Reconstruction of bone defects around the ankle with retrograde gentamicin-coated tibial intramedullary nail (ETN PROtect™) for tibiotalocalcaneal arthrodesis: a case series.

PURPOSE: The objective of this study was to describe the use of retrograde gentamicin-coated tibial intramedullary nail (ETN PROtect™) in patients with tibial defects who required a tibiotalocalcaneal arthrodesis (TTC). METHODS: Consecutive series case review of seven men treated with TTC using retrograde PROtect™ between January 2018 and December 2023. The main outcomes evaluated were fracture union, complications, and the health-related quality of life using the EuroQol five-dimension three-level questionnaire (EQ-5D-3L). RESULTS: The mean age was 45.3 ± 8.0 years. Six patients had a clinical history of chronic osteomyelitis, and one case underwent TTC for congenital pseudoarthrosis. Fracture union was achieved in 5 of 7 patients between 4 and 11 months after surgery. Three patients developed complications; two patients had fistulas, and one had persistent pain. At the end of the follow-up, a median of 70 points (interquartile range: 60 to 90) on the EQ-5D-3L was reported. No complications directly attributed to the use of the PROtect™ were reported. CONCLUSION: TTC with retrograde PROtect™ is a prophylactic treatment option in patients with tibial defects treated with external fixation requiring a tibiotalar and subtalar arthrodesis. This novel use of PROtect™ allows simultaneous fixation of the tibiotalocalcaneal joint and protection of the regenerated bone, facilitating earlier rehabilitation in patients at high risk for postoperative infections.

Classical Simulations on Quantum Computers: Interface-Driven Peptide Folding on Simulated Membrane Surfaces.

BACKGROUND: Antimicrobial peptides (AMPs) are crucial in the fight against infections and play significant roles in various health contexts, including cancer, autoimmune diseases, and aging. A key aspect of AMP functionality is their selective interaction with pathogen membranes, which often exhibit altered lipid compositions. These interactions are thought to induce a conformational shift in AMPs from random coil to alpha-helical structures, essential for their lytic activity. Traditional computational approaches have faced challenges in accurately modeling these structural changes, especially in membrane environments, thereby opening and opportunity for more advanced approaches. METHOD: This study extends an existing quantum computing algorithm, initially designed for peptide folding simulations in homogeneous environments, to address the complexities of AMP interactions at interfaces. Our approach enables the prediction of the optimal conformation of peptides located in the transition region between hydrophilic and hydrophobic phases, resembling lipid membranes. The new method was tested on three 10-amino-acid-long peptides, each characterized by distinct hydrophobic, hydrophilic, or amphipathic properties, across different media and at interfaces between solvents of different polarity. RESULTS: The developed method successfully modeled the structure of the peptides without increasing the number of qubits required compared to simulations in homogeneous media, making it more feasible with current quantum computing resources. Despite the current limitations in computational power and qubit availability, the findings demonstrate the significant potential of quantum computing in accurately characterizing complex biomolecular processes, particularly AMP folding at membrane models. CONCLUSIONS: This research highlights the promising applications of quantum computing in biomolecular simulations, paving the way for future advancements in the development of novel therapeutic agents. We aim to offer a new perspective on enhancing the accuracy and applicability of biomolecular simulations in the context of AMP interactions with membrane models.

Immune Cell Densities Predict Response to Immune Checkpoint-Blockade in Head and Neck Cancer.

