE, Cochrane, and CINAHL from inception until October 6, 2020. Following an independent and duplicate review of titles, abstracts, and full texts, we included prospective studies with an average population age >65 years, where exercise was formally prescribed for a medical or surgical condition. We excluded studies where exercise was prescribed for a chronic musculoskeletal condition. Risk of bias was assessed using the Quality in Prognostic studies tool or Cochrane risk of bias tool, as appropriate. Predictors of adherence were identified and graded for quality using an adaptation of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework for predictor studies. RESULTS: We included 19 observational studies and 4 randomized controlled trials (n=5785) Indications for exercise included cardiac (n=6), pulmonary rehabilitation (n=7), or other (n=10; surgical, medical, and neurologic). Of the 10 studies that reported adherence as the percent of prescribed sessions completed, average adherence was 80% (range 60-98%; standard deviation (SD) 11%). Of the 10 studies that reported adherence as a categorical threshold demarking adherent vs not adherent, average adherence was 57.5% (range 21-83%; SD 21%). Moderate-quality evidence suggested that positive predictors of adherence were self-efficacy and good self-rated mental health; negative predictors were depression (high quality) and distance from the exercise facility. Moderate-quality evidence suggested that comorbidity and age were not predictive of adherence. CONCLUSIONS: These findings can inform the design of future exercise programs as well as the identification of individuals who may require extra support to benefit from prescribed exercise. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018108242.

Evaluating changes in GABAergic and glutamatergic pathways in early life following prenatal stress and postnatal neurosteroid supplementation.

BACKGROUND: A correct balance of activity of the GABA and glutamate systems is vital for optimal neurodevelopment and general CNS function, and the dysregulation of this balance has been implicated in a number of neurological conditions. Maternal exposure to stressors is known to have long lasting, deleterious impacts on neurobehaviour, and similarly, results in dysregulation of inhibitory and excitatory pathways in the offspring. The current study aimed to examine effects on these pathways in a guinea pig model of prenatal stress and to elucidate whether increased neuroprotective support by postnatal neurosteroid supplementation would ameliorate adverse outcomes. METHODS: Prenatal stress was achieved by exposing pregnant guinea pigs dams to a strobe light for 2hrs/day on gestational age (GA) 50, 55, 60 and 65. Dams were allowed to spontaneously deliver (~GA70) and pups were orally administered either allopregnanolone analogue, ganaxolone (5 mg/kg/day in 45% cyclodextrin), the translocator protein (TSPO) agonist, emapunil (XBD173; 0.3 mg/kg/day in 1% tragacanth gum) or vehicle on postnatal days (PND) 1-7. Hippocampal samples were collected at PND30 to measure relative mRNA expression of components involved in the inhibitory GABAergic pathway and exctitatory glutamatergic pathway by real-time PCR. GABAergic interneurons were quantified by assessing immunohistochemical protein expression of markers parvalbumin, calbindin and calretinin. RESULTS: mRNA expression of GABAergic pathway components at one week of age indicated immature expression profiles of the GABAA receptors as well as decreased GABA synthesis and transport suggesting reduced extrasynaptically-mediated tonic inhibition. Expression profiles of the pathways examined evolved between one week and one month of age but an imbalance in inhibitory/excitatory components persisted. The allopregnanolone analogue ganaxolone offered some protection against excitotoxicity in female hippocampus, however neurosteroid supplementation with ganaxolone or emapunil were unable to fully correct the GABAergic/glutamatergic imbalance observed following prenatal stress. CONCLUSION: Prenatal stress leads to programmed lasting effects on the major inhibitory and excitatory pathways in the guinea pig brain that continue evolving between the equivalent of early and late childhood. Neurosteroid therapies particularly improved outcomes in females. Further studies are required to identify additional therapeutic targets that are able to fully restore imbalances in the excitatory and inhibitory systems, which may act to prevent development of childhood behavioural disorders.

Association between frailty and patient outcomes after cancer surgery: a population-based cohort study.

