Use of oxygen therapy for pneumocephalus: a systematic review.

Pneumocephalus is the pathologic collection of air in the intracranial cavity. In sufficient volumes, it can contribute to symptoms ranging from headaches to death. For conservative treatment, oxygen use is commonplace. Although this is an accepted tenet of clinical practice, it is not necessarily founded on robust trials. An electronic search of databases EMBASE and MEDLINE and the Cochrane Library was undertaken as per the 2020 Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) statement. Three articles were included. Although the modes of oxygen delivery were heterogenous (non-rebreather versus endotracheal versus hyperbaric chamber), all studies concluded favorably on the use of oxygen therapy for increased reabsorption of pneumocephalus.

Questionnaire survey on medical futility and termination of resuscitation in cardiac arrest patients among emergency physicians in Hong Kong.

INTRODUCTION: The perceptions of medical futility and decisions about termination of resuscitation (TOR) for out-of-hospital cardiac arrest (OHCA) are highly heterogeneous and dependent on the practice of the attending emergency physicians. The objective of this study was to report and investigate the knowledge, attitudes, and practices regarding medical futility and TOR during management of OHCA in Hong Kong. METHODS: A cross-sectional survey was conducted among emergency medicine physicians in Hong Kong. The questionnaire assessed participants' background, knowledge, attitudes, and behaviours concerning medical futility and TOR in management of OHCA. Composite scores were calculated to reflect knowledge, attitudes, and practices of OHCA treatment. Subgroup analysis and multiple regression analysis were used to explore the relationship between participants' background, knowledge, attitudes, and behaviours. RESULTS: The response rate to this survey was 57% (140/247). Independent predictors of less aggressive resuscitation in OHCA patients included status as a Fellow of the Hong Kong College of Emergency Medicine (ß= -0.314, P=0.028) and being an Advanced Cardiac Life Support instructor (ß= -0.217, P=0.032). There was no difference in aggressiveness of resuscitation in terms of years of clinical experience (ß=0.015, P=0.921), knowledge of TOR (ß=0.057, P=0.509), or attitudes about TOR (ß= -0.103, P=0.214). The correlation between knowledge and attitudes was low (Spearman's coefficient=0.02, P=0.795). CONCLUSION: Clinical practice and behaviour of TOR was not demonstrated to have associations with knowledge or attitude. Status as a Fellow of the Hong Kong College of Emergency Medicine or Advanced Cardiac Life Support instructor were the only two parameters identified that had significant relationships with earlier TOR in medically futile patients with OHCA.

Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.

Neurexin 1 (NRXN1), a presynaptic cell adhesion molecule, is implicated in several neurodevelopmental disorders characterized by synaptic dysfunction including autism, intellectual disability and schizophrenia. To gain insight into NRXN1's involvement in human cortical development we used quantitative real-time PCR to examine the expression trajectories of NRXN1, and its predominant isoforms, NRXN1-α and NRXN1-ß, in prefrontal cortex from fetal stages to aging. In addition, we investigated whether prefrontal cortical expression levels of NRXN1 transcripts are altered in schizophrenia or bipolar disorder in comparison with non-psychiatric control subjects. We observed that all three NRXN1 transcripts were highly expressed during human fetal cortical development, markedly increasing with gestational age. In the postnatal dorsolateral prefrontal cortex, expression levels were negatively correlated with age, peaking at birth until ~3 years of age, after which levels declined markedly to be stable across the lifespan. NRXN1-ß expression was modestly but significantly elevated in the brains of patients with schizophrenia compared with non-psychiatric controls, whereas NRXN1-α expression was increased in bipolar disorder. These data provide novel evidence that NRXN1 expression is highest in human dorsolateral prefrontal cortex during critical developmental windows relevant to the onset and diagnosis of a range of neurodevelopmental disorders, and that NRXN1 expression may be differentially altered in neuropsychiatric disorders.

Liquid bridging of cylindrical colloids in near-critical solvents.