Immune checkpoint blockade (ICB) is the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), yet efficacy remains low. The current approach for predicting the likelihood of response to ICB is a single proportional biomarker (PD-L1) expressed in immune and tumor cells (Combined Positive Score, CPS) without differentiation by cell type, potentially explaining its limited predictive value. Tertiary Lymphoid Structures (TLS) have shown a stronger association with ICB response than PD-L1. However, their exact composition, size, and spatial biology in HNSCC remain understudied. A detailed understanding of TLS is required for future use as a clinically applicable predictive biomarker. Methods: Pre-ICB tumor tissue sections were obtained from 9 responders (complete response, partial response, or stable disease) and 11 non-responders (progressive disease) classified via RECISTv1.1. A custom multi-immunofluorescence (mIF) staining assay was designed, optimized, and applied to characterize tumor cells (pan-cytokeratin), T cells (CD4, CD8), B cells (CD19, CD20), myeloid cells (CD16, CD56, CD163), dendritic cells (LAMP3), fibroblasts (α Smooth Muscle Actin), proliferative status (Ki67) and immunoregulatory molecules (PD1). Spatial metrics were compared among groups. Serial tissue sections were scored for TLS in both H&E and mIF slides. A machine learning model was employed to measure the effect of these metrics on achieving a response to ICB (SD, PR, or CR). Results: A higher density of B lymphocytes (CD20+) was found in responders compared to non-responders to ICB (p=0.022). A positive correlation was observed between mIF and pathologist identification of TLS (R 2 = 0.66, p-value= <0.0001). TLS trended toward being more prevalent in responders to ICB (p=0.0906). The presence of TLS within 100 µm of the tumor was associated with improved overall (p=0.04) and progression-free survival (p=0.03). A multivariate machine learning model identified TLS density as a leading predictor of response to ICB with 80% accuracy. Conclusion: Immune cell densities and TLS spatial location within the tumor microenvironment play a critical role in the immune response to HNSCC and may potentially outperform CPS as a predictor of ICB response.

Dendritic cell effector mechanisms and tumor immune microenvironment infiltration define TLR8 modulation and PD-1 blockade.

The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased CLEC9A+ dendritic cell and CLEC7A/SYK expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8+ T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13+CD8+ T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.

CS-PHOC: weekly census counts of Southern Ocean phocids at Cape Shirreff, Livingston Island.

Rapid climatic warming of the Antarctic Peninsula is driving regional population declines and distribution shifts of predators and prey. Affected species include Antarctic ice seals and the southern elephant seal, all of which rely on the peninsula region for critical stages of their life cycle. However, data collection is difficult in this remote region, and therefore long-term time series with which to identify and investigate population trends in these species are rare. We present the Cape Shirreff Phocid Census (CS-PHOC) dataset: weekly counts of phocids (crabeater, leopard, southern elephant, and Weddell seals) hauled out at Cape Shirreff, Livingston Island, during most austral summers since 1997. Data from these censuses were cleaned and aggregated, resulting in robust and comparable count data from 284 censuses across 23 field seasons. The CS-PHOC dataset, which is publicly available through the SCAR Biodiversity Portal, will be updated yearly to provide important information about Southern Ocean phocids in the Antarctic Peninsula.

Refractory Duodenal Ulcer in a Patient With Median Arcuate Ligament Compression: A Treatment Challenge.

Flexible esophagogastroduodenoscopy is the gold standard for the management of acute upper gastrointestinal bleeding. This is a case of a man who was admitted in the emergency department because of melena with hypotension because of an ulcer in the anterior face of the duodenal bulb, refractory to 3 attempts of endoscopic therapy. Then, a gastroduodenal arterial embolization was tried, being impossible because of the presence of the median arcuate ligament, compressing the celiac trunk. A balloon-expandable stent was inserted in the celiac trunk, and then, the embolization was performed. After unsuccessful endoscopic management, the arterial embolization is one of the treatment options in nonvariceal acute upper gastrointestinal bleeding.

Epidemiology, Outcomes, and Trend Analysis of Hospitalized Infants With Respiratory Syncytial Virus (RSV) Bronchiolitis From 1997 to 2019.

