Platelet Angiopoietin-1 Protects Against Murine Models of Tumor Metastasis.

BACKGROUND: In addition to their fundamental roles in preserving vascular integrity, platelets also contribute to tumor angiogenesis and metastasis. However, despite being a reservoir for angiogenic and metastatic cytokines, platelets also harbor negative regulators of tumor progression. Angpt1 (angiopoietin-1) is a cytokine essential for developmental angiogenesis that also protects against tumor cell metastasis through an undefined mechanism. Although activated platelets release Angpt1 from α-granules into circulation, the contributions of platelet Angpt1 to tumor growth, angiogenesis, and metastasis have not been investigated. METHODS: Using cytokine arrays and ELISAs, we first compared platelet Angpt1 levels in breast and melanoma mouse tumor models to tumor-free controls. We then assessed tumor growth and metastasis in mice lacking megakaryocyte and platelet Angpt1 (Angpt1Plt KO). The spontaneous metastasis of mammary-injected tumor cells to the lungs was quantified using RT-PCR (reverse transcription-polymerase chain reaction). The lung colonization of intravenously injected tumor cells and tumor cell extravasation were determined using fluorescent microscopy and flow cytometry. RESULTS: Platelet Angpt1 is selectively upregulated in the PyMT (polyoma middle tumor antigen) breast cancer mouse model, and platelets are the principal source of Angpt1 in blood circulation. While primary tumor growth and angiogenesis were unaffected, Angpt1Plt KO mice had both increased spontaneous lung metastasis and tumor cell lung colonization following mammary or intravenous injection, respectively. Although platelet Angpt1 did not affect initial tumor cell entrapment in the lungs, Angpt1Plt KO mice had increased tumor cell retention and extravasation. Serum from Angpt1Plt KO mice increased endothelial permeability and reduced VE (vascular endothelial)-cadherin expression at endothelial junctions compared with serum from control mice (Angpt1WT). CONCLUSIONS: Platelets provide an intravascular source of Angpt1 that restrains tumor metastasis by preserving the lung microvasculature to limit tumor cell extravasation.

Perspectives of people with HIV on implementing long acting cabotegravir plus rilpivirine in clinics and community settings in the UK: results from the anti-sexist, anti-racist, anti-ageist ILANA study.

INTRODUCTION: The equity-focused ILANA study evaluated feasibility, acceptability, appropriateness of delivering on-label two-monthly cabotegravir and rilpivirine (CAB+RPV) injections for HIV-1 therapy in clinics and community settings. METHODS: The study, which mandated inclusive recruitment, was conducted May-December 2022 at six UK sites. Injections were delivered in clinic (months 1-6), and in clinic or community setting according to patient choice (months 6-12). Surveys were completed at baseline, M4 and M12 using validated measures for feasibility (FIM), acceptability (AIM), and appropriateness (IAM). Primary endpoint: proportion of participants agreeing that the injection and community setting were feasible (FIM>4) at M12. Fourteen participants completed interviews at baseline and M12. RESULTS: Community settings offered by sites included: home visits (n=3), HIV support organisations (n=2), community clinic (n=1). Of 114 participants,54% were female, 70% racially minoritised and 40% aged >50. 27/114 chose to receive injections in community settings. FIM/AIM/IAM scores at M12 were high for the injection (79.0-87.4%) and lower for the community setting (44.2-47.4%) overall. Subgroup analyses indicated differences in scores by gender and ethnicity. Among those who attended the community, FIM/AIM/IAM scores for the community setting at M12 were high (73.1-80.8%). Concerns about stigma, inconvenience, and losing access to trusted clinicians negatively influenced perceptions of receiving injections at community settings, amongst other factors. CONCLUSION: CAB+RPV injections were considered highly feasible, acceptable, and appropriate, however few chose community delivery. Those that chose community delivery found it highly acceptable and feasible. Further exploration of CAB+RPV delivery in alternative community sites not offered (e.g. primary care or pharmacies) is warranted.

Multicentre service evaluation of injectable cabotegravir and rilpivirine delivery and outcomes across 12 UK clinics (SHARE LAI-net).

INTRODUCTION: Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics. METHODS: Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia. RESULTS: In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV. CONCLUSION: In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure.

Comprehensive mutational profiling identifies new driver events in cutaneous leiomyosarcoma.