BACKGROUND: Frailty is associated with poor postoperative outcomes, but existing data do not describe frailty's interaction with tumour characteristics at the time of cancer surgery. Our objective was to estimate the association between frailty and long-term survival, and to explore any interaction with tumour stage and grade. METHODS: This was a population-based cohort study conducted using linked provincial health administrative data in Ontario, Canada (2009-20). Using a cancer registry, we identified adults having elective cancer surgery. Frailty was measured using a validated index (range 0-1; higher score=greater frailty). Associations between frailty and long-term postoperative survival (primary outcome) were estimated using proportional hazards regression. Secondary outcomes were length of stay, discharge destination, days alive at home, and healthcare costs. RESULTS: We identified and included 52 012 patients. Mean frailty score was 0.13 (standard deviation 0.07). During follow-up, 19 378 (37.3%) patients died. After adjustment for risk factors, each 10% increase in frailty was associated with a 1.60-fold relative decrease in survival (95% confidence interval: 1.56-1.64). The frailty-survival association was strongest for patients with lower stage and grade cancers. Increased frailty was associated with longer hospital stays (3 days), fewer days alive and at home (42 days yr-1), more frequent discharge to a nursing facility (2.38-fold), and increased healthcare costs ($6048). CONCLUSIONS: Patient frailty is associated with decreased long-term survival after cancer surgery. The association is stronger for early-stage and -grade cancers, which would otherwise have a better survival prognosis.

The Association of Frailty with Outcomes after Cancer Surgery: A Systematic Review and Metaanalysis.

BACKGROUND: Cancer is common in older adults, who often have concurrent frailty. Frailty is a strong predictor of adverse outcomes in surgical patients. Our objective is to systematically review the association of frailty with postoperative mortality and other adverse outcomes in adult patients who have undergone nonemergency cancer surgery. METHODS: After registration (CRD42020171163), we systematically reviewed PubMed, MEDLINE, EMBASE, and CINAHL databases to identify all studies reporting an association between a preoperative frailty measurement and a relevant outcome (primary: all-cause mortality in-hospital or within 30 days of surgery; secondary outcomes: postoperative complications, length of stay, discharge disposition, mortality between 30 days and 1 year, postoperative function, and delirium). All stages of the review were completed in duplicate. Risk of bias was assessed using the Quality in Prognostic Studies (QUIPS) tool. Metaanalysis was used to pool effect estimates using random-effects models. RESULTS: A total of 2877 studies were identified, and 71 were included. Frailty was significantly associated with mortality within 30 days (adjusted odds ratio (OR) 3.02, 95% confidence interval (CI) 1.77-5.15), adverse discharge disposition (adjusted OR 2.14, 95% CI 1.52-3.02), postoperative complications (adjusted OR 2.39, 95% CI 1.64-3.49), longer-term mortality (unadjusted OR 4.32, 95% CI 2.15-8.67), and length of stay (mean difference 2.30, 95% CI 1.10-3.50). The number of studies presenting adequately adjusted estimates was small. Findings may be limited due to publication bias. CONCLUSIONS: In adults having elective cancer surgery, frailty is strongly associated with adverse health outcomes. Preoperative frailty assessment should be considered in prognostication.

Prehabilitation in adult patients undergoing surgery: an umbrella review of systematic reviews.

