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ABSTRACTBackground Effective vaccine management is crucial to maintain vaccine potency. To achieve this, elements, such as temperature management, stock management, infrastructure, cold chain equipment and waste management, need to be properly implemented. Therefore, this study was conducted to assess the vaccine storage and stock management practices in public health facilities within Vihiga County.Methods A descriptive cross-sectional design was used. Eighty-six public health facilities were selected and one staff involved in handling vaccines from each facility participated in the study. The study utilised survey questionnaires and observational checklists to collect data.Results All facilities visited use standard vaccine requisition forms for ordering and receiving vaccines and physical stock counts are done in all facilities. The majority of immunising healthcare workers knew how to condition icepacks 88.4%; however, 57.0% did not know all the heat-, cold- and light-sensitive vaccines. Status of vaccine equipment, knowledge of healthcare workers and stock management practices were positively associated with vaccine cold chain management at 52.8%.Conclusion Knowledge of vaccine handlers and stock management practices should be improved to enhance effective vaccine management. Besides, there is a need for the County Government of Vihiga to purchase sufficient WHO-recommended refrigerators.

This study delves into the crucial intersection of climate resilience and sustainable agriculture by investigating the application of nature-based solutions (NBS) as adaptive strategies employed by cocoa farmers in Ghana. A total sample of 381 cocoa farmers were selected using the multi-stage sampling technique. Farmers perceive notable changes (increase) in amount of rainfall, degree of temperature and number of rainy days. While the planting of shade trees is adopted by majority of the cocoa farmers to fight climate variability, they also perceive it to be the most effective. Factors that influence cocoa farmers' extent of adopting nature-based solutions are religion, age, years of formal education, land ownership, access to climate information, farm size and income. Climate variability (temperature, rainfall, wind) makes cocoa farmers vulnerable by affecting their social, financial and physical capitals. Nature based solutions (planting shade trees, climate-resilient varieties, early warning systems, knowledge sharing and efficient water management) increase cocoa farmers' resilience against climate variability. Ultimately, the study's outcomes hold implications for both local and global efforts to enhance agricultural resilience and secure livelihoods in an era of climate uncertainty.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 has mainly affected the respiratory system but has expanded to other systems, including the gastrointestinal system. We present an 80-year-old man with sharp epigastric pain and vomiting. Laboratory investigations revealed elevated pancreatic enzymes, and contrast-enhanced computed tomography of the abdomen suggested acute pancreatitis. He was undergoing treatment for acute pancreatitis when he developed respiratory compromise, leading to the use of oxygen. Computed tomography of the chest revealed bilateral pleural effusion. However, a positive nasopharyngeal swab suggested severe acute respiratory syndrome coronavirus 2 infection. He was treated for the viral infection with various medications until clinically stable before being self-isolated at home. His follow-up visits revealed a favorable outcome, with progressive resolve occurring 4 weeks after the onset. There is no specific conclusion regarding pancreatic involvement in severe acute respiratory syndrome coronavirus 2 infection. There are several confounding factors in the etiology of acute pancreatitis during concomitant severe acute respiratory syndrome coronavirus 2 infection. However, further research is warranted to evaluate whether pancreatic involvement is one of the clinical presentations or subsequent complications of severe acute respiratory syndrome coronavirus 2 infection.

Background: Video-based interventions have the potential to contribute to long-lasting improvements in health-seeking behaviours. Ghana's upsurge rate of information and communication technology usage presents an opportunity to improve the awareness of HPV vaccination and screening rates of cervical cancer among women in Ghana. This research aimed to assess the impact of video-based educational intervention centred on the Health Belief and Transtheoretical Models of behavioural changes in promoting HPV vaccination, cervical carcinoma awareness and willingness to have Pap smear test (PST) among women in Ghana.Methods: To achieve the intended sample size, convenient, purposive and stratified random sampling techniques were used. SPSS v. 23.0 was used in the data analysis. Percentages and frequencies were used to represent participants' demographic characteristics, knowledge of (1) cervical carcinoma, (2) human papillomavirus vaccine, and (3) Pap smear test. The chi-square test by McNemar was employed to evaluate variations in the post- and pre-intervention responses. A p-value < 0.05 was considered statistically significant. The level of significance was adjusted owing to multiple comparisons by using the Bonferroni's correction.Results: Before the intervention, 84.2% of the participant had some knowledge or information about cervical cancer, but after the intervention, 100% of the participant became aware of cervical cancer which represents 15.8% increment at a P < .001. The willingness to have a pap smear test increased from 35.8% to 94.2% (df = 58.4%, P < .001) after the educational intervention. The willingness to be vaccinated increased from 47.5% to 81.7% (df = 34.2%, P < .001) after the educational intervention. Six months after the intervention, participants were followed-up. 253 (42.2%) participants had gone for cervical cancer screening (Pap smear test) while 347 (57.8%) participants had not been screened. In terms of HPV vaccination, 192 participants (32.0%) had begun their HPV vaccination cycle.Conclusion: The study results show that health education, using videos, may be influential in perception changing, self-efficacy improvement and the understanding of cervical carcinoma screening and HPV vaccination.

Background: Cervical cancer (CC) is the fourth most commonly diagnosed cancer among women. Ghana is a low-middle- income country with annual diagnosed cases of 3,151 and 2,119 deaths. The high prevalence rate of cervical cancer in Ghana is mainly due to ineffective preventive measures and insufficient knowledge about the disease. Therefore, our objective was to evaluate the level of knowledge and awareness of cervical cancer and attitude toward human papillomavirus and its vaccine among Ghanaians.Methods: This descriptive cross-sectional survey on the awareness of cervical cancer and attitude toward human papillomavirus and its vaccine was carried out from March 2019 to February 2020. SPSS v. 23.0 was used in the data analysis. The participants' demographic characteristics, knowledge of cervical carcinoma, human papillomavirus vaccine and HPV, and the likelihood to be vaccinated were represented as percentages and frequencies. The difference between males and females was assessed using the chi-square test. The logistic regression analysis was used to evaluate the relationship of possible related indicators with the willingness to receive the HPV vaccine. A p < 0.05 was considered statistically significant.Results: A total of 1,376 participants were involved in the final analysis. Among the 1,376 participants involved in this survey, 1,240 participants (90.1%) representing 456 males (33.1%) and 784 females (57.0%) were aware of the terminology “cervical cancer” with a significant p = 0.001. When stratified by gender, women had significantly greater knowledge, compared to men in terms of “cervical cancer being common in middle age (35–50) females” (75.5 vs. 67.5%, respectively, p ≤ 0.001). When stratified by gender, women had significantly greater knowledge of human papillomavirus (54.5 vs. 43.6%, respectively, p < 0.001) and the human papillomavirus vaccine (39.3 vs. 33.1%, respectively, p = 0.019) compared to men.Conclusion: Majority of the respondents had poor knowledge regarding cervical cancer risk factors, symptoms, HPV, and its vaccine. Hence, this indicates a wakeup call for government to increase the awareness and knowledge level via the media and health professionals.