BACKGROUND: Cutaneous leiomyosarcoma (cLMS) is a rare soft tissue neoplasm, showing smooth muscle differentiation, that arises from the mesenchymal cells of the dermis. To-date, genetic investigation of these tumours has involved studies with small sample sizes and limited analyses that identified recurrent somatic mutations in RB1 and TP53, copy number gain of MYCOD and IGF1R, and copy number loss of PTEN. OBJECTIVES: To better understand the molecular pathogenesis of cLMS, we comprehensively explored the mutational landscape of these rare tumours to identify candidate driver events. METHODS: In this retrospective, multi-institutional study, we performed whole-exome sequencing and RNA sequencing on 38 cases of cLMS. RESULTS: TP53 and RB1 were identified as significantly mutated, thus, represent validated driver genes of cLMS. COSMIC mutational signatures SBS7a/b and DBS1 were recurrent, thus, ultraviolet light exposure may be an aetiological factor driving cLMS. Analysis of significantly recurrent somatic copy number alterations, which represent candidate driver events, found focal (<10Mb) deletions encompassing TP53 and KDM6B, and amplifications encompassing ZMYM2, MYOCD, MAP2K4 and NCOR1. A larger (24 Mb) recurrent deletion encompassing CYLD was also identified as significant. Significantly recurrent broad copy number alterations, involving at least half of a chromosome arm, included deletions of 6p/q, 10p/q, 11q, 12q, 13q and 16p/q, and amplification of 15q. Notably PTEN is located on 10q, RB1 on 13q and IGFR1 on 15q. Fusion gene analysis identified recurrent CRTC1/3::MAML2 fusions, as well as many novel fusions in individual samples. CONCLUSIONS: Our analysis of the largest number of cLMS cases to-date highlights the importance of large cohort sizes and the exploration beyond small targeted gene panels when performing molecular analyses, as it allowed a comprehensive exploration of the mutational landscape of these tumours and identification of novel candidate driver events. It also uniquely afforded the opportunity to compare the molecular phenotype of cLMS with LMS of other tissue types, such as uterine and soft tissue LMS. Given that molecular profiling has resulted in the development of novel targeted treatment approaches for uterine and soft tissue LMS, our study now allows the same opportunities to become available for patients with cLMS.

Complementary feeding practices of caregivers of infants with Down syndrome as compared to caregivers of typically developing infants.

Caregiver feeding practices during the complementary feeding period (6 months-2 years) may be particularly important for infants with Down syndrome (DS) as they are at higher risk for later health conditions (e.g., obesity, diabetes) that can be influenced by early feeding practices. However, how well caregivers of infants with DS are meeting infant feeding evidence-based practices is relatively unknown. Caregivers of infants with DS (N = 75) and caregivers of typically developing (TD) infants (N = 66) aged 0-2 years completed an online survey about their infant feeding practices and information sources. Caregiver practices and information sources were statistically compared between groups. Results indicated that there are significant differences in the feeding practices of caregivers of infants with DS when compared to caregivers of TD infants. Caregivers of infants with DS were less likely to meet infant feeding evidence-based practices than caregivers of TD infants. Caregivers of infants with DS were also more concerned about their infant's food intake and later weight status. Some individual feeding practices also significantly differed between groups, with caregivers of infants with DS more likely to meet evidence-based practices of purchasing iron rich foods and avoiding added salt, but less likely to use responsive feeding practices than caregivers of TD infants. Caregivers of infants with DS were also less likely to receive information about how to navigate the complementary feeding period than caregivers of TD infants. Coupled with existing research, the results of the present study suggest that infant feeding evidence-based practices should be reviewed for their appropriateness for this population and additional support for caregivers of infants with DS should be implemented to help them navigate this important period.

Posterior reversible encephalopathy syndrome in the setting of IgA vasculitis.

IgA vasculitis (IgAV), formerly known as Henoch-Scholein purpura, is a small vessel vasculitis, most commonly seen in pediatric patients, that can affect numerous internal organs including the kidneys, lungs, gastrointestinal tract, and the central nervous system (CNS). CNS manifestations of this condition include hypertensive encephalopathy, thrombosis, optic neuropathy, seizures, CNS vasculitis, and a more recently described phenomenon known as posterior reversible encephalopathy syndrome (PRES). Symptoms of PRES include hypertension, altered mental status, and seizures caused by vasogenic disruption of the blood-brain barrier, and the condition is diagnosed by characteristic edema-related gray-white matter changes in the parieto-occipital lobes on magnetic resonance imaging. Herein, we present a rare case of PRES as a presenting sign of IgAV to increase awareness about this unusual association.

Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice.

OBJECTIVES: Prior studies noted that chondrocyte SIRT6 activity is repressed in older chondrocytes rendering cells susceptible to catabolic signalling events implicated in osteoarthritis (OA). This study aimed to define the effect of Sirt6 deficiency on the development of post-traumatic and age-associated OA in mice. METHODS: Male cartilage-specific Sirt6-deficient mice and Sirt6 intact controls underwent destabilisation of the medial meniscus (DMM) or sham surgery at 16 weeks of age and OA severity was analysed at 6 and 10 weeks postsurgery. Age-associated OA was assessed in mice aged 12 and 18 months of age. OA severity was analysed by micro-CT, histomorphometry and scoring of articular cartilage structure, toluidine blue staining and osteophyte formation. SIRT6-regulated pathways were analysed in human chondrocytes by RNA-sequencing, qRT-PCR and immunoblotting. RESULTS: Sirt6-deficient mice displayed enhanced DMM-induced OA severity and accelerated age-associated OA when compared with controls, characterised by increased cartilage damage, osteophyte formation and subchondral bone sclerosis. In chondrocytes, RNA-sequencing revealed that SIRT6 depletion significantly repressed cartilage extracellular matrix (eg, COL2A1) and anabolic growth factor (eg, insulin-like growth factor-1 (IGF-1)) gene expression. Gain-of-function and loss-of-function studies in chondrocytes demonstrated that SIRT6 depletion attenuated, whereas adenoviral overexpression or MDL-800-induced SIRT6 activation promoted IGF-1 signalling by increasing Aktser473 phosphorylation. CONCLUSIONS: SIRT6 deficiency increases post-traumatic and age-associated OA severity in vivo. SIRT6 profoundly regulated the pro-anabolic and pro-survival IGF-1/Akt signalling pathway and suggests that preserving the SIRT6/IGF-1/Akt axis may be necessary to protect cartilage from injury-associated or age-associated OA. Targeted therapies aimed at increasing SIRT6 function could represent a novel strategy to slow or stop OA.

Evaluation of pre-implantation genetic testing for aneuploidy outcomes in patients without infertility undergoing in vitro fertilization compared to infertile controls.

PURPOSE: To evaluate pre-implantation genetic testing for aneuploidy (PGT-A) outcomes in patients without infertility compared to infertile patients. METHODS: We performed a retrospective cohort study of all patients without an infertility diagnosis ("fertile" patients) who utilized PGT-A at a large university-affiliated fertility center between 2016 and 2021. Fertile patients were 1-to-3 matched to infertile controls by age and number of oocytes retrieved. The primary outcome was blastocyst aneuploidy rate. Secondary outcomes included ovarian reserve markers, laboratory outcomes, and other PGT-A outcomes [rates of euploidy, mosaicism, and potentially transferrable (euploid + mosaic) embryos]. RESULTS: 283 fertile and 849 infertile patients were included. Median age, anti-Mullerian hormone, and day 2 estradiol levels were equivalent among groups; day 2 follicle-stimulating hormone levels were higher in fertile patients (6.9 vs. 6.5 IU/mL, p < 0.01). The aneuploidy rate was similar among fertile and infertile patients (33.7% vs. 31.8%, p = 0.11); the euploidy rate was higher (50.8% vs. 47.0%, p < 0.01), and the mosaicism rate was lower in fertile patients (13.3% vs. 19.2%, p < 0.01). The rate of transferrable embryos was similar among groups (64.0% vs. 66.3%, p = 0.07), as was the percentage of patients yielding ≥ 1 euploid embryo (90.1% vs. 87.3%, p = 0.25). When controlling for significant covariates, multiple linear regression showed that aneuploidy rate was equivalent in both cohorts. CONCLUSION: Aneuploidy rate was similar in fertile and infertile patients. Fertile patients had slightly higher euploidy and lower mosaicism than infertile patients. Still, compared to fertile patients, infertile patients had equivalent rates of transferrable embryos and were just as likely to yield ≥ 1 euploid embryo.