BACKGROUND: The certainty that prehabilitation improves postoperative outcomes is not clear. The objective of this umbrella review (i.e. systematic review of systematic reviews) was to synthesise and evaluate evidence for prehabilitation in improving health, experience, or cost outcomes. METHODS: We performed an umbrella review of prehabilitation systematic reviews. MEDLINE, Embase, Cochrane, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Joanna Briggs Institute's database, and Web of Science were searched (inception to October 20, 2020). We included all systematic reviews of elective, adult patients undergoing surgery and exposed to a prehabilitation intervention, where health, experience, or cost outcomes were reported. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. Primary syntheses of any prehabilitation were stratified by surgery type. RESULTS: From 1412 titles, 55 systematic reviews were included. For patients with cancer undergoing surgery who participate in any prehabilitation, moderate certainty evidence supports improvements in functional recovery. Low to very low certainty evidence supports reductions in complications (mixed, cardiovascular, and cancer surgery), non-home discharge (orthopaedic surgery), and length of stay (mixed, cardiovascular, and cancer surgery). There was low to very low certainty evidence that exercise prehabilitation reduces the risk of complications, non-home discharge, and length of stay. There was low to very low certainty evidence that nutritional prehabilitation reduces risk of complications, mortality, and length of stay. CONCLUSIONS: Low certainty evidence suggests that prehabilitation may improve postoperative outcomes. Future low risk of bias, randomised trials, synthesised using recommended standards, are required to inform practice. Optimal patient selection, intervention design, and intervention duration must also be determined.

Neurosteroid-based intervention using Ganaxolone and Emapunil for improving stress-induced myelination deficits and neurobehavioural disorders.

BACKGROUND: Prenatal stress is associated with long-term disturbances in white matter development and behaviour in children, such as attention deficit hyperactivity disorder (ADHD) and anxiety. Oligodendrocyte maturation and myelin formation is a tightly orchestrated process beginning during gestation, and therefore is very vulnerable to the effects of maternal prenatal stresses in mid-late pregnancy. The current study aimed to examine the effects of prenatal stress on components of the oligodendrocyte lineage to identify the key processes that are disrupted and to determine if postnatal therapies directed at ameliorating white matter deficits also improve behavioural outcomes. METHODS: Pregnant guinea pig dams were exposed to control-handling or prenatal stress with strobe light exposure for 2hrs/day on gestational age (GA) 50, 55, 60 and 65, and allowed to spontaneously deliver ~GA70. Pups were administered oral ganaxolone (5 mg/kg/day in 45% cyclodextrin) or the TSPO agonist, emapunil (XBD173; 0.3 mg/kg/day in 1% tragacanth gum) or vehicle, on postnatal days (PND) 1-7. Behavioural outcomes were assessed using open field and elevated plus maze testing on PND7 and PND27. Hippocampal samples were collected at PND30 to assess markers of oligodendrocyte development through assessment of total oligodendrocytes (OLIG2) and mature cells (myelin basic protein; MBP), and total neurons (NeuN) by immunostaining. Real-time PCR was conducted on hippocampal regions to assess markers of the oligodendrocyte lineage, markers of neurogenesis and components of the neurosteroidogenesis pathway. Plasma samples were collected for steroid quantification of cortisol, allopregnanolone, progesterone and testosterone by ELISA. RESULTS: Prenatal stress resulted in hyperactivity in male offspring, and anxiety-like behaviour in female offspring in the guinea pig at an age equivalent to late childhood. Postnatal ganaxolone and emapunil treatment after prenatal stress restored the behavioural phenotype to that of control in females only. The oligodendrocyte maturation lineage, translation of MBP mRNA-to-protein, and neurogenesis were disrupted in prenatally-stressed offspring, resulting in a decreased amount of mature myelin. Emapunil treatment restored mature myelin levels in both sexes, and reversed disruptions to the oligodendrocyte lineage in female offspring, an effect not seen with ganaxolone treatment. CONCLUSION: The marked and persisting behavioural and white matter perturbations observed in a clinically relevant guinea pig model of prenatal stress highlights the need for postnatal interventions that increase myelin repair and improve long-term outcomes. The effectiveness of emapunil treatment in restoring female offspring behaviour, and promoting maturation of myelin indicates that early therapeutic interventions can reverse the damaging effects of major stressful events in pregnancy. Further studies optimising target mechanisms and dosing are warranted.

A Systematic Review and Meta-Analysis of Preoperative Frailty Instruments Derived From Electronic Health Data.