Purpose: Data on prostate cancer (PCa) treatment in Africa remains under-reported. We present a review of the management of PCa at the cancer center of the largest tertiary referral facility in Ghana, with emphasis on curative treatment. Methods: We retrospectively reviewed data on 1,074 patients seen at the National Center for Radiotherapy and Nuclear Medicine from 2003 to 2016. Patient and disease characteristics at presentation are presented using descriptive statistics. The χ2 and Fisher’s exact tests and Mann-Whitney U test were used to analyze differences between categorical and continuous variables, respectively. Methods of survival analysis were used to evaluate the relative risk of biochemical disease-free survival (bDFS). Results: Seventy percent of the study population presented with localized disease. High-risk disease presentation accounted for 64.4% of these patients. Only 57.6% of patients with localized disease received curative radiotherapy. The 5-year overall survival for the curative cohort was 96% (interquartile range, 93% to 98%). The 5-year bDFS rates for low-, intermediate-, and high-risk groups were 95%, 70%, and 48%, respectively. Both Gleason score and pretreatment prostate-specific antigen were significant predictors for bDFS in multivariable analysis. Conclusion: We show that the majority of patients with PCa have locally advanced disease at the time of presentation for radiotherapy. bDFS was significantly better for low- and intermediate-risk than for high-risk disease. These data emphasize the dire need to re-evaluate screening and patient education of PCa in regions of the world with high incidence and mortality as well as the need for improved access to care and treatment delivery.

Introduction: The present study aimed to generate intensity-modulated beams with Aluminium compensating filters for a conventional telecobalt machine based on the outputs of a treatment planning system (TPS) performing forward planning and cannot simulate directly the compensating filter. Materials and Methods: In order to achieve the beam intensity modulation during treatment planning with the TPS, we used a bolus placed on the surface of a tissue-equivalent phantom. The treatment plans replicated on the telecobalt machine with the bolus were represented with compensating filters placed at a certain distance from the phantom surface. An equation was proposed for the conversion of the bolus thickness to the compensating filter thickness such that any point within the phantom would receive the planned dose. Correction factors were introduced into the proposed equation to account for the influences of field size, treatment depth, and applied bolus thickness. The proposed equation was obtained based on the analyses of empirical data measured in a full scatter water phantom with and without the compensating filter. Results: According to the results, the dosimetric verification of the proposed approach outputs in a solid water phantom with calibrated Gafchromic EBT2 films were comparable to that of the TPS with deviation of ±4.73% (mean: 2.98±1.05%). Conclusion: As the findings of the present study indicated, the discrepancy between the measured doses and TPS-estimated doses was within the tolerance of ±5%, which is recommended for dose delivery in external beam radiotherapy. Therefore, the proposed approach is recommended for clinical application.

BACKGROUND: It is argued that use of the term 'accident' has a negative effect on prevention efforts as the term implies that such events are due to chance. AIM: To test the hypothesis that use of 'injury' in place of 'accident' can influence professional attitudes towards 'accident/injury' prevention. SETTING: Leeds Health Authority area serving the population (n=740,000) of the city of Leeds in the Yorkshire region of England. METHOD: A randomised comparative study. Altogether 183 health visiting staff in the Leeds area were randomised (by place of work) to one of two groups. Each group received a similar postal questionnaire assessing attitudes relating to accident/injury prevention. One group received a questionnaire using only accident terminology while the other used injury terminology throughout. RESULTS: Fifty responses in the accident group were received and 39 in the injury group. Analysis by Mann-Whitney U tests showed little difference in group responses. The only significant finding was that respondents in the 'accident' group were more likely to rank 'accident prevention' of higher importance relative to respondents in the 'injury' group (median 2, 25%-75% quartiles 1.8-4.0 compared with median 4, 25%-75% quartiles 2.0-5.0, p=0.04). However, this may have been a chance finding due to the multiple comparisons made. CONCLUSIONS: This study has shown little difference in health visitor responses when 'accident' is replaced with 'injury'. It is possible that the effect of changing terminology is more nebulous--influencing society at large. However, it would be as well to recognise the lack of evidence and clarity relating to the terminology debate. Otherwise, there is a danger that the 'injury' believers may become alienated from the 'accident' diehards. [ABSTRACT FROM AUTHOR]

Purpose: This study presents the experience of a brachytherapy team in Ghana with a focus on technology transfer and outcome. The team was initially proctored by experienced physicians from Europe and South Africa. Material and methods : A total of 90 consecutive patients underwent either brachytherapy alone or brachytherapy in combination with external beam radiotherapy for prostate carcinoma between July 2008 and February 2014 at Korle Bu Teaching Hospital, Accra, Ghana. Patients were classified as low-risk, intermediate, and high-risk according to the National Comprehensive Cancer Network (NCCN) criteria. All low-risk and some intermediate risk group patients were treated with seed implantation alone. Some intermediate and all high-risk group patients received brachytherapy combined with external beam radiotherapy. Results: The median patient age was 64.0 years (range 46-78 years). The median follow-up was 58 months (range 18-74 months). Twelve patients experienced biochemical failure including one patient who had evidence of metastatic disease and died of prostate cancer. Freedom from biochemical failure rates for low, intermediate, and high-risk cases were 95.4%, 90.9%, and 70.8%, respectively. Clinical parameters predictive of biochemical outcome included: clinical stage, Gleason score, and risk group. Pre-treatment prostate specific antigen (PSA) was not a statistically significant predictor of biochemical failure. Sixty-nine patients (76.6%) experienced grade 1 urinary symptoms in the form of frequency, urgency, and poor stream. These symptoms were mostly self-limiting. Four patients needed catheterization for urinary retention (grade 2). One patient developed a recto urethral fistula (grade 3) following banding for hemorrhoids. Conclusions : Our results compare favorably with those reported by other institutions with more extensive experience. We believe therefore that, interstitial permanent brachytherapy can be safely and effectively performed in a resource challenged environment if adequate training and proctoring is provided.