Background  Most children with respiratory syncytial virus (RSV) infection have a self-limiting course that can be managed with supportive care, and hospitalization is uncommon. The objectives of this study were to evaluate the epidemiology, outcomes, associated comorbidities, and temporal trends in the prevalence of infants one to 24 months of age who required hospitalization for RSV infection in the United States of America from 1997 to 2019. Methods In this retrospective cross-sectional study, we utilized the Kids' Inpatient Database (KID) to investigate the prevalence and outcomes of RSV bronchiolitis within a large cohort of discharged patients from 1997 to 2019. We included children one to 24 months of age admitted with a diagnosis of RSV bronchiolitis. Neonates were excluded from the analysis. A chi-square for linear trend was used to analyze trends in the prevalence of RSV bronchiolitis hospitalization, the presence of complex chronic conditions (CCC), congenital heart disease (CHD), the use of non-invasive and invasive mechanical ventilation (NIV and IMV), and hospital mortality. Results There were a total of 566,786 infants aged one to 24 months hospitalized with RSV infection out of a total of 9,309,597 discharges during the eight-year cohort, with a hospital prevalence of 60.9 per 1000 discharges and a hospital mortality rate of 0.09% (95% confidence interval (CI): 0.08%-0.1%). There was no trend in hospitalization rates of RSV infections per 100,000 U.S. population during the study period, with a decrease in hospital mortality trend. Children with RSV bronchiolitis were more likely to have government insurance and reside in zip codes with the lowest income quartile. There was a significant seasonal and regional variation in RSV-related hospitalizations. The presence of CCC was identified in 2.4% of the RSV group compared to 5.1% of non-RSV discharges (odds ratio (OR): 0.46, 95% CI: 0.45-0.47; p<0.001). The prevalence of RSV among all discharges has significantly increased over the study period, rising from 51.6 cases per 1000 discharges in 1997 to 180.1 cases per 1000 discharges in 2019 (p<0.001). The prevalence of CCC and CHD among RSV patients has also shown an upward trend, with CCC cases increasing from 1,411 in 1997 to 2,795 in 2019 and CHD cases rising from 1,795 to 3,622 during the same period. The use of invasive mechanical ventilation, non-invasive ventilation, and extracorporeal membrane oxygenation has consistently increased over time. Additionally, complications such as the need for cardiopulmonary resuscitation have demonstrated a similar increasing trend, although they have remained overall low. However, population-based hospitalization rates showed no significant trend. Conclusions The hospitalization rates at a population level in the United States for RSV infection in children aged one to 24 months remained steady from 1997 to 2019, while hospital mortality rates showed a declining trend. There is an increased proportion of comorbid conditions and increased resource utilization in children with RSV. These findings are important for monitoring the effectiveness of preventive strategies for severe RSV infections.

Comparing embolic particles for prostatic artery embolization to treat lower urinary tract symptoms in patients with benign prostatic hyperplasia.

PURPOSE: Compare the safety and efficacy of polyvinyl alcohol particles (PVA) versus trisacryl gelatin microspheres (Embospheres) versus hydrogel microspheres coated with polyzene-F (Embozenes) for prostatic artery embolization (PAE) to treat patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A single-center prospective cohort study from 2019 to 2023, including patients with international prostate symptom score (IPSS) ≥ 15 and/or quality of life score (QoL) ≥ 4. Allocation to embolic agents was performed chronologically: 100-300 µm PVA (n = 53), followed by 300-500 µm Embospheres (n = 50), and finally, 400 µm Embozenes (n = 50). All patients were evaluated at baseline and at 1 and 6 months after PAE with IPSS/QoL; peak urinary flow rate, post-void residual volume, and prostate volume with ultrasound and prostate-specific antigen. Adverse events and the need for prostatic re-interventions were assessed. RESULTS: There were no significant baseline differences between the three groups except for patient age (62.5 years PVA; 66.1 years Embospheres and 66.6 years Embozenes; p = 0.019). There were no major adverse events and no differences between groups regarding minor adverse events. All outcome measures improved significantly from baseline, with no significant differences between groups. Mean ± standard deviation IPSS/QoL improvement at 6 months: -10.7 ± 7.9/-2.2 ± 1.7 PVA; -10.4 ± 7.3/-2.0 ± 1.5 Embospheres; -10.4 ± 7.0/-2.2 ± 1.6 Embozenes (p = 0.987). Re-intervention rates after 6 months: 9% (n = 5/53) PVA; 14% (n = 7/50) Embospheres; 8% (n = 4/50) Embozenes (p = 0.591). CONCLUSIONS: PAE with PVA particles, Embospheres, and Embozenes is equally safe and effective in treating BPH-related lower urinary tract symptoms. CLINICAL RELEVANCE STATEMENT: This is the first prospective study showing equivalence between the most frequently used embolic agents for prostatic artery embolization. KEY POINTS: Different particles can be used interchangeably for prostatic artery embolization. The improvements in measured metrics were the same between groups, with no differences in adverse events. The need for prostatic medication and re-intervention rates were the same at 1 and 6 months after embolization.