BACKGROUND: Frailty is a strong predictor of adverse outcomes in the perioperative period. Given the increasing availability of electronic medical data, we performed a systematic review and meta-analysis with primary objectives of describing available frailty instruments applied to electronic data and synthesizing their prognostic value. Our secondary objectives were to assess the construct validity of frailty instruments that have been applied to perioperative electronic data and the feasibility of electronic frailty assessment. METHODS: Following protocol registration, a peer-reviewed search strategy was applied to Medline, Excerpta Medica dataBASE (EMBASE), Cochrane databases, and the Comprehensive Index to Nursing and Allied Health literature from inception to December 31, 2019. All stages of the review were completed in duplicate. The primary outcome was mortality; secondary outcomes included nonhome discharge, health care costs, and length of stay. Effect estimates adjusted for baseline illness, sex, age, procedure, and urgency were of primary interest; unadjusted and adjusted estimates were pooled using random-effects models where appropriate or narratively synthesized. Risk of bias was assessed. RESULTS: Ninety studies were included; 83 contributed to the meta-analysis. Frailty was defined using 22 different instruments. In adjusted data, frailty identified from electronic data using any instrument was associated with a 3.57-fold increase in the odds of mortality (95% confidence interval [CI], 2.68-4.75), increased odds of institutional discharge (odds ratio [OR], 2.40; 95% CI, 1.99-2.89), and increased costs (ratio of means, 1.54; 95% CI, 1.46-1.63). Most instruments were not multidimensional, head-to-head comparisons were lacking, and no feasibility data were reported. CONCLUSIONS: Frailty status derived from electronic data provides prognostic value as it is associated with adverse outcomes, even after adjustment for typical risk factors. However, future research is required to evaluate multidimensional instruments and their head-to-head performance and to assess their feasibility and clinical impact.

Impaired Oligodendrocyte Development Following Preterm Birth: Promoting GABAergic Action to Improve Outcomes.

Preterm birth is associated with poor long-term neurodevelopmental and behavioral outcomes, even in the absence of obvious brain injury at the time of birth. In particular, behavioral disorders characterized by inattention, social difficulties and anxiety are common among children and adolescents who were born moderately to late preterm (32-37 weeks' gestation). Diffuse deficits in white matter microstructure are thought to play a role in these poor outcomes with evidence suggesting that a failure of oligodendrocytes to mature and myelinate axons is responsible. However, there remains a major knowledge gap over the mechanisms by which preterm birth interrupts normal oligodendrocyte development. In utero neurodevelopment occurs in an inhibitory-dominant environment due to the action of placentally derived neurosteroids on the GABAA receptor, thus promoting GABAergic inhibitory activity and maintaining the fetal behavioral state. Following preterm birth, and the subsequent premature exposure to the ex utero environment, this action of neurosteroids on GABAA receptors is greatly reduced. Coinciding with a reduction in GABAergic inhibition, the preterm neonatal brain is also exposed to ex utero environmental insults such as periods of hypoxia and excessive glucocorticoid concentrations. Together, these insults may increase levels of the excitatory neurotransmitter glutamate in the developing brain and result in a shift in the balance of inhibitory: excitatory activity toward excitatory. This review will outline the normal development of oligodendrocytes, how it is disrupted under excitation-dominated conditions and highlight how shifting the balance back toward an inhibitory-dominated environment may improve outcomes.

Effects of prenatal stress on behavioural and neurodevelopmental outcomes are altered by maternal separation in the neonatal period.