Within mean field theory, we investigate the bridging transition between a pair of parallel cylindrical colloids immersed in a binary liquid mixture as a solvent that is close to its critical consolute point Tc. We determine the universal scaling functions of the effective potential and of the force between the colloids. For a solvent that is at the critical concentration and close to Tc, we find that the critical Casimir force is the dominant interaction at close separations. This agrees very well with the corresponding Derjaguin approximation for the effective interaction between the two cylinders, while capillary forces originating from the extension of the liquid bridge turn out to be more important at large separations. In addition, we are able to infer from the wetting characteristics of the individual colloids the first-order transition of the liquid bridge connecting two colloidal particles to the ruptured state. While specific to cylindrical colloids, the results presented here also provide an outline for identifying critical Casimir forces acting on bridged colloidal particles as such and for analyzing the bridging transition between them.

Adjuvant S-1 chemotherapy after curative resection of gastric cancer in Chinese patients: assessment of treatment tolerability and associated risk factors.

INTRODUCTION: The use of adjuvant chemotherapy with S-1 (tegafur, gimeracil, and oteracil potassium) has been shown to improve the outcome of patients with gastric cancer. There are limited data on the tolerability of S-1 in Chinese patients. In this multicentre retrospective study, we assessed the toxicity profile in local patients. METHODS: Patients with stage II-IIIC gastric adenocarcinoma who had undergone curative resection and who had received S-1 adjuvant chemotherapy were included in the study. Patient demographics, tumour characteristics, chemotherapy records, as well as biochemical, haematological, and other toxicity profiles were extracted from medical charts. Potential factors associated with grade 2-4 toxicities were identified. RESULTS: Adjuvant S-1 was administered to 30 patients. Overall, 19 (63%) patients completed eight cycles. The most common grade 3-4 adverse events included neutropaenia (10%), anaemia (6.7%), septic episode (16.7%), diarrhoea (6.7%), hyperbilirubinaemia (6.7%), and syncope (6.7%). Dose reductions were made in 22 (73.3%) patients and 12 (40.0%) patients had dose delays. Univariate analyses showed that patients who underwent total gastrectomy were more likely to experience adverse haematological events (P=0.034). Patients with nodal involvement were more likely to report adverse non-haematological events (P=0.031). Patients with a history of regular alcohol intake were more likely to have earlier treatment withdrawal (P=0.044). Lower body weight (P=0.007) and lower body surface area (P=0.017) were associated with dose interruptions. CONCLUSIONS: The tolerability of adjuvant S-1 in our patient population was similar to that in other Asian patient populations. The awareness of S-1-related toxicities and increasing knowledge of potential associated factors may enable optimisation of S-1 therapy.

Frailty and mortality in kidney transplant recipients.

We have previously described strong associations between frailty, a measure of physiologic reserve initially described and validated in geriatrics, and early hospital readmission as well as delayed graft function. The goal of this study was to estimate its association with postkidney transplantation (post-KT) mortality. Frailty was prospectively measured in 537 KT recipients at the time of transplantation between November 2008 and August 2013. Cox proportional hazards models were adjusted for confounders using a novel approach to substantially improve model efficiency and generalizability in single-center studies. We precisely estimated the confounder coefficients using the large sample size of the Scientific Registry of Transplantation Recipients (n = 37 858) and introduced these into the single-center model, which then estimated the adjusted frailty coefficient. At 5 years, the survivals were 91.5%, 86.0% and 77.5% for nonfrail, intermediately frail and frail KT recipients, respectively. Frailty was independently associated with a 2.17-fold (95% CI: 1.01-4.65, p = 0.047) higher risk of death. In conclusion, regardless of age, frailty is a strong, independent risk factor for post-KT mortality, even after carefully adjusting for many confounders using a novel, efficient statistical approach.

The neglected co-star in the dementia drama: the putative roles of astrocytes in the pathogeneses of major neurocognitive disorders.

Alzheimer's disease (AD) and vascular dementia are the major causes of cognitive disorders worldwide. They are characterized by cognitive impairments along with neuropsychiatric symptoms, and that their pathogeneses show overlapping multifactorial mechanisms. Although AD has long been considered the most common cause of dementia, individuals afflicted with AD commonly exhibit cerebral vascular abnormalities. The concept of mixed dementia has emerged to more clearly identify patients with neurodegenerative phenomena exhibiting both AD and cerebral vascular pathologies-vascular damage along with ß-amyloid (Aß)-associated neurotoxicity and τ-hyperphosphorylation. Cognitive impairment has long been commonly explained through a 'neuro-centric' perspective, but emerging evidence has shed light over the important roles that neurovascular unit dysfunction could have in neuronal death. Moreover, accumulating data have been demonstrating astrocytes being the essential cell type in maintaining proper central nervous system functioning. In relation to dementia, the roles of astrocytes in Aß deposition and clearance are unclear. This article emphasizes the multiple events triggered by ischemia and the cytotoxicity exerted by Aß either alone or in association with endothelin-1 and receptor for advanced glycation end products, thereby leading to neurodegeneration in an 'astroglio-centric' perspective.