OBJECTIVES: To examine the effect of socioeconomic status on the attitudes parents of preschool children towards child home safety issues and practice of home safety measures. SETTING: A community based study in the Lanarkshire Health Board area, a mixed urban-rural setting in central Scotland. METHODS: A postal survey of two random samples of parents of preschool children (aged 3 years). One sample (A) involved parents living in more affluent areas and the other (B) parents living in less affluent areas. RESULTS: In general, parents in both groups showed similar attitudes towards home safety. The only significant differences to emerge were over parental perceptions of the safety of the neighbourhood in which they lived and over the availability of money to keep their child safe (group B > group A, p < 0.0042). Parents from group B also tended to report similar or safer levels of home safety behaviour to parents from group A. CONCLUSIONS: The findings do not suggest that differences in the injury experience of children from more and less affluent backgrounds are due to differences in parental attitude, knowledge, or practice of home safety measures. Thus, the study does not support the selective targeting of families from less affluent areas with educational interventions. Instead, the findings do support the use of a multi-method approach to home safety, where educational approaches are complemented by environmental modification. [ABSTRACT FROM AUTHOR]

Empowerment is a necessary determinant of young people’s participation in national, regional and district or local level decision-making processes. For inclusiveness in any social intervention programme, the policy process should be all-embracing sharing of knowledge and active stakeholders’ participation which includes the youth. This paper delineates the context of Local Enterprise and Skills Development Programme (LESDEP) by focusing on the extent to which the programme beneficiaries (youth) were empowered to play active roles in the decision policy processes which goes beyond the rhetoric. In particular, to unpack the perception that young people empowerment in a youth-oriented programme has the potential of curbing the problem of exclusion. Inferences from the concept of an empowerment might be the premise for rethinking the debate surrounding youth empowerment in the initiatives oriented towards young people. Youth in Ghana has a very little aptitude and plays an inconsequential role in policy design; therefore, the need arises for youth empowerment to enable them to engage in the broader national policies. Having assumed a negative deviation after a further analysis using empowerment perception index (EPI), the study revealed that youth marginal involvement and consultation in decision making cannot constitute empowerment to any degree. Given the crucial implications of this for youth policy implementations at the national as well as subnational level, the paper recommended some pathways for ensuring youth empowerment in youth-oriented programmes in Ghana.

Ray tracing is one of the photorealistic rendering method. Ray tracing process takes a long time because of the calculation of lighting effects and optical effects caused by the material of the object. The length of rendering time increases with the increasing complexity of the shape of the object, such as a mesh object. To minimize processing time, generally done by reducing the complexity of the mesh, which reduces the number of face that forms a mesh object. How to reduce the number of face is to combine adjacent face to face. The downside of this method is that the object surface resulting display will look grainy/triangular - facet (checkered). The proposed method in this study aims to refine the visualization of objects that complexity is not high. Triangular surface mesh - terms appear due to the calculation of the same color for each face that form a mesh. If the face has a color gradation, the mesh will look smooth surface. To produce a color gradation on a broad face, normal calculation was used, ie in proportion adopting b - splines curve calculations. Testing is done by comparing the results of the use of normal B - splines to the simple method of subdivision (a method of face vast divide into several smaller face , so that the finer the mesh surface) with ray tracing rendering method. From the experimental results, it can be concluded that the results of ray tracing using b - splines normal when compared with the subdivision, the results are not too different. From the aspect of long rendering process, the more the number of face of a mesh, it also increase the effectiveness of rendering time process. However, the increase is not proportional to the increase in the number of mesh

The World Health Organization (WHO) early warning indicators (EWIs) of HIV drug resistance (HIVDR) assess factors at individual ART sites that are known to create situations favourable to the emergence of HIVDR.In 2014, the Namibia HIV care and treatment program abstracted the following adult and pediatric EWIs from all public ART sites (50 main sites and 143 outreach sites): On-time pill pick-up, Retention in care, Pharmacy stock-outs, Dispensing practices, and Viral load suppression. Comparisons were made between main and outreach sites and between 2014 and 2012 using the Wilcoxon signed-rank test in a matched analysis.The national estimates were: On-time pill pick-up 81.9% (95% CI 81.1-82.8) for adults and 82.4% (81.3-83.4) for pediatrics, Retention in care 79% retained on ART after 12 months for adults and 82% for pediatrics, Pharmacy stock-outs 94% of months without a stock-out for adults and 88% for pediatrics, and Dispensing practices 0.01% (0.001-0.056) dispensed mono- or dual-therapy for adults and 0.01% (0.001-0.069) for pediatrics. Viral load suppression was significantly affected by low rates of Viral load completion. Main sites had higher On-time pill pick-up than outreach sites for adults (p

This paper investigates the applicability of the assumed wind fields in International Electrotechnical Commission (IEC) standard 61400 Part 2, the design standard for small wind turbines, for a turbine operating in the built environment, and the effects these wind fields have on the predicted performance of a 5 kW Aerogenesis turbine using detailed aeroelastic models developed in Fatigue Aerodynamics Structures and Turbulence (FAST). Detailed wind measurements were acquired at two built environment sites: from the rooftop of a Bunnings Ltd. warehouse at Port Kennedy (PK) (Perth, Australia) and from the small wind turbine site at the University of Newcastle at Callaghan (Newcastle, Australia). For both sites, IEC 61400-2 underestimates the turbulence intensity for the majority of the measured wind speeds. A detailed aeroelastic model was built in FAST using the assumed wind field from IEC 61400-2 and the measured wind fields from PK and Callaghan as an input to predict key turbine performance parameters. The results of this analysis show a modest increase in the predicted mean power for the higher turbulence regimes of PK and Callaghan as well as higher variation in output power. Predicted mean rotor thrust and blade flapwise loading showed a minor increase due to higher turbulence, with mean predicted torque almost identical but with increased variations due to higher turbulence. Damage equivalent loading for the blade flapwise moment was predicted to be 58% and 11% higher for a turbine operating at Callaghan and PK respectively, when compared with IEC 61400-2 wind field. Time series plots for blade flapwise moments and power spectral density plots in the frequency domain show consistently higher blade flapwise bending moments for the Callaghan site with both the sites showing a once-per-revolution response.

This paper presents a method to optimise the material layout of a fibreglass-reinforced composite constructed small wind turbine blade. The method was developed with the intent of reducing blade mass without compromising the blade’s structural performance or longevity. The bi-directional evolutionary layout optimisation method utilises finite element analysis to redesign the composite lay of the blade structure based on a strain energy criterion. Details of the procedure of this method are documented in the paper. The bi-directional evolutionary optimisation technique was applied to the existing structure of a 2.5 m composite blade from an Aerogenesis 5 kW wind turbine. The optimisation technique was able to reduce the current mass of the blade by 15% without any increase in blade deflection with strains kept below a fatigue endurance limit when subject to aerodynamic and centrifugal loading conditions at design conditions. The initial results from this study are promising and could help lower manufacturing costs of small wind turbine blades.