Multi-Omic Temporal Landscape of Plasma and Synovial Fluid-Derived Extracellular Vesicles Using an Experimental Model of Equine Osteoarthritis.

Extracellular vesicles (EVs) contribute to osteoarthritis pathogenesis through their release into joint tissues and synovial fluid. Synovial fluid-derived EVs have the potential to be direct biomarkers in the causal pathway of disease but also enable understanding of their role in disease progression. Utilizing a temporal model of osteoarthritis, we defined the changes in matched synovial fluid and plasma-derived EV small non-coding RNA and protein cargo using sequencing and mass spectrometry. Data exploration included time series clustering, factor analysis and gene enrichment interrogation. Chondrocyte signalling was analysed using luciferase-based transcription factor activity assays. EV protein cargo appears to be more important during osteoarthritis progression than small non-coding RNAs. Cluster analysis revealed plasma-EVs represented a time-dependent response to osteoarthritis induction associated with supramolecular complexes. Clusters for synovial fluid-derived EVs were associated with initial osteoarthritis response and represented immune/inflammatory pathways. Factor analysis for plasma-derived EVs correlated with day post-induction and were primarily composed of proteins modulating lipid metabolism. Synovial fluid-derived EVs factors represented intermediate filament and supramolecular complexes reflecting tissue repair. There was a significant interaction between time and osteoarthritis for CRE, NFkB, SRE, SRF with a trend for osteoarthritis synovial fluid-derived EVs at later time points to have a more pronounced effect.

Multi-State Implementation of Go NAPSACC to Support Healthy Practices in the Early Care and Education Setting.

Childhood obesity in the United States is a serious problem that puts children at risk for poor health. Effective state-wide interventions are needed to address childhood obesity risk factors. Embedding evidence-based initiatives into state-level Early Care and Education (ECE) systems has the potential to improve health environments and promote healthy habits for the 12.5 million children attending ECE programs. Go NAPSACC, an online program that was adapted from an earlier paper version of Nutrition and Physical Activity Self-Assessment for Child Care (NAPSACC or NAP SACC), provides an evidence-based approach that aligns with national guidance from Caring for Our Children and the Centers for Disease Control and Prevention. This study describes approaches undertaken across 22 states from May 2017 to May 2022 to implement and integrate Go NAPSACC into state-level systems. This study describes challenges encountered, strategies employed, and lessoned learned while implementing Go NAPSACC state-wide. To date, 22 states have successfully trained 1,324 Go NAPSACC consultants, enrolled 7,152 ECE programs, and aimed to impact 344,750 children in care. By implementing evidence-based programs, such as Go NAPSACC, ECE programs state-wide can make changes and monitor progress on meeting healthy best practice standards, increasing opportunities for all children to have a healthy start.

Characteristics of HIV post-exposure prophylaxis recipients at six English sexual health clinics during COVID-19.

OBJECTIVES: Disruption to sexual health services during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]) pandemic may have adversely affected the provision of HIV post-exposure prophylaxis (PEP), possibly leading to increased HIV transmission. Globally, services have reported a reduction in the number of PEP prescriptions dispensed during lockdowns, although it is unclear why. Our primary objective was to describe the temporal change in weekly HIV PEP dispensed at six English sexual health clinics in 2020. METHODS: We performed a cross-sectional review of PEP prescriptions from six English centres during 2020. RESULTS: During 2020, 2884 PEP prescriptions were dispensed across the six centres studied, a fall of 34.5% from the 4403 PEP prescriptions in 2019. Before the COVID-related lockdown in 2020, the PEP dispensed was stable at 82.5 per week. Following the first lockdown, this fell to a nadir of 13 in week 14 (Figure 1). Prescriptions rose to a peak of 79 in week 37 and then declined to 32 prescriptions in the last week of 2020. There was no difference in the following characteristics of PEP recipients before and during the first lockdown: age, ethnicity, country of birth or the service the recipient attended. CONCLUSION: Whatever the reason for the fall in PEP seen in England over 2020, it is essential that HIV testing and access to HIV prevention is maintained for those in need.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Nuclear magnetic resonance spectroscopy of biofluids for osteoarthritis.