Gender Disparities in Adverse Events Resulting From Low-Value Practices in Family Practice in Spain: A Retrospective Cohort Study.

Objectives: This study aimed to evaluate gender-based disparities in preventable adverse events due to low-value practices (LVPs) in primary care. Methods: A retrospective cohort study in Alicante, Spain. Results: A total of 1,516 patient records were examined, finding that older individuals and women experienced more LVP-related events. Female patients faced a higher volume of such events than males with the same health issue. Interaction analysis revealed patients treated by male physicians had more severe events, while those attended by females experienced milder ones. Adverse events were more frequent in LVPs associated with gender-based reasons. Conclusion: These results highlight the need for tailored healthcare professional awareness programs on overuse's impact on safety. Addressing outcome differences between male and female patients should inform awareness campaigns.

Primary cilia as a targetable node between biliary injury, senescence and regeneration in liver transplantation.

BACKGROUND & AIMS: Biliary complications are a major cause of morbidity and mortality in liver transplantation. Up to 25% of patients that develop biliary complications require additional surgical procedures, re-transplantation or die in the absence of a suitable regraft. Here, we investigate the role of the primary cilium, a highly specialised sensory organelle, in biliary injury leading to post-transplant biliary complications. METHODS: Human biopsies were used to study the structure and function of primary cilia in liver transplant recipients that develop biliary complications (n = 7) in comparison with recipients without biliary complications (n = 12). To study the biological effects of the primary cilia during transplantation, we generated murine models that recapitulate liver procurement and cold storage, and assessed the elimination of the primary cilia in biliary epithelial cells in the K19CreERTKif3afl/fl mouse model. To explore the molecular mechanisms responsible for the observed phenotypes we used in vitro models of ischemia, cellular senescence and primary cilia ablation. Finally, we used pharmacological and genetic approaches to target cellular senescence and the primary cilia, both in mouse models and discarded human donor livers. RESULTS: Prolonged ischemic periods before transplantation result in ciliary shortening and cellular senescence, an irreversible cell cycle arrest that blocks regeneration. Our results indicate that primary cilia damage results in biliary injury and a loss of regenerative potential. Senescence negatively impacts primary cilia structure and triggers a negative feedback loop that further impairs regeneration. Finally, we explore how targeted interventions for cellular senescence and/or the stabilisation of the primary cilia improve biliary regeneration following ischemic injury. CONCLUSIONS: Primary cilia play an essential role in biliary regeneration and we demonstrate that senolytics and cilia-stabilising treatments provide a potential therapeutic opportunity to reduce the rate of biliary complications and improve clinical outcomes in liver transplantation. IMPACT AND IMPLICATIONS: Up to 25% of liver transplants result in biliary complications, leading to additional surgery, retransplants, or death. We found that the incidence of biliary complications is increased by damage to the primary cilium, an antenna that protrudes from the cell and is key to regeneration. Here, we show that treatments that preserve the primary cilia during the transplant process provide a potential solution to reduce the rates of biliary complications.

Testing the Validity and Reliability of a Standardized Virtual Examination for Concussion.