Effective interaction between a colloid and a soft interface near criticality.

Within mean-field theory we determine the universal scaling function for the effective force acting on a single colloid located near the interface between two coexisting liquid phases of a binary liquid mixture close to its critical consolute point. This is the first study of critical Casimir forces emerging from the confinement of a fluctuating medium by at least one shape responsive, soft interface, instead of by rigid walls only as studied previously. For this specific system, our semi-analytical calculation illustrates that knowledge of the colloid-induced, deformed shape of the interface allows one to accurately describe the effective interaction potential between the colloid and the interface. Moreover, our analysis demonstrates that the critical Casimir force involving a deformable interface is accurately described by a universal scaling function, the shape of which differs from that one for rigid walls.

Frailty and early hospital readmission after kidney transplantation.

Early hospital readmission (EHR) after kidney transplantation (KT) is associated with increased morbidity and higher costs. Registry-based recipient, transplant and center-level predictors of EHR are limited, and novel predictors are needed. We hypothesized that frailty, a measure of physiologic reserve initially described and validated in geriatrics and recently associated with early KT outcomes, might serve as a novel, independent predictor of EHR in KT recipients of all ages. We measured frailty in 383 KT recipients at Johns Hopkins Hospital. EHR was ascertained from medical records as ≥1 hospitalization within 30 days of initial post-KT discharge. Frail KT recipients were much more likely to experience EHR (45.8% vs. 28.0%, p = 0.005), regardless of age. After adjusting for previously described registry-based risk factors, frailty independently predicted 61% higher risk of EHR (adjusted RR = 1.61, 95% CI: 1.18-2.19, p = 0.002). In addition, frailty improved EHR risk prediction by improving the area under the receiver operating characteristic curve (p = 0.01) as well as the net reclassification index (p = 0.04). Identifying frail KT recipients for targeted outpatient monitoring and intervention may reduce EHR rates.

Enhancing the egg's natural defence against bacterial penetration by increasing cuticle deposition.

The cuticle is a proteinaceous layer covering the avian egg and is believed to form a defence to microorganism ingress. In birds that lay eggs in challenging environments, the cuticle is thicker, suggesting evolutionary pressure; however, in poultry, selection pressure for this trait has been removed because of artificial incubation. This study aimed to quantify cuticle deposition and to estimate its genetic parameters and its role on trans-shell penetration of bacteria. Additionally, cuticle proteins were characterised to establish whether alleles for these genes explained variation in deposition. A novel and reliable quantification was achieved using the difference in reflectance of the egg at 650 nm before and after staining with a specific dye. The heritability of this novel measurement was moderate (0.27), and bacteria penetration was dependent on the natural variation in cuticle deposition. Eggs with the best cuticle were never penetrated by bacteria (P < 0.001). The cuticle proteome consisted of six major proteins. A significant association was found between alleles of one of these protein genes, ovocleidin-116 (MEPE), and cuticle deposition (P = 0.015) and also between alleles of estrogen receptor 1 (ESR1) gene and cuticle deposition (P = 0.008). With the heritability observed, genetic selection should be possible to increase cuticle deposition in commercial poultry, so reducing trans-generational transmission of microorganisms and reversing the lack of selection pressure for this trait during recent domestication.

Emerging challenges of the impacts of pharmaceuticals on aquatic ecosystems: A diatom perspective.