Abstract Background The aim of this study was to compare the stiffness characteristics of Taylor Spatial Frame (TSF) fixed with transverse wires and half pins. Design & Methods Experiments were carried out at the biomechanics laboratory at Cardiff University. All mechanical testing was performed with a servo hydraulic test frame (MTS 858 Mini Bionix II(R), MTS Corp., Mineapolis, USA). Custom built mounts were used to attach the bone rigidly to the one end of machine and the TSF ring to the other. Rings were fixed with 1.8 mm transverse wires or hydroxy-apatite coated 6.5 mm half pins in 45degrees, 60degrees, 75degrees and 90degrees divergence angles. Bone was loaded with axial load to 400 N and torque to 20 Nm in an indestructible manner. Load/displacement curve data were analyzed for slope and axial and angular displacements. Results For larger diameter rings (180 mm), for axial stiffness there was no statistically significant difference between the transverse wires (4 wires with 2 rings) and the half pins (2 pins with 1 ring) (p > 0.05). For 155 mm internal diameter rings, half pins provided statistically higher axial stiffness than transverse wires (p = 0.036). The half pins show significantly more torsion stiffness in both ring diameters (p < 0.05) in comparison to transverse wires. As in axial stiffness, small diameter rings show increased stiffness in torsion. There is increase in axial and torsion stiffness with the increase in the divergence angle between the wires or pins (p < 0.05). Conclusion & Clinical Relevance Half pins provide greater stiffness to TSF frames and allow for axial micro motion as well. This work provides a rationale for clinical decision making about the use of tensioned transverse wires in comparison to half pins in construction of a TSF frame

Autoreactive B cells play an important but ill-defined role in autoimmune type 1 diabetes (T1D). To better understand their contribution, we performed single cell gene and BCR-seq analysis on pancreatic islet antigen-reactive (IAR) B cells from the peripheral blood of nondiabetic (ND), autoantibody positive prediabetic (AAB), and recent-onset T1D individuals. We found that the frequency of IAR B cells was increased in AAB and T1D. IAR B cells from these donors had altered expression of B cell signaling, pro-inflammatory, infection, and antigen processing and presentation genes. Both AAB and T1D donors demonstrated a significant increase in certain heavy and light chain V genes, and these V genes were enriched in islet-reactivity. Public clones of IAR B cells were restricted almost entirely to AAB and T1D donors. IAR B cells were clonally expanded in the autoimmune donors, particularly the AAB group. Notably, a substantial fraction of IAR B cells in AAB and T1D donors appeared to be polyreactive, which was corroborated by analysis of recombinant monoclonal antibodies. These results expand our understanding of autoreactive B cell activation during T1D and identify unique BCR repertoire changes that may serve as biomarkers for increased disease risk., Competing Interests: Competing interests: The authors declare no competing financial interests.

Importance: Increasing influenza vaccination rates is a public health priority. One method recommended by the US Centers for Disease Control and Prevention and others is for health systems to send reminders nudging patients to be vaccinated., Objective: To evaluate and compare the effect of electronic health record (EHR)-based patient portal reminders vs text message reminders on influenza vaccination rates across a health system., Design, Setting, and Participants: This 3-arm randomized clinical trial was conducted from September 7, 2022, to April 30, 2023, among primary care patients within the University of California, Los Angeles (UCLA) health system., Interventions: Arm 1 received standard of care. The health system sent monthly reminder messages to patients due for an influenza vaccine by portal (arm 2) or text (arm 3). Arm 2 had a 2 × 2 nested design, with fixed vs responsive monthly reminders and preappointment vs no preappointment reminders. Arm 3 had 1 × 2 design, with preappointment vs no preappointment reminders. Preappointment reminders for eligible patients were sent 24 and 48 hours before scheduled primary care visits. Fixed reminders (in October, November, and December) involved identical messages via portal or text. Responsive portal reminders involved a September message asking patients about their plans for vaccination, with a follow-up reminder if the response was affirmative but the patient was not yet vaccinated., Main Outcomes and Measures: The primary outcome was influenza vaccination by April 30, 2023, obtained from the UCLA EHR, including vaccination from pharmacies and other sources., Results: A total of 262 085 patients (mean [SD] age, 45.1 [20.7] years; 237 404 [90.6%] adults; 24 681 [9.4%] children; 149 349 [57.0%] women) in 79 primary care practices were included (87 257 in arm 1, 87 478 in arm 2, and 87 350 in arm 3). At the entire primary care population level, none of the interventions improved influenza vaccination rates. All groups had rates of approximately 47%. There was no statistical or clinically significant improvement following portal vs text, preappointment reminders vs no preappointment reminders (portal and text reminders combined), or responsive vs fixed monthly portal reminders., Conclusions and Relevance: At the population level, neither portal nor text reminders for influenza vaccination were effective. Given that vaccine hesitancy may be a major reason for the lack of impact of portal or text reminders, more intensive interventions by health systems are needed to raise influenza vaccination coverage levels., Trial Registration: ClinicalTrials.gov Identifier: NCT05525494.

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma 1,2 . T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance 3 . Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD + ) catabolism, is highly expressed in exhausted CD8 + T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38 hi CD8 + T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD + pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD + axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models., Competing Interests: R.W.J. is a member of the advisory board for and has a financial interest in Xsphera Biosciences Inc., a company focused on using ex vivo profiling technology to deliver functional, precision immune-oncology solutions for patients, providers, and drug development companies. R.W.J. has received honoraria from Incyte (invited speaker), G1 Therapeutics (advisory board), Bioxcel Therapeutics (invited speaker). R.W.J. has ownership interest in U.S. patents US20200399573A9 and US20210363595A1. R.W.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. A.M has served a consultant/advisory role for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, ManaT Bio, Flare Therapeutics, venBio Partners, BioNTech, Rheos Medicines and Checkmate Pharmaceuticals, is currently a part-time Entrepreneur in Residence at Third Rock Ventures, is an equity holder in ManaT Bio, Asher Biotherapeutics and Abata Therapeutics, and has received research funding support from Bristol-Myers Squibb. A.M.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. J.M.S., L-C.C, N.S, M.M., N.N., R.S. are current employees with Teiko.bio and own stock. E E. and S.A.E. were employed with Teiko.bio in the past 2 years and own stock. R.S. and M.H.S. are Teiko.bio’s co-founders and R.S. serves on the company board. M.H.S. serves as an advisor for Teiko.bio and owns stock. M.E.W. worked as a contractor for Teiko.bio during this project. M.H.S. has received a speaking honorarium from Standard BioTools and Kumquat Bio, has been a paid consultant for Five Prime, Ono, January, Earli, Astellas, and Indaptus, and has received research funding from Roche/Genentech, Pfizer, Valitor, and Bristol Myers Squibb.X.W. and C.R.F. report a patent on the B7-H3 CAR T cells (US10519214B2). K.T.F. serves on the Board of Directors of Clovis Oncology, Strata Oncology, Kinnate, and Scorpion Therapeutics; Scientific Advisory Boards of PIC Therapeutics, Apricity, C-Reveal, Tvardi, ALX Oncology, xCures, Monopteros, Vibliome, Karkinos, Soley Therapeutics, Alterome, Immagene, and intrECate; consultant to Nextech, Takeda, Novartis, Transcode Therapeutics, and Roche/Genentech. R.T.M. consults for Bristol Myers Squibb. G.M.B. has sponsored research agreements through her institution with: Olink Proteomics, Teiko Bio, InterVenn Biosciences, and Palleon Pharmaceuticals. She has served on advisory boards for: Iovance, Merck, Nektar Therapeutics, Novartis, and Ankyra Therapeutics. She consults for: Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics. She holds equity in Ankyra Therapeutics. M.S.F received funding from Calico Life Sciences, Bristol-Myers Squibb, Istari Oncology and served as a consultant for Galvanize Therapeutics. N.H. holds equity in BioNTech and is an advisor for Related Sciences/Danger Bio, Repertoire Immune Medicines and CytoReason, and receives research funding from Calico Life Sciences and Bristol-Myers Squibb. D.L serves on the scientific advisory board for Oncovalent Therapeutics, and received honorariums from Genentech.