Background and Objectives: We determined inter-modality (in-person vs telemedicine examination) and inter-rater agreement for telemedicine assessments (2 different examiners) using the Telemedicine Buffalo Concussion Physical Examination (Tele-BCPE), a standardized concussion examination designed for remote use. Methods: Patients referred for an initial evaluation for concussion were invited to participate. Participants had a brief initial assessment by the treating neurologist. After a patient granted informed consent to participate in the study, the treating neurologist obtained a concussion-related history before leaving the examination room. Using the Tele-BCPE, 2 virtual examinations in no specific sequence were then performed from nearby rooms by the treating neurologist and another neurologist. After the 2 telemedicine examinations, the treating physician returned to the examination room to perform the in-person examination. Intraclass correlation coefficients (ICC) determined inter-modality validity (in-person vs remote examination by the same examiner) and inter-rater reliability (between remote examinations done by 2 examiners) of overall scores of the Tele-BCPE within the comparison datasets. Cohen's kappa, κ, measured levels of agreement of dichotomous ratings (abnormality present vs absent) on individual components of the Tele-BCPE to determine inter-modality and inter-rater agreement. Results: For total scores of the Tele-BCPE, both inter-modality agreement (ICC = 0.95 [95% CI 0.86-0.98, p < 0.001]) and inter-rater agreement (ICC = 0.88 [95% CI 0.71-0.95, p < 0.001]) were reliable (ICC >0.70). There was at least substantial inter-modality agreement (κ ≥ 0.61) for 25 of 29 examination elements. For inter-rater agreement (2 telemedicine examinations), there was at least substantial agreement for 8 of 29 examination elements. Discussion: Our study demonstrates that the Tele-BCPE yielded consistent clinical results, whether conducted in-person or virtually by the same examiner, or when performed virtually by 2 different examiners. The Tele-BCPE is a valid indicator of neurologic examination findings as determined by an in-person concussion assessment. The Tele-BCPE may also be performed with excellent levels of reliability by neurologists with different training and backgrounds in the virtual setting. These findings suggest that a combination of in-person and telemedicine modalities, or involvement of 2 telemedicine examiners for the same patient, can provide consistent concussion assessments across the continuum of care.

Comparative Analysis of Immune Gene Transcription in Sea Bream (Sparus aurata) Challenged with RGNNV or RGNNV/SJNNV Betanodaviruses.

Gilthead sea bream and European sea bass display different resistance-susceptibility patterns during infection with different nervous necrosis virus (NNV) species, which may derive from differences in the triggered immune response. Based on this premise, we analysed the transcription of several selected immune-related genes in sea bream experimentally infected with NNV isolates obtained from sea bass (DlNNV, RGNNV) or sea bream (SaNNV, RGNNV/SJNNV). Viral replication only occurred in SaNNV-inoculated fish; therefore, the differences between the immune response elicited by both viruses may be the key to understanding the mechanism behind the inhibition of DlNNV replication. Principal component analysis clustered samples according to the viral isolate from 1 day post infection onwards and evidenced differences in the immune response against both viruses, even though no mortalities or symptoms were recorded. The response against DlNNV is characterized by higher rtp3 transcription early after the infection, longer-lasting il-10 transcription and stronger induction of casp1 and hsp70. These genes should be targets for future studies in order to elucidate their role in hampering NNV replication in sea bream, which is essential for developing effective prophylactic measures.

Closing the computational biology 'knowledge gap': Spanish Wikipedia as a case study.

MOTIVATION: Wikipedia is a vital open educational resource in computational biology. The quality of computational biology coverage in English-language Wikipedia has improved steadily in recent years. However, there is an increasingly large 'knowledge gap' between computational biology resources in English-language Wikipedia, and Wikipedias in non-English languages. Reducing this knowledge gap by providing educational resources in non-English languages would reduce language barriers which disadvantage non-native English speaking learners across multiple dimensions in computational biology. RESULTS: Here, we provide a comprehensive assessment of computational biology coverage in Spanish-language Wikipedia, the second most accessed Wikipedia worldwide. Using Spanish-language Wikipedia as a case study, we generate quantitative and qualitative data before and after a targeted educational event, specifically, a Spanish-focused student editing competition. Our data demonstrates how such events and activities can narrow the knowledge gap between English and non-English educational resources, by improving existing articles and creating new articles. Finally, based on our analysis, we suggest ways to prioritize future initiatives to improve open educational resources in other languages. AVAILABILITY AND IMPLEMENTATION: Scripts for data analysis are available at: https://github.com/ISCBWikiTeam/spanish.