BACKGROUND: Osteoarthritis is a common degenerative musculoskeletal disease of synovial joints. It is characterized by a metabolic imbalance resulting in articular cartilage degradation, reduced elastoviscosity of synovial fluid and an altered chondrocyte phenotype. This is often associated with reduced mobility, pain and poor quality of life. Subsequently, with an ageing world population, osteoarthritis is of increasing concern to public health. Nuclear magnetic resonance (NMR) spectroscopy can be applied to characterize the metabolomes of biofluids, determining changes associated with osteoarthritis pathology, identifying potential biomarkers of disease and alterations to metabolic pathways. SOURCES OF DATA: A comprehensive search of PubMed and Web of Science databases using combinations of the following keywords: 'NMR Spectroscopy', 'Blood', 'Plasma', 'Serum', 'Urine', 'Synovial Fluid' and 'Osteoarthritis' for articles published from 2000 to 2020. AREAS OF AGREEMENT: The number of urine metabolomics studies using NMR spectroscopy to investigate osteoarthritis is low, whereas the use of synovial fluid is significantly higher. Several differential metabolites have previously been identified and mapped to metabolic pathways involved in osteoarthritis pathophysiology. AREAS OF CONTROVERSY: Conclusions are sometimes conservative or overinflated, which may reflect the variation in reporting standards. NMR metabolic experimental design may require further consideration, as do the animal models used for such studies. GROWING POINTS: There are various aspects which require improvement within the field. These include stricter adherence to the Metabolomics Standards Initiative, inclusive of the standardization of metabolite identifications; increased utilization of integrating NMR metabolomics with other 'omic' disciplines; and increased deposition of raw experimental files into open access online repositories, allowing greater transparency and enabling additional future analyses. AREAS TIMELY FOR DEVELOPING RESEARCH: Overall, this research area could be improved by the inclusion of more heterogeneous cohorts, reflecting varying osteoarthritis phenotypes, and larger group sizes ensuring studies are not underpowered. To correlate local and systemic environments, the use of blood for diagnostic purposes, over the collection of synovial fluid, requires increased attention. This will ultimately enable biomarkers of disease to be determined that may provide an earlier diagnosis, or provide potential therapeutic targets for osteoarthritis, ultimately improving patient prognosis.

Sexually transmitted infection (STI) research priority-setting: a two-stage study including the perspectives of patients, the public, clinicians and stakeholders.

OBJECTIVES: Patient and public involvement (PPI) in research priority-setting remains limited, especially for non-HIV STI. We identify and compare the top 10 patient and public STI research priorities with those of clinicians and STI stakeholders. METHODS: This two-stage study was conducted in May-August 2019. First, STI research priorities were canvassed through qualitative questionnaires issued to all patients attending a large sexual health clinic, all clinicians in region-wide mailing lists, all stakeholders identified through existing networks and the Charity Commission database, and to the Liverpool public. Raw responses were organised by theme into a shortlist of 25. In stage 2, these were ranked through priority-setting activities by telephone with patients and the public (n=8) and some clinicians (n=3), and in two workshops with clinicians (n=26) and stakeholders (n=5), respectively. The top 10 priorities were compared. RESULTS: Of 373 surveys submitted, 106 were analysed (83 patient and public; 23 clinician and stakeholder). Exclusions included lack of completion and responses out of scope. Among patient and public respondents, 55% (n=46) were aged 18-24 years, 51% (n=42) identified as heterosexual women and 23% (n=19) as men who have sex with men. Clinicians included all cadres; stakeholders were academics, commissioners and third sector representatives. In stage 2, 4 of 10 themes (STI education, targeted services for high-risk groups, antibiotic resistance and counselling for those with STI) were prioritised by all. Remote STI services and rapid diagnostics also ranked highly but the rationale differed between groups. CONCLUSION: This is the first non-HIV STI research priority-setting exercise to be reported in the UK. It identifies overlaps and differences between public and provider concerns, highlights gaps in the public understanding of STI research, and shows how PPI can promote research responsive to the concerns of both those who use and deliver services.

The effects of PD-1/PD-L1 checkpoint inhibitors on recurrent/metastatic head and neck squamous cell carcinoma: a critical review of the literature and meta-analysis.