BACKGROUND: Chronic psychosocial stress during pregnancy and/or after birth, and the associated elevation in cortisol, is linked with the onset of behavioural disorders in childhood. Previously, prenatal stress has been shown to reduce neurosteroid pathways in the fetus and the levels of the neurosteroid and GABAA receptor agonist, allopregnanolone. In late gestation, elevated levels of GABAergic activity increases inhibitory tone and protects against excessive excitation. These levels of allopregnanolone may also contribute to promoting myelination, thus stress-induced suppression of protective neurosteroid levels may disrupt neurodevelopmental processes and can result in reduced myelination. The objective of this study was to examine whether prenatal and postnatal stress reduces levels of inhibitory pathways to result in behavioural, myelin, and GABAergic/glutamatergic pathway deficits in the hippocampus at a postnatal time point in the guinea pig equivalent to childhood in humans. METHODS: Pregnant guinea pig dams were exposed to prenatal stress (PRE) with strobe light exposure for 2 h/day on gestational age (GA) 50, 55, 60 and 65 (term is ∼GA70), with postnatal stress (POST) caused by maternal separation for 2 h/day from postnatal day (PND) 1-7), or a double-hit of both stressors (PRE + POST). Control dams and offspring groups (CON) were handled at the same time each day without causing stress. Behavioural outcomes were assessed using open field and elevated plus maze testing on PND27. After euthanasia on PND30, plasma samples were collected for steroid quantification of cortisol, allopregnanolone and progesterone by ELISA. Hippocampal samples were collected to assess markers of oligodendrocyte development and mature cells by myelin basic protein (MBP) immunostaining and GABAergic and glutamatergic pathway component gene expression by real time PCR. RESULTS: Male guinea pig offspring exposed to prenatal stress exhibited hyperactive-like behaviour at childhood equivalence, while female offspring displayed anxious-like behaviour, to a lesser extent. In both sexes, MBP immunostaining was significantly decreased in the hippocampal region following prenatal stress, despite normal levels of MBP mRNA, which suggests a disruption to the MBP protein translation pathway. Many components of the GABAergic and glutamatergic pathways were disrupted following prenatal stress, notably GABAA receptor subunits, GABA production and uptake, glutamate ionotropic and metabotropic receptor subunits and glutamate transport. Following prenatal + postnatal stress, many of the behavioural and neurodevelopmental deficits were improved compared to the prenatal stress only group. CONCLUSION: We conclude that prenatal stress disrupts GABAergic and glutamatergic pathways that may contribute to reduced myelination and subsequent behavioural deficits in the offspring. The deficits seen following prenatal stress are ameliorated when paired with subsequent postnatal stress, which highlights the early postnatal period as an important treatment window.

The Role of Volume in the Perceptibility of Topical Vaginal Formulations: User Sensory Perceptions and Experiences of Heterosexual Couples During Vaginal Sex.

Users' sensory perceptions and experiences (USPEs; perceptibility) of drug formulations can critically impact product adoption and adherence, especially when products rely on appropriate user behaviors (timing of administration, dosing measurement) for effectiveness. The use of topical gel formulations for effective antihuman immunodeficiency virus/sexually transmitted infection (HIV/STI) vaginal microbicides has been associated with messiness and other use-associated challenges, resulting in low adherence. Nonetheless, such formulations remain attractive due to good pharmacokinetics and resulting pharmacodynamics through their volume and surface contact for drug delivery into luminal fluids and mucosa. Consequently, advocates and scientists continue to pursue topical forms [semisolid (e.g., gel, suppository); solid (e.g., film)] to deliver select drugs and offer user choice in HIV/STI prevention. The current data build on previously validated USPE scales evaluating perceptibility of gels with various biophysical/rheological properties. Specifically, increased formulation parameter space adds a new set of properties inherent in quick-dissolving film. We compared film, a product adding no discernable volume to the vaginal environment, to 2 and 3.5 mL hydroxyethyl cellulose gel to consider the impact of volume on user experience. We also examined the USPE scales for evaluation of male sexual partners' experiences. The original USPE scales functioned as expected. Additionally, six new USPE scales were identified in this enhanced parameter space. Significant differences were noted between USPEs in pairwise comparisons, with largest differences between film and high-volume gel. Product developers and behavioral scientists can use these scales to design products, optimizing user experience and maximizing adherence and delivery of efficacious anti-HIV/STI pharmaceuticals. They can be extended to evaluation of additional formulations, devices, and compartments, as well as single- and multipurpose pharmaceuticals. In broader contexts, USPEs could be of value in evaluating formulations and devices to prevent/treat other diseases (e.g., ophthalmologic, dermatologic). Steadfast attention should be given to patient experience, and, where applicable, experiences of partners and/or caregivers.