Unlocking the specificity of antimicrobial peptide interactions for membrane-targeted therapies.

Antimicrobial peptides (AMPs) are increasingly recognized as potent therapeutic agents, with their selective affinity for pathological membranes, low toxicity profile, and minimal resistance development making them particularly attractive in the pharmaceutical landscape. This study offers a comprehensive analysis of the interaction between specific AMPs, including magainin-2, pleurocidin, CM15, LL37, and clavanin, with lipid bilayer models of very different compositions that have been ordinarily used as biological membrane models of healthy mammal, cancerous, and bacterial cells. Employing unbiased molecular dynamics simulations and metadynamics techniques, we have deciphered the intricate mechanisms by which these peptides recognize pathogenic and pathologic lipid patterns and integrate into lipid assemblies. Our findings reveal that the transverse component of the peptide's hydrophobic dipole moment is critical for membrane interaction, decisively influencing the molecule's orientation and expected therapeutic efficacy. Our approach also provides insight on the kinetic and dynamic dependence on the peptide orientation in the axial and azimuthal angles when coming close to the membrane. The aim is to establish a robust framework for the rational design of peptide-based, membrane-targeted therapies, as well as effective quantitative descriptors that can facilitate the automated design of novel AMPs for these therapies using machine learning methods.

Incidence, Risk Factors, and Survival of Bone Metastases and Skeletal-Related Events in Melanoma Patients: A Systematic Review and Quality Assessment of 29 Studies.

Background: Skeletal metastases make up 17% of all metastases from advanced-stage melanoma. Bone metastases are associated with increased morbidity and mortality and decreased quality of life due to their association with skeletal-related events (SREs), including pathological fracture, spinal cord compression, hypercalcemia, radiotherapy, and surgery. The study aimed to determine the incidence of bone metastases and SREs in melanoma, identify possible risk factors for the development of bone metastases and SREs, and investigate survival rates in this patient population. Methods: A computer-based literature search was conducted using Pubmed, Embase, and Cochrane Central Register of Controlled Trials up to July 2023. The Newcastle-Ottawa Quality Assessment Scale (NOS) was utilized for quality assessment. Study characteristics, patient information, risk factors for developing bone metastases and SREs, and characteristics for survival were recorded. Results: We included 29 studies. The average bone metastasis-free interval ranged from four to 72 months. Incidence of bone metastases varied from 2 % to 49 % across 14 studies. 69 % (20/29) of studies described the location of bone metastases, with 24 % (7/29) focusing solely on spinal metastases. In one study, 129 SREs were recorded in 71 % (59/83) of the patient cohort, with various manifestations. The use of bone-directed agents was independently associated with lower risk of SREs. Survival after detection of bone metastasis ranged from three to 13 months. Factors associated with survival included clinical, tumor-related, and treatment features. Conclusion: This review highlights the notable prevalence and risk factors of developing bone metastases and subsequent SREs in patients with melanoma. The surge in bone metastases poses a challenge in complication management, given the high prevalence of SREs. While this study offers a comprehensive overview of the incidence, risk factors, and outcomes associated with bone metastases and SREs in melanoma patients that may guide patient and physician decision-making, a notable gap lies in the limited availability of high-quality data and the heterogeneous design of the existing literature. Future research should address predictive factors for bone metastases and SREs in melanoma to facilitate patient and physician decision-making and ultimately improve outcomes in this patient population.