INTRODUCTION: 50% of patients with locally advanced HNSCC eventually present with disease recurrence or metastasis. Interaction of programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), allows tumour cells to evade immune attack by inhibiting T-cell activation. PD-1/PD-L1 checkpoint inhibitors block this immunosuppressive effect. This study aims to investigate the efficacy of anti-PD-1/PD-L1 agents for recurrent/metastatic (R/M) HNSCC in terms of survival, toxicity, and response. It will test the hypothesis that immunotherapy improves treatment outcomes for R/M HNSCC patients. MATERIAL AND METHODS: Studies were identified through an electronic search of databases EMBASE and Medline. Data on survival, response and toxicity following PD-1/PD-L1 inhibition was extracted from included studies and compared. A subgroup meta-analysis compared these outcomes in PD-1/PD-L1 inhibition versus the standard of care (SOC). RESULTS: Thirteen studies (n = 1798) were included in this review. Overall survival following PD-1/PD-L1 checkpoint inhibition ranged from 6 to 13 months. The most common treatment-related adverse events (TRAEs) were fatigue, hypothyroidism and nausea; Grade ≥3 TRAEs occurred in 13% of patients. Meta-analysis of RCTs showed that anti-PD-1/PD-L1 agents improved survival and reduced toxicity compared to the SOC. This was demonstrated by a 37% lower risk of death (OR = 0.63, 95% CI = 0.51-0.78, I2 = 18%, p ≤ 0.0001) and a 77% lower risk of any-grade TRAEs (OR = 0.23, 95% CI = 0.18-0.29, I2 = 90%, p ≤ 0.00001) with immunotherapy versus SOC. DISCUSSION: Based on the observed safety and efficacy, PD-1/PD-L1 checkpoint inhibition improves treatment outcomes for R/M HNSCC patients. PD-1/PD-L1 inhibitors significantly prolonged survival and reduced toxicity compared to the SOC, however further randomised trials are needed to investigate their role in HNSCC.

Postmortem Cortical Transcriptomics of Lewy Body Dementia Reveal Mitochondrial Dysfunction and Lack of Neuroinflammation.

OBJECTIVE: Prevalence of Lewy body dementias (LBD) is second only to Alzheimer's disease (AD) among people with neurodegenerative dementia. LBD cause earlier mortality, more intense neuropsychiatric symptoms, more caregivers' burden, and higher costs than AD. The molecular mechanisms underlying LBD are largely unknown. As advancing molecular level mechanistic understanding is essential for identifying reliable peripheral biomarkers and novel therapeutic targets for LBD, the authors aimed to identify differentially expressed genes (DEG), and dysfunctional molecular networks in postmortem LBD brains. METHODS: The authors investigated the transcriptomics of postmortem anterior cingulate and dorsolateral prefrontal cortices of people with pathology-verified LBD using next-generation RNA-sequencing. The authors verified the identified DEG using high-throughput quantitative polymerase chain reactions. Functional implications of identified DEG and the consequent metabolic reprogramming were evaluated by Ingenuity pathway analyses, genome-scale metabolic modeling, reporter metabolite analyses, and in silico gene silencing. RESULTS: The authors identified and verified 12 novel DEGs (MPO, SELE, CTSG, ALPI, ABCA13, GALNT6, SST, RBM3, CSF3, SLC4A1, OXTR, and RAB44) in LBD brains with genome-wide statistical significance. The authors documented statistically significant down-regulation of several cytokine genes. Identified dysfunctional molecular networks highlighted the contributions of mitochondrial dysfunction, oxidative stress, and immunosenescence toward neurodegeneration in LBD. CONCLUSION: Our findings support that chronic microglial activation and neuroinflammation, well-documented in AD, are notably absent in LBD. The lack of neuroinflammation in LBD brains was corroborated by statistically significant down-regulation of several inflammatory markers. Identified DEGs, especially down-regulated inflammatory markers, may aid distinguishing LBD from AD, and their biomarker potential warrant further investigation.

Effect of sedation or general anesthesia on elbow goniometry and thoracic limb circumference measurements in dogs with naturally occurring elbow osteoarthritis.

