The incidence of stroke is predicted to rise because of the rapidly ageing population. However, over the past two decades, findings of randomised trials have identified several interventions that are ...effective in prevention of stroke. Reliable data on time-trends in stroke incidence, major risk factors, and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence. We aimed to obtain these data.
We ascertained changes in incidence of transient ischaemic attack and stroke, risk factors, and premorbid use of preventive treatments from 1981–84 (Oxford Community Stroke Project; OCSP) to 2002–04 (Oxford Vascular Study; OXVASC).
Of 476 patients with transient ischaemic attacks or strokes in OXVASC, 262 strokes and 93 transient ischaemic attacks were incident events. Despite more complete case-ascertainment than in OCSP, age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29% (relative incidence 0·71, 95% CI 0·61–0·83, p=0·0002). Incidence declined by more than 50% for primary intracerebral haemorrhage (0·47, 0·27–0·83, p=0·01) but was unchanged for subarachnoid haemorrhage (0·83, 0·44–1·57, p=0·57). Thus, although 28% more incident strokes (366 vs 286) were expected in OXVASC due to demographic change alone (33% increase in those aged 75 or older), the observed number fell (262 vs 286). Major reductions were recorded in mortality rates for incident stroke (0.63, 0.44–0.90, p=0.02) and in incidence of disabling or fatal stroke (0·60, 0·50–0·73, p<0·0001), but no change was seen in case-fatality due to incident stroke (17·2% vs 17·8%; age and sex adjusted relative risk 0·85, 95% CI 0·57-1·28, p=0·45). Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers, mean total cholesterol, and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet, lipid-lowering, and blood pressure lowering drugs (all p<0.0001).
The age-specific incidence of major stroke in Oxfordshire has fallen by 40% over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors.
Although theoretical models consider social networks as pathways for disease transmission, strong empirical support, particularly for indirectly transmitted parasites, is lacking for many wildlife ...populations. We found multiple genetic strains of the enteric bacterium Salmonella enterica within a population of Australian sleepy lizards (Tiliqua rugosa), and we found that pairs of lizards that shared bacterial genotypes were more strongly connected in the social network than were pairs of lizards that did not. In contrast, there was no significant association between spatial proximity of lizard pairs and shared bacterial genotypes. These results provide strong correlative evidence that these bacteria are transmitted from host to host around the social network, rather than that adjacent lizards are picking up the same bacterial genotype from some common source.
Sialic acid sugar-carrying glycans, sialoglycans, are aberrantly expressed on many tumor cells and have emerged as potent regulatory molecules involved in creating a tumor-supportive ...microenvironment. Sialoglycans can be recognized by sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of immunomodulatory receptors. Most mammalian Siglecs transmit inhibitory signals comparable with the immune checkpoint inhibitor programmed death protein 1 (PD-1), but some are activating. Recent studies have shown that tumor cells can exploit sialoglycan–Siglec interactions to modulate immune cell function, contributing to an immunosuppressive tumor microenvironment (TME). Interference with sialoglycan synthesis or sialoglycan–Siglec interactions might improve antitumor immunity. Many questions regarding specificity, signaling, and regulatory function of sialoglycan–Siglec interactions remain. We posit that sialoglycans and Siglecs present as potential glyco-immune ‘checkpoints’ for cancer immunotherapy.
Aberrant sialic acid sugar expression is commonly found in different cancer types and immune cells express immunomodulatory Siglec receptors that can recognize these sialic acids in