Hypnotic treatment improves sleep architecture and EEG disruptions and rescues memory deficits in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is associated with disrupted cognition and sleep abnormalities. Sleep loss negatively impacts cognitive function, and one untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We tested whether ML297, a hypnotic acting on G-protein-activated inward-rectifying potassium (GIRK) channels, could reverse sleep phenotypes and disrupted memory in Fmr1-/y mice. Fmr1-/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM architecture, altered sleep electroencephalogram (EEG) oscillations, and reduced EEG coherence between cortical areas; these are partially reversed following ML297 administration. Treatment following contextual fear or spatial learning restores disrupted memory consolidation in Fmr1-/y mice. During memory recall, Fmr1-/y mice show an altered balance of activity among hippocampal principal neurons vs. parvalbumin-expressing interneurons; this is partially reversed by ML297. Because sleep disruption could impact neurophysiological phenotypes in FXS, augmenting sleep may improve disrupted cognition in this disorder.

T-cells and CD45-cells discovery in the central nervous system of healthy and nodavirus-infected teleost fish Dicentrarchus labrax.

To achieve insights in antiviral immune defense of the central nervous system (CNS), we investigated T cells and CD45 cells in the marine fish model Dicentrarchus labrax infected with the CNS-tropic virus betanodavirus. By employing markers for pan-T cells (mAb DLT15) and CD45-cells (mAb DLT22) in immunofluorescence (IIF) of leukocytes from brain, we obtained 3,7 ± 2.3 % of T cells and 7.3 ± 3.2 % of CD45+ cells. Both IIF and immunoelectron microscopy confirmed a leukocyte/glial morphology for the immunoreactive cells. Quantitative immunohistochemistry (qIHC) of brain/eye sections showed 1.9 ± 0.8 % of T+ cells and 2 ± 0.9 % of CD45+ cells in the brain, and 3.6 ± 1.9 % and 4.1 ± 2.2 % in the eye, respectively. After in vivo RGNNV infection the number of T cells/CD45+ leukocytes in the brain increased to 8.3 ± 2.1 % and 11.6 ± 4.4 % (by IIF), and 26.1 ± 3.4 % and 45.6 ± 5.9 % (by qIHC), respectively. In the eye we counted after infection 8.5 ± 4.4 % of T cells and 10.2 ± 5.8 % of CD45 cells. Gene transcription analysis of brain mRNA revealed a strong increase of gene transcripts coding for: antiviral proteins Mx and ISG-12; T-cell related CD3ε/δ, TcRß, CD4, CD8α, CD45; and for immuno-modulatory cytokines TNFα, IL-2, IL-10. A RAG-1 gene product was also present and upregulated, suggesting somatic recombination in the fish brain. Similar transcription data were obtained in the eye, albeit with differences. Our findings provide first evidence for a recruitment and involvement of T cells and CD45+ leukocytes in the fish eye-brain axis during antiviral responses and suggest similarities in the CNS immune defense across evolutionary distant vertebrates.

The Impact of Preprocedural Platelet Function Testing on Periprocedural Complication Rates Associated With Pipeline Flow Diversion: An International Multicenter Study.

BACKGROUND AND OBJECTIVES: Dual antiplatelet therapy (DAPT) is necessary to minimize the risk of periprocedural thromboembolic complications associated with aneurysm embolization using pipeline embolization device (PED). We aimed to assess the impact of platelet function testing (PFT) on reducing periprocedural thromboembolic complications associated with PED flow diversion in patients receiving aspirin and clopidogrel. METHODS: Patients with unruptured intracranial aneurysms requiring PED flow diversion were identified from 13 centers for retrospective evaluation. Clinical variables including the results of PFT before treatment, periprocedural DAPT regimen, and intracranial complications occurring within 72 h of embolization were identified. Complication rates were compared between PFT and non-PFT groups. Differences between groups were tested for statistical significance using the Wilcoxon rank sum, Fisher exact, or χ 2 tests. A P -value <.05 was statistically significant. RESULTS: 580 patients underwent PED embolization with 262 patients dichotomized to the PFT group and 318 patients to the non-PFT group. 13.7% of PFT group patients were clopidogrel nonresponders requiring changes in their pre-embolization DAPT regimen. Five percentage of PFT group [2.8%, 8.5%] patients experienced thromboembolic complications vs 1.6% of patients in the non-PFT group [0.6%, 3.8%] ( P = .019). Two (15.4%) PFT group patients with thromboembolic complications experienced permanent neurological disability vs 4 (80%) non-PFT group patients. 3.7% of PFT group patients [1.5%, 8.2%] and 3.5% [1.8%, 6.3%] of non-PFT group patients experienced hemorrhagic intracranial complications ( P > .9). CONCLUSION: Preprocedural PFT before PED treatment of intracranial aneurysms in patients premedicated with an aspirin and clopidogrel DAPT regimen may not be necessary to significantly reduce the risk of procedure-related intracranial complications.