Pharmaceuticals are a ubiquitous group of emerging pollutants of considerable importance due to their biological potency and potential to elicit effects in wildlife and humans. Pharmaceuticals have been quantified in terrestrial, marine, fresh, and transitional waters, as well as the fauna and macro-flora that inhabit them. Pharmaceuticals can enter water ways through different human and veterinary pathways with traditional wastewater treatment, unable to completely remove pharmaceuticals, discharging often unknown quantities to aquatic ecosystems. However, there is a paucity of available information regarding the effects of pharmaceuticals on species at the base of aquatic food webs, especially on phytoplankton, with research typically focussing on fish and aquatic invertebrates. Diatoms are one of the main classes of phytoplankton and are some of the most abundant and important organisms in aquatic systems. As primary producers, diatoms generate ∼40 % of the world's oxygen and are a vital food source for primary consumers. Diatoms can also be used for bioremediation of polluted water bodies but perhaps are best known as bio-indicators for water quality studies. However, this keystone, non-target group is often ignored during ecotoxicological studies to assess the effects of pollutants of concern. Observed effects of pharmaceuticals on diatoms have the potential to be used as an indicator of pharmaceutical-induced impacts on higher trophic level organisms and wider ecosystem effects. The aim of this review is to present a synthesis of research on pharmaceutical exposure to diatoms, considering ecotoxicity, bioremediation and the role of diatoms as bio-indicators. We highlight significant omissions and knowledge gaps which need addressing to realise the potential role of diatoms in future risk assessment approaches and help evaluate the impacts of pharmaceuticals in the aquatic environment at local and global scales.

A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred. CONCLUSION: In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration.

Identification of miRNAs associated with the follicular-luteal transition in the ruminant ovary.

Little is known about the involvement of microRNAs (miRNAs) in the follicular-luteal transition. The aim of this study was to identify genome-wide changes in miRNAs associated with follicular differentiation in sheep. miRNA libraries were produced from samples collected at defined stages of the ovine oestrous cycle and representing healthy growing follicles, (diameter, 4.0-5.5  mm), pre-ovulatory follicles (6.0-7.0  mm), early corpora lutea (day 3 post-oestrus) and late corpora lutea (day 9). A total of 189 miRNAs reported in sheep or other species and an additional 23 novel miRNAs were identified by sequencing these libraries. miR-21, miR-125b, let-7a and let-7b were the most abundant miRNAs overall, accounting for 40% of all miRNAs sequenced. Examination of changes in cloning frequencies across development identified nine different miRNAs whose expression decreased in association with the follicular-luteal transition and eight miRNAs whose expression increased during this transition. Expression profiles were confirmed by northern analyses, and experimentally validated targets were identified using miRTarBase. A majority of the 29 targets identified represented genes known to be actively involved in regulating follicular differentiation in vivo. Finally, luteinisation of follicular cells in vitro resulted in changes in miRNA levels that were consistent with those identified in vivo, and these changes were temporally associated with changes in the levels of putative miRNA targets in granulosa cells. In conclusion, this is the first study to characterise genome-wide miRNA profiles during different stages of follicle and luteal development. Our data identify a subset of miRNAs that are potentially important regulators of the follicular-luteal transition.

Complex traits analysis of chicken growth using targeted genetical genomics.

Dissecting the genetic control of complex trait variation remains very challenging, despite many advances in technology. The aim of this study was to use a major growth quantitative trait locus (QTL) in chickens mapped to chromosome 4 as a model for a targeted approach to dissect the QTL. We applied a variant of the genetical genomics approach to investigate genome-wide gene expression differences between two contrasting genotypes of a marked QTL. This targeted approach allows the direct quantification of the link between the genotypes and the genetic responses, thus narrowing the QTL-phenotype gap using fewer samples (i.e. microarrays) compared with the genome-wide genetical genomics studies. Four differentially expressed genes were localized under the region of the QTL. One of these genes is a potential positional candidate gene (AADAT) that affects lysine and tryptophan metabolism and has alternative splicing variants between the two genotypes. In addition, the lysine and glycolysis metabolism pathways were significantly enriched for differentially expressed genes across the genome. The targeted approach provided a complementary route to fine mapping of QTL by characterizing the local and the global downstream effects of the QTL and thus generating further hypotheses about the action of that QTL.

Interferon dysregulation and virus-induced cell death in avian influenza H5N1 virus infections.