OBJECTIVE: To evaluate the effect of sedation or general anesthesia (GA) on elbow goniometry and thoracic limb circumference (TLC) measurements in dogs with elbow osteoarthritis (OA). STUDY DESIGN: Prospective study. ANIMALS: Twenty-four client-owned dogs with radiographically confirmed elbow OA. METHODS: Elbow goniometry and TLC measurements were made before and after either sedation or GA by using a hand-held goniometer and spring tension measuring tape, respectively. Observers were not allowed to review their pre-sedation or pre-GA measurements at the time of obtaining measurements on dogs under sedation or GA. Mixed analysis of variance models were used to compare elbow goniometry and TLC measurements before and after sedation or GA. RESULTS: Eleven and thirteen dogs were included in the sedation and GA groups, respectively. Mean elbow flexion decreased by 5° and 3° and mean elbow extension increased by 6° and 2° under sedation and GA, respectively. Total range of motion increased by 11° under sedation and by 5° under GA. Each of these changes was statistically significant (P < .05) except elbow extension under GA (P = .129). Sedation and GA did not influence TLC measurements (P > .05). CONCLUSION: Sedation or GA led to slight and similar increase in elbow flexion and extension but did not influence TLC measurements in dogs with elbow OA. CLINICAL SIGNIFICANCE: Sedation or GA can cause slight alterations to goniometric measurements in canine elbows with OA. The protocols used in this study for sedation and GA seem interchangeably acceptable for goniometry and TLC measurements in dogs with elbow OA.

Confirming the Presence of Unrecognized Meniscal Injuries on Magnetic Resonance Imaging in Pediatric and Adolescent Patients With Anterior Cruciate Ligament Tears.

BACKGROUND: Prior research has shown decreased accuracy of meniscal injury detection using magnetic resonance imaging (MRI) for anterior cruciate ligament (ACL)-deficient adult patients as well as ACL-deficient pediatric and adolescent patients. The objectives of this study were the following: (1) assess the diagnostic ability of MRI in detecting meniscal injuries for pediatric and adolescent patients undergoing arthroscopic ACL reconstruction and (2) characterize the unrecognized meniscal injuries. METHODS: The sensitivity, specificity, positive predictive value, and negative predictive value of meniscal tears (medial, lateral, or both) on MRI were calculated for the 107 patients in this cohort. Fisher exact tests were used to compare event frequencies between medial meniscal (MM) and lateral meniscal (LM) tears. One-way analysis of variance tests were performed to compare event rates between the location and type of unrecognized meniscal tears. RESULTS: The median age of the cohort was 15 (range: 7 to 18). The sensitivity, specificity, positive predictive value, and negative predictive value of MRI in detecting meniscal tears (medial, lateral, or both) in ACL-deficient pediatric and adolescent patients was 62.3%, 68.4%, 78.2%, and 50.0%, respectively. There were 26 (24.3%) cases in which a meniscal injury was not detected on MRI, but was discovered arthroscopically (MM: 5 knees, LM: 20 knees, both: 1 knee). These unrecognized meniscal injuries were more commonly the LM than the MM (77.8%, P-value=0.100), a vertical/longitudinal tear type (77.8%, P-value <0.001), and located in the posterior horn (74.1%, P-value <0.001). CONCLUSIONS: In this ACL-deficient pediatric and adolescent cohort, there were 26 (24.3%) patients with unrecognized meniscal injuries. A vertical tear in the posterior horn was the most commonly unrecognized meniscal injury, supporting the findings of prior research postulating that the location and configuration of a tear influence the accuracy of MRI in detecting these injuries. More research is needed to investigate strategies to improve the detection of meniscal tears in pediatric and adolescent patients preoperatively. These findings have implications with regard to patient counseling, operative planning, anticipatory guidance with regard to postoperative rehabilitation, recovery expectations, and surgical outcomes. LEVEL OF EVIDENCE: Level IV.

Community screening for visual impairment in older people.