Genomic prediction within and across maize landrace derived populations using haplotypes.

Genomic prediction (GP) using haplotypes is considered advantageous compared to GP solely reliant on single nucleotide polymorphisms (SNPs), owing to haplotypes' enhanced ability to capture ancestral information and their higher linkage disequilibrium with quantitative trait loci (QTL). Many empirical studies supported the advantages of haplotype-based GP over SNP-based approaches. Nevertheless, the performance of haplotype-based GP can vary significantly depending on multiple factors, including the traits being studied, the genetic structure of the population under investigation, and the particular method employed for haplotype construction. In this study, we compared haplotype and SNP based prediction accuracies in four populations derived from European maize landraces. Populations comprised either doubled haploid lines (DH) derived directly from landraces, or gamete capture lines (GC) derived from crosses of the landraces with an inbred line. For two different landraces, both types of populations were generated, genotyped with 600k SNPs and phenotyped as lines per se for five traits. Our study explores three prediction scenarios: (i) within each of the four populations, (ii) across DH and GC populations from the same landrace, and (iii) across landraces using either DH or GC populations. Three haplotype construction methods were evaluated: 1. fixed-window blocks (FixedHB), 2. LD-based blocks (HaploView), and 3. IBD-based blocks (HaploBlocker). In within population predictions, FixedHB and HaploView methods performed as well as or slightly better than SNPs for all traits. HaploBlocker improved accuracy for certain traits but exhibited inferior performance for others. In prediction across populations, the parameter setting from HaploBlocker which controls the construction of shared haplotypes between populations played a crucial role for obtaining optimal results. When predicting across landraces, accuracies were low for both, SNP and haplotype approaches, but for specific traits substantial improvement was observed with HaploBlocker. This study provides recommendations for optimal haplotype construction and identifies relevant parameters for constructing haplotypes in the context of genomic prediction.

Immunotherapy time of infusion impacts survival in head and neck cancer: A propensity score matched analysis.

The adaptive immune response is physiologically regulated by the circadian rhythm. Data in lung and melanoma malignancies suggests immunotherapy infusions earlier in the day may be associated with improved response; however, the optimal time of administration for patients with head and neck squamous cell carcinoma (HNSCC) is not known. We aimed to evaluate the association of immunotherapy infusion time with overall survival (OS) and progression free survival (PFS) in patients with HNSCC in an Institutional Review Board-approved, retrospective cohort study. 113 patients met study inclusion criteria and 98 patients were included in a propensity score-matched cohort. In the full unmatched cohort (N = 113), each additional 20 % of infusions received after 1500 h conferred an OS hazard ratio (HR) of 1.35 (95 % C.I.1.2-1.6; p-value = 0.0003) and a PFS HR of 1.34 (95 % C.I.1.2-1.6; p-value < 0.0001). A propensity score-matched analysis of patients who did or did not receive ≥20 % of infusions after 1500 h showed that those who were administered ≥20 % of infusions after 1500 h trended towards a shorter OS (HR = 1.35; p-value = 0.26) and a shorter PFS (HR = 1.57, 95 % C.I. 1.02-2.42, p-value = 0.04). Each additional 20 % of infusions received after 1500 h remained robust in the matched cohort multivariable analysis and was associated with shorter OS (adjusted HR = 1.4 (95 % C.I.1.2-1.8), p-value < 0.001). Patients with advanced HNSCC who received more of their infusions in the afternoon were associated with shorter OS and PFS and scheduling immunotherapy infusions earlier in the day may be warranted.