Background: Subjective cognitive complaints (SCC) may be an early indicator of future cognitive decline. However, findings comparing SCC and objective cognitive performance have varied, particularly in the memory domain. Even less well established is the relationship between subjective and objective complaints in non-amnestic domains, such as in executive functioning, despite evidence indicating very early changes in these domains. Moreover, particularly early changes in both amnestic and non-amnestic domains are apparent in those carrying the Apolipoprotein-E ɛ4 allele, a primary genetic risk for Alzheimer's disease (AD)., Objective: This study investigated the role of the ɛ4 allele in the consistency between subjective and objective executive functioning in 54 healthy, cognitively intact, middle-aged and older adults., Methods: Participants ( M age  = 64.07, SD  = 9.27, range = 48-84; ɛ4+ = 18) completed the Frontal Systems Behavior Scale (FrSBe) Executive Dysfunction Scale (EXECDYS) to measure subjective executive functioning (SEF) and multiple executive functioning tasks, which were condensed into a single factor., Results: After accounting for age, depression, and anxiety, objective executive functioning performance significantly predicted SEF. Importantly, ɛ4 moderated this effect. Specifically, those carrying the ɛ4 allele had significantly less accurate self-awareness of their executive functioning compared to ɛ4 non-carriers., Conclusions: Utilizing an approach that integrates self-evaluation of executive functioning with objective neurocognitive assessment may help identify the earliest signs of impending cognitive decline, particularly in those with genetic risk for AD. Such an approach could sensitively determine those most prone to future cognitive decline prior to symptom onset, when interventions could be most effective., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Background: Immune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs are needed. In this study, we aimed to identify immune features detectable in peripheral blood and associated with the development of severe irAEs that required clinical intervention., Methods: We used a 43-marker mass cytometry panel to characterize peripheral blood mononuclear cells from 28 unique patients with melanoma across 29 lines of ICI therapy before treatment (baseline), before the onset of irAEs (pre-irAE) and at the peak of irAEs (irAE-max). In the 29 lines of ICI therapy, 18 resulted in severe irAEs and 11 did not., Results: Unsupervised and gated population analysis showed that patients with severe irAEs had a higher frequency of CD4 + naïve T cells and lower frequency of CD16 + natural killer (NK) cells at all time points. Gated population analysis additionally showed that patients with severe irAEs had fewer T cell immunoreceptor with Ig and ITIM domain (TIGIT + ) regulatory T cells at baseline and more activated CD38 + CD4 + central memory T cells (TCM) and CD39 + and Human Leukocyte Antigen-DR Isotype (HLA-DR) + CD8 + TCM at peak of irAEs. The differentiating immune features at baseline were predominantly seen in patients with gastrointestinal and cutaneous irAEs and type 1 diabetes. Higher frequencies of CD4 + naïve T cells and lower frequencies of CD16 + NK cells were also associated with clinical benefit to ICI therapy., Conclusions: This study demonstrates that high-dimensional immune profiling can reveal novel blood-based immune signatures associated with risk and mechanism of severe irAEs. Development of severe irAEs in melanoma could be the result of reduced immune inhibitory capacity pre-ICI treatment, resulting in more activated TCM cells after treatment., Competing Interests: Competing interests: SH-L has been scientific advisor/consultant for: Amgen, Ascendis, Astellas, BMS, Genmab, Merck, Nektar, Neon Therapeutics, Novartis, Regeneron, Vaccinex, Xencor; and has done contracted research through her affiliated institutions with Astellas, BioAtla, BMS, Boehringer Ingelheim, Checkmate, Dragonfly, F Star, Genentech, Kite Pharma, Merck, Neon Therapeutics, OncoC4, Pfizer, Plexxikon, Vaccinex, Vedanta, Xencor. US reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, AstraZeneca and Gilead and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. JH conducts clinical trials from the following entities: BMS, Merck, Amgen, Philogen, Lyell, Lovance, NCI, Takara, Natera, Skyline. JM, AE-W, MK-B, ALE, JPM : None. JMS, NS, L-CC, WDC, COM and NN are currently employed by Teiko Bio and are shareholders. SAE and CPH was formerly employed by Teiko Bio and is a current shareholder. MHS and RS are founders, shareholders and board members of Teiko.bio. MHS has received a speaking honorarium from Standard BioTools. and Kumquat Bio, has been a paid consultant for Five Prime, Ono, January, Earli, Astellas, and Indaptus, and has received research funding from Roche/Genentech, Pfizer, Valitor, and Bristol Myers Squibb. WDC was employed by Fate Therapeutics within the last 24 months. NN was employed by Atreca within the last 24 months., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