1. Hyper-induction of cytokines and chemokines was found in human blood macrophages infected with the avian influenza H5N1 and H9N2/G1 viruses, as compared to those infected with human influenza H1N1 virus. 2. IRF3 played a significant role in the hyperinduction of cytokines including IFN-ß, IFN-λ1,IFN-α subtypes, MCP-1, and TNF-α, and also played a part in subsequent cytokine-induced cell signalling cascades. 3. Compared with H1N1 viruses, avian influenza viruses including H5N1/97 and its precursors triggered a caspase-mediated but delayed apoptotic response in human macrophages. 4. Therapies that can minimise immunopathology-associated dysregulation of innate immunity without impairing effective host defence may be valuable adjuncts to antiviral therapy.

Many quantitative trait loci for feather growth in an F(2) broiler × layer cross collocate with body weight loci.

1. A genome-wide scan of 467 F(2) progeny of a broiler x layer cross was conducted to identify quantitative trait loci (QTL) affecting the rate of growth of the tail, wing and back feathers, and the width of the breast feather tract, at three weeks of age. 2. Correlations between the traits ranged from 0·36 to 0·61. Males had longer tail and wing feathers and shorter back feathers than females. Breast feather tract width was greater in females than males. 3. QTL effects were generally additive and accounted for 11 to 45% of sex average feather lengths of the breeds, and 100% of the breast feather tract width. Positive and negative alleles were inherited from both lines, whereas the layer allele was larger than the broiler allele after adjusting for body weight. 4. A total of 4 genome-significant and 4 suggestive QTL were detected. At three or 6 weeks of age, 5 of the QTL were located in similar regions as QTL for body weight. 5. Analysis of a model with body weight at three weeks as a covariate identified 5 genome significant and 6 suggestive QTL, of which only two were coincident with body weight QTL. One QTL for feather length at 148 cM on GGA1 was identified at a similar location in the unadjusted analysis. 6. The results suggest that the rate of feather growth is largely controlled by body weight QTL, and that QTL specific for feather growth also exist.

Using Real-world Data to Define a Validated Nomogram for Advanced Bladder Cancer Patients Who Respond to Immunotherapy.

AIMS: Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. MATERIALS AND METHODS: A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. RESULTS: The median follow-up was 18.9 (15.8-21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4-10.5) and 4.5 months (3.5-5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.

Defining Biochemical Cure After Low Dose Rate Prostate Brachytherapy: External Validation of 4-year Prostate-specific Antigen Nadir as a Predictor of 10- and 15-year Disease-free Survival.

AIMS: To externally validate a proposed biochemical definition of cure following low dose rate (LDR) brachytherapy for prostate cancer - 4-year post-implant prostate-specific antigen (PSA) ≤0.2 ng/ml - in a UK population, and report the long-term (10- and 15-year) outcomes for patients stratified by National Comprehensive Cancer Network (NCCN) risk groups, through analysis of a large, prospectively collected, single-centre database. MATERIALS AND METHODS: All patients treated with LDR brachytherapy for prostate cancer at a single UK centre between 2001 and November 2020 (n = 1142) were eligible; 632 patients met the inclusion criteria for the analysis. The primary end point was disease-free survival (DFS), defined as freedom from clinical, radiological or PSA progression requiring androgen deprivation therapy. Four-year PSA was categorised as ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml. Kaplan-Meier analysis to 15 years was undertaken for each group, and sensitivity and specificity of 4-year PSA as a surrogate for long-term cure were calculated. Kaplan-Meier analysis to 15 years was repeated, stratifying patients by NCCN risk groups. RESULTS: The median cohort age was 63 years; the median follow-up was 9.1 years (range 3.5-18.7). In total, 248 patients were available for analysis at year 10, 46 at year 15. Sixty-four patients (10.1%) relapsed during the study period. The 10-year DFS for 4-year PSA categories ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml (95% confidence intervals) were 97.5% (95.4-99.6), 89.0% (82.4-96.1), 81.5% (70.5-94.2) and 41.8% (29.7-58.9), respectively. The 10-year DFS results for NCCN low, favourable-intermediate and unfavourable-intermediate risk disease were 93.1% (89.6-96.7), 92.1% (87.6-96.9) and 75.9% (67.8-84.9), respectively. CONCLUSIONS: Patients with 4-year PSA ≤0.2 ng/ml may be considered cured, and could be discharged to general practitioner follow-up. LDR brachytherapy is an excellent treatment option for patients with low and favourable-intermediate risk prostate cancer, but those with unfavourable-intermediate risk disease should be considered for treatment intensification strategies.