BACKGROUND: Visual problems in older people are common and frequently under-reported. The effects of poor vision in older people are wide reaching and include falls, confusion and reduced quality of life. Much of the visual impairment in older ages can be treated (e.g. cataract surgery, correction of refractive error). Vision screening may therefore reduce the number of older people living with sight loss. OBJECTIVES: The objective of this review was to assess the effects on vision of community vision screening of older people for visual impairment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 10); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 23 November 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared vision screening alone or as part of a multi-component screening package as compared to no vision screening or standard care, on the vision of people aged 65 years or over in a community setting. We included trials that used self-reported visual problems or visual acuity testing as the screening tool. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. We graded the certainty of the evidence using GRADE. MAIN RESULTS: Visual outcome data were available for 10,608 people in 10 trials. Four trials took place in the UK, two in Australia, two in the United States and two in the Netherlands. Length of follow-up ranged from one to five years. Three of these studies were cluster-randomised trials whereby general practitioners or family physicians were randomly allocated to undertake vision screening or no vision screening. All studies were funded by government agencies. Overall we judged the studies to be at low risk of bias and only downgraded the certainty of the evidence (GRADE) for imprecision.Seven trials compared vision screening as part of a multi-component screening versus no screening. Six of these studies used self-reported vision as both screening tool and outcome measure, but did not directly measure vision. One study used a combination of self-reported vision and visual acuity measurement: participants reporting vision problems at screening were treated by the attending doctor, referred to an eye care specialist or given information about resources that were available to assist with poor vision. There was a similar risk of "not seeing well" at follow-up in people screened compared with people not screened in meta-analysis of six studies (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.97 to 1.14, 4522 participants high-certainty evidence). One trial reported "improvement in vision" and this occurred slightly less frequently in the screened group (RR 0.85, 95% CI 0.52 to 1.40, 230 participants, moderate-certainty evidence).Two trials compared vision screening (visual acuity testing) alone with no vision screening. In one study, distance visual acuity was similar in the two groups at follow-up (mean difference (MD) 0.02 logMAR, 95% CI -0.02 to 0.05, 532 participants, high-certainty evidence). There was also little difference in near acuity (MD 0.02 logMAR, 95% CI -0.03 to 0.07, 532 participants, high-certainty evidence). There was no evidence of any important difference in quality of life (MD -0.06 National Eye Institute 25-item visual function questionnaire (VFQ-25) score adjusted for baseline VFQ-25 score, 95% CI -2.3 to 1.1, 532 participants, high-certainty evidence). The other study could not be included in the data analysis as the number of participants in each of the arms at follow-up could not be determined. However the authors stated that there was no significant difference in mean visual acuity in participants who had visual acuity assessed at baseline (39 letters) as compared to those who did not have their visual acuity assessed (35 letters, P = 0.25, 121 participants).One trial compared a detailed health assessment including measurement of visual acuity (intervention) with a brief health assessment including one question about vision (standard care). People given the detailed health assessment had a similar risk of visual impairment (visual acuity worse than 6/18 in either eye) at follow-up compared with people given the brief assessment (RR 1.07, 95% CI 0.84 to 1.36, 1807 participants, moderate-certainty evidence). The mean composite score of the VFQ-25 was 86.0 in the group that underwent visual acuity screening compared with 85.6 in the standard care group, a difference of 0.40 (95% CI -1.70 to 2.50, 1807 participants, high-certainty evidence). AUTHORS' CONCLUSIONS: The evidence from RCTs undertaken to date does not support vision screening for older people living independently in a community setting, whether in isolation or as part of a multi-component screening package. This is true for screening programmes involving questions about visual problems, or direct measurements of visual acuity.The most likely reason for this negative review is that the populations within the trials often did not take up the offered intervention as a result of the vision screening and large proportions of those who did not have vision screening appeared to seek their own intervention. Also, trials that use questions about vision have a lower sensitivity and specificity than formal visual acuity testing. Given the importance of visual impairment among older people, further research into strategies to improve vision of older people is needed. The effectiveness of an optimised primary care-based screening intervention that overcomes possible factors contributing to the observed lack of benefit in trials to date warrants assessment; trials should consider including more dependent participants, rather than those living independently in the community.

Colour in digital pathology: a review.

Colour is central to the practice of pathology because of the use of coloured histochemical and immunohistochemical stains to visualize tissue features. Our reliance upon histochemical stains and light microscopy has evolved alongside a wide variation in slide colour, with little investigation into the implications of colour variation. However, the introduction of the digital microscope and whole-slide imaging has highlighted the need for further understanding and control of colour. This is because the digitization process itself introduces further colour variation which may affect diagnosis, and image analysis algorithms often use colour or intensity measures to detect or measure tissue features. The US Food and Drug Administration have released recent guidance stating the need to develop a method of controlling colour reproduction throughout the digitization process in whole-slide imaging for primary diagnostic use. This comprehensive review introduces applied basic colour physics and colour interpretation by the human visual system, before discussing the importance of colour in pathology. The process of colour calibration and its application to pathology are also included, as well as a summary of the current guidelines and recommendations regarding colour in digital pathology.