LINE-1 retrotransposons are sequences capable of copying themselves to new genomic loci via an RNA intermediate. New studies implicate LINE-1 in a range of diseases, especially in the context of aging, but without an accurate understanding of where and when LINE-1 is expressed, a full accounting of its role in health and disease is not possible. We therefore developed a method-5' scL1seq-that makes use of a widely available library preparation method (10x Genomics 5' single cell RNA-seq) to measure LINE-1 expression in tens of thousands of single cells. We recapitulated the known pattern of LINE-1 expression in tumors-present in cancer cells, absent from immune cells-and identified hitherto undescribed LINE-1 expression in human epithelial cells and mouse hippocampal neurons. In both cases, we saw a modest increase with age, supporting recent research connecting LINE-1 to age related diseases., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Cellular senescence (CS) is a state of irreversible cell cycle arrest, and the accumulation of senescent cells contributes to age-associated organismal decline. The detrimental effects of CS are due to the senescence-associated secretory phenotype (SASP), an array of signaling molecules and growth factors secreted by senescent cells that contribute to the sterile inflammation associated with aging tissues. Recent studies, both in vivo and in vitro, have highlighted the heterogeneous nature of the senescence phenotype. Single-cell transcriptomics has revealed that oncogene-induced senescence (OIS) is characterized by the presence of subpopulations of cells expressing different SASP profiles. We have generated a comprehensive dataset via single-cell transcriptional profiling of genetically homogenous clonal cell lines from different forms of senescence, including OIS, replicative senescence, and DNA damage-induced senescence. We identified subpopulations of cells that are common to all three major forms of senescence and show that the expression profiles of these subpopulations are driven by markers formerly identified in individual forms of senescence. These common signatures are characterized by chromatin modifiers, inflammation, extracellular matrix remodeling, and ribosomal protein gene expression (measured at the RNA level). The expression patterns of these subpopulations recapitulate primary and juxtacrine secondary senescence, a phenomenon where a pre-existing (primary) senescent cell induces senescence in a neighboring (secondary) cell through cell-to-cell contact. Hence, our results demonstrate that the formation of juxtacrine secondary populations of cells is common to multiple types of senescence and occurs in competition with primary senescence. Finally, we show that these subpopulations show differential susceptibility to the senolytic agent Navitoclax, suggesting that senolytic agents targeting the apoptotic pathways may be clearing only a subset of senescent cells based on their inflammatory profiles., Competing Interests: Declaration of Interests J.M.S. is a cofounder and SAB chair of Transposon Therapeutics and consults for Atropos Therapeutics, Gilead Sciences, and Oncolinea. The others declare no conflict of interest.

Inclusion of Black participants in clinical research is a national priority. Mobile applications and remote data collection may increase study access for diverse populations. This study examined the reliability and feasibility of two mobile smartphone application-based cognitive measures in a diverse middle aged and older adult sample. Black (n = 44; M age  = 59.93) and non-Hispanic white (NHW; n = 50; M age  = 61.06) participants completed traditional paper-based neuropsychological testing and two app-based measures, Arrows and Number Match. Intraclass correlations demonstrated poor to moderate reliability (range: .417-.569) between performance on the app-based versions and performance on the traditional versions. Performance score differences by racial group were not statistically significant. Both Black and NHW participants rated the app-based measures as feasible and acceptable, though Black participants endorsed a stronger likelihood of future use. These findings add to the growing literature on remote cognitive testing .

In ice hockey, the butterfly style/stance is a technique distinguished by the goalkeepers (goalie) dropping to their knees to block attempts to score. Although this goalie style has been around for many years, comparisons between on and off-ice attire has not been undertaken. Therefore, this preliminary study compared differences in torso acceleration and energy expenditure by way of the Metabolic Equivalent of Task (MET) during off-ice and on-ice butterfly stances/saves. Seven participants each performed 8 on-ice butterfly saves/stances whilst wearing full hockey attire followed by 8 off-ice butterfly stances without wearing full hockey attire whilst torso acceleration was collected. The off-ice movement significantly increased vertical torso acceleration (p < 0.01, d > 0.90) with increased MET, compared to on-ice motion. Despite no significant difference in anteroposterior and mediolateral torso kinematics, vector magnitudes were significantly greater (p < 0.01, d > 0.90) when the stance was performed off-ice. The increased vertical acceleration observed when goalies performed the movement off-ice could be due to a failure to maintain adequate posture without the support of the external load. The results of this study may help inform off-ice training interventions for ice hockey goalkeeping.

While the sport of short-distance (Sprint) triathlon provides an opportunity to research the effect of the center of mass (CoM) when cycling and running, much remains to be done. The literature has failed to consistently or adequately report how changes to hand position influence subsequent running as inferred by the magnitude of CoM acceleration. The demands of cycle training in a drops and aerodynamic position followed by running remain unquantified in Sprint Distance triathlon. Thus, far data collected indicate that the cycle to run transition (T2) is important for overall race success. While many age-groupers participate in Sprint Distance triathlon, the lack of T2 based research make comparisons between cycle hand position and ensuing running difficult. The motion of the human body when cycling and running in triathlon can be described by the motion of its CoM in a local coordinate system. Unobtrusive wearable sensors have proven to be an informative resource to monitor the magnitude of CoM accelerations in running. However, the extent to which they are used in cycling is unclear. Therefore, the aim of the present study was to analyse the temporal magnitudes of CoM acceleration when cycling position and cadence is changed and to analyse these effects on running after cycling. Ten recreational triathletes completed two 20 km cycling trials at varied cadence in a drops position (parts of the handlebars that curve outward, Cycle Drops) and an aerodynamic position (arms bent, forearms parallel to the ground, Cycle Aero ) immediately followed by a 5 km run at self-selected pace. Torso kinematics by way of CoM acceleration magnitude were captured in a typical training setting using a triaxial accelerometer. CoM acceleration was quantified in m/s 2 and variability was measured by the coefficient of variation (CV) and root mean square (RMS). Results from Cycle Aero indicated that acceleration of the CoM in longitudinal (CV = 1%) and mediolateral directions (CV = 3%) was significantly reduced ( p < 0.001) compared to Cycle Drops . As for rate of perceived exertion (RPE), a significant difference was observed with triathletes reporting higher values in Cycle Aero alongside a greater CoM acceleration magnitude in the anteroposterior direction. The CoM varied significantly from Run Aero with less longitudinal (CV = 0.2, p < 0.001) and mediolateral acceleration observed (CV = 7.5%, p < 0.001) compared to Run Drops . Although greater longitudinal acceleration was observed in the initial 1 km epoch of Run Aero , triathletes then seemingly adjusted their CoM trajectory to record lower magnitudes until completion of the 5 km run, completing the run quicker compared to Run Drops (22.56 min 1 ± 0.2, 23.34 min 1 ± 0.5, p < 0.001, CV = 1.3%). Coaches may look to use triaxial accelerometers to monitor performance in both cycling and running after cycling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Evans, James, Rowlands and Lee.)

Indoor spin cycling has gained popularity as a training modality for triathletes. Part of its appeal is that it can form a component of a structured periodised training program and provide an alternative to outdoor cycling. Indices of physiological components (i.e., the metabolic equivalent, caloric cost, perceived exertion) and changes in the body position can be inferred by wearable technology such as an accelerometer. This pilot study aimed to investigate the relationship between the rating of perceived exertion, heart rate reserve, and the metabolic equivalent between the whole body centre of mass acceleration using a sacrum mounted triaxial accelerometer during 20 minutes of 6 varied power conditions of indoor spin cycling. Compared with other conditions, cycling at a steady state (>152-205 W) resulted in extremely large effects (> 0.9) in mediolateral acceleration and the rating of perceived exertion (p < 0.0001). The relationship between the body position (aerodynamic to drops) induced significant changes in anteroposterior acceleration magnitude (p < 0.0001), although moving from drops to the aerodynamic position was not significant despite a large increase in heart rate reserve and extremely large effects of perceived exertion. The rating of perceived exertion scale and the metabolic equivalent comparative to the whole body centre of mass acceleration magnitude and power displayed a strong correlation (r = 0.865). An individually determined whole body centre of mass accelerations combined with perceived exertion, the metabolic equivalent and heart rate reserve could potentially contribute to improved indoor triathlete spin cycling performance., (© 2022 Stuart A Evans, Daniel A James, David Rowlands, James B Lee, published by Sciendo.)

Appropriate cycling cleat adjustment could improve triathlon performance in both cycling and running. Prior recommendations regarding cleat adjustment have comprised aligning the first metatarsal head above the pedal spindle or somewhat forward. However, contemporary research has questioned this approach in triathlons due to the need to run immediately after cycling. Subsequently, moving the pedal cleat posteriorly could be more appropriate. This study evaluated the effectiveness of a triaxial accelerometer to determine acceleration magnitudes of the trunk in outdoor cycling in two different bicycle cleat positions and the consequential impact on trunk acceleration during running. Seven recreational triathletes performed a 20 km cycle and a 5 km run using their own triathlon bicycle complete with aerodynamic bars and gearing. Interpretation of data was evaluated based on cadence changes whilst triathletes cycled in an aerodynamic position in two cleat positions immediately followed by a self-paced overground run. The evaluation of accelerometer-derived data within a characteristic overground setting suggests a significant increase in total trunk acceleration magnitude during cycling with a posterior cleat with significant increases to longitudinal acceleration ( p = 0.04) despite a small effect ( d = 0.2) to the ratings of perceived exertion (RPE). Cycling with a posterior cleat significantly reduced longitudinal trunk acceleration in running and overall acceleration magnitudes ( p < 0.0001) with a large effect size ( d = 0.9) and a significant reduction in RPE ( p = 0.02). In addition, running after cycling in a posterior cleat was faster compared to running after cycling in a standard cleat location. Practically, the magnitude of trunk acceleration during cycling in a posterior cleat position as well as running after posterior cleat cycling differed from that when cycling in the fore-aft position followed by running. Therefore, the notion that running varies after cycling is not merely an individual athlete's perception, but a valid observation that can be modified when cleat position is altered. Training specifically with a posterior cleat in cycling might improve running performance when trunk accelerations are analysed.

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16 Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16 Ink4a -positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16 Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

In the multisport of triathlon cycling is the longest of the three sequential disciplines. Triathlon bicycles differ from road bicycles with steeper seat tube angles with a change to saddle height altering the seat tube angle. This study evaluated the effectiveness of a tri axial accelerometer to determine acceleration magnitudes of the trunk in outdoor cycling in two saddle positions. Interpretation of data was evaluated based on cadence changes whilst triathletes cycled in an aerodynamic position in two saddle positions. The evaluation of accelerometer derived data within a characteristic overground setting suggests a significant reduction in mediolateral acceleration of the trunk, yielding a 25.1% decrease when saddle height was altered alongside reduced rate of perceived exertion (3.9%). Minimal differences were observed in anteroposterior and longitudinal acceleration. Evaluation of sensor data revealed a polynomial expression of the subtle changes between both saddle positions. This study shows that a triaxial accelerometer has capability to continuously measure acceleration magnitude of trunk movements during an in-the-field, varied cadence cycle protocol. Accessible and practical sensor technology could be relevant for postural considerations when exploring saddle position in dynamic settings.

Interactions between platelets, leukocytes and the vessel wall provide alternative pathological routes of thrombo-inflammatory leukocyte recruitment. We found that when platelets were activated by a range of agonists in whole blood, they shed platelet-derived extracellular vesicles which rapidly and preferentially bound to blood monocytes compared to other leukocytes. Platelet-derived extracellular vesicle binding to monocytes was initiated by P-selectin-dependent adhesion and was stabilised by binding of phosphatidylserine. These interactions resulted in the progressive transfer of the platelet adhesion receptor GPIbα to monocytes. GPIbα +- monocytes tethered and rolled on immobilised von Willebrand Factor or were recruited and activated on endothelial cells treated with TGF-β1 to induce the expression of von Willebrand Factor. In both models monocyte adhesion was ablated by a function-blocking antibody against GPIbα. Monocytes could also bind platelet-derived extracellular vesicle in mouse blood in vitro and in vivo Intratracheal instillations of diesel nanoparticles, to model chronic pulmonary inflammation, induced accumulation of GPIbα on circulating monocytes. In intravital experiments, GPIbα + -monocytes adhered to the microcirculation of the TGF-β1-stimulated cremaster muscle, while in the ApoE -/- model of atherosclerosis, GPIbα + -monocytes adhered to the carotid arteries. In trauma patients, monocytes bore platelet markers within 1 hour of injury, the levels of which correlated with severity of trauma and resulted in monocyte clearance from the circulation. Thus, we have defined a novel thrombo-inflammatory pathway in which platelet-derived extracellular vesicles transfer a platelet adhesion receptor to monocytes, allowing their recruitment in large and small blood vessels, and which is likely to be pathogenic., (Copyright© 2020 Ferrata Storti Foundation.)

Objective: Subjective memory complaints (SMCs) are associated with mild cognitive impairment and dementia but are understudied in African Americans (AAs). We compared SMC endorsement in white and AA participants and evaluated predictors of diagnostic progression., Methods: Initial visit variables, including SMC and memory performance, were compared within a cognitively normal race-matched sample of white and AA participants ( N total = 912; 456 each race ) to assess the presence and predictors of SMC, the predictors of future diagnostic progression, and the change in memory performance over time., Results: More white (32.9%) than AA (24.3%) participants reported SMC ( P < .01, ϕ = -.10). Subjective memory complaint was predicted by memory performance ( B = -0.03, standard error [SE] = 0.013, odds ratio [OR] = .968, P < .05) and race ( B = -0.99, SE = 0.080, OR = .373, P < .001). Subjective memory complaints and memory performance were associated with progression, χ 2 (3, n = 912) = 102.37, P < .001. African American race (-2.05 ± 0.24 SE) and SMC (-0.45 ± 0.21 SE) were associated with worse memory performance at baseline and over time, χ 2 (3) = 13.54, P < .01., Conclusions: In contrast to previous research, our study found that SMC is associated with diagnostic progression and objective memory declines in both white and AA participants.

Recent advances in genomics and imaging technologies have increased our ability to interrogate the 3D conformation of chromosomes and to better understand principles of organization and dynamics, as well as how their alteration can lead to disease. In this review we describe how these technologies have shed new light into the role of the 3D organization of the genome in defining cellular states in aging and age-associated diseases. We compare the genomic organization in cellular senescence and cancer, discuss the role of the lamina in maintaining the structural and functional integrity of the genome, and we highlight the recent findings on how this organization breaks down in disease states., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The FACE-CARAS (Functional Analysis in Care Environments-Child and Adolescent Risk-Assessment Suite) toolkit has been developed to support practitioners in Child and Adolescent Mental Health Services (CAMHS) in performing a structured risk assessment. It covers a number of risk domains including violence, suicide, self-harm, experienced abuse, and exploitation. Interrater and internal reliability has already been established but not predictive validity., Aims/hypothesis: Our aim was to establish the predictive validity of the FACE-CARAS in a CAMHS population., Methods: Records from 123 young people with FACE-CARAS ratings completed by clinicians were examined in a retrospective file review to extract data on a relevant list of adverse outcomes at three and at 6 months following the assessment. Although this was not a prospective longitudinal study, researchers were blind to the clinicians' ratings, allowing valid testing of predictive power. Cases were drawn from across generic and specialist CAMHS teams in approximately equal proportions. Data were analysed using receiver operator characteristic statistics., Results: Areas under the curve values in five of the seven risk areas approached or were greater than 0.8 indicated that the FACE-CARAS profile score was a good potential predictor of risks of self-harm, suicidal behaviours, serious self-neglect, abuse or exploitation by others, and violence to others at both 3 and 6 months. It was weakly "predictive" of accidental self-harm and no better than chance at signalling physical ill health., Conclusions: Findings support the use of the "profile summary" section of the tool as likely to generate clinically useful risk predictions. We were concerned that clinical use of the scale did not conform to research standards and often left subscales incompletely rated; however, the fact that the tool nonetheless proved a good predictor of most key adversities under scrutiny may add weight to its value in clinical practice. Further work with the FACE-CARAS subscales is recommended., (© 2019 John Wiley & Sons, Ltd.)

Background: Exposure to air pollution is associated with cardiovascular disease, including increased morbidity and mortality rates., Objective: The aim of this investigation was to assess the effect, in rats, of intratracheal instillation of particulate air pollution on biomarkers of leucocyte activation and vascular endothelial damage., Methods: Air pollution particles (PM10) were instilled into rats, and blood samples were taken three days and six weeks post instillation. Plasma neutrophil elastase and Von Willebrand factor were measured by ELISA., Results: Plasma neutrophil elastase increased from 175±44 ng/ml at baseline to 288±26 ng/ml 3 days post instillation (p = 0.038). vWF increased from 0.160±0.015 IU/ml at baseline to 0.224±0.015 IU/ml at 3 days post and 0.208±0.01 IU/ml at 6 weeks post (p = 0.006, ANOVA). sICAM-1 increased from 17.75±0.70 ng/ml at baseline to 19.03±0.33 ng/ml at 3 days post and 21.72±1.16 ng/ml at 6 weeks post (p = 0.009, ANOVA)., Conclusion: Instillation caused prolonged systemic inflammation, activation of blood leucocytes and damage to the vascular endothelium.

Introduction: Smokeless tobacco (SLT) use continues to be a significant public health challenge in the United States, particularly among young males in rural areas, where use remains disproportionately high. In support of the U.S. Food and Drug Administration's first nationwide SLT public education campaign, formative research was conducted to inform campaign strategy development and test creative concepts. Methods: Qualitative research methods were used to inform the strategic direction of the campaign, identify salient message themes, and refine creative concepts. Focus groups were conducted with 252 rural male youth ages 12-17 in seven states. Groups were organized by SLT status (i.e., at-risk for initiating vs. experimenting with SLT) and age group. Results: SLT use is culturally ingrained in rural communities, and rural youth are commonly exposed to SLT through close relationships. Among this group, "dipping" (SLT use) has strong cultural significance and is perceived as safe. Members of the target audience are receptive to straightforward facts delivered by authentic messengers about the potentially harmful consequences of SLT use, specifically those that leverage the progression of short-term consequences (e.g., white patches) to long-term health effects. Conclusions: This study addresses SLT literature gaps related to youth knowledge, attitudes, and beliefs by summarizing audience learnings from formative research that was used to develop the first national SLT public education campaign., Competing Interests: No competing financial interests exist.

Background: Prescription drug marketing to physicians often includes clinical trial data. Prior research has shown that physicians may not have the necessary knowledge to understand all clinical trial results and they can be influenced by how these results are reported. This study focused on physicians' reactions to and evaluations of clinical trial data presented in professional prescription drug promotion., Methods: We conducted 60-minute interviews with practicing physicians across the United States (50 primary care physicians and 22 endocrinologists). Physicians viewed prescription drug promotional materials that contained clinical trial data and answered follow-up questions., Results: Physicians demonstrated low to moderate knowledge about clinical trial-related terms found in promotional prescription drug materials., Discussion: Results from this qualitative analysis underscore a need to determine how clinical trial data in prescription drug promotional materials affect physicians' attitudes and decision making., Competing Interests: Conflict of interest: none declared., (© Copyright 2018 by the American Board of Family Medicine.)

Polycomb group (PcG) factors maintain facultative heterochromatin and mediate many important developmental and differentiation processes. EZH2, a PcG histone H3 lysine-27 methyltransferase, is repressed in senescent cells. We show here that downregulation of EZH2 promotes senescence through two distinct mechanisms. First, depletion of EZH2 in proliferating cells rapidly initiates a DNA damage response prior to a reduction in the levels of H3K27me3 marks. Second, the eventual loss of H3K27me3 induces p16 (CDKN2A) gene expression independent of DNA damage and potently activates genes of the senescence-associated secretory phenotype (SASP). The progressive depletion of H3K27me3 marks can be viewed as a molecular "timer" to provide a window during which cells can repair DNA damage. EZH2 is regulated transcriptionally by WNT and MYC signaling and posttranslationally by DNA damage-triggered protein turnover. These mechanisms provide insights into the processes that generate senescent cells during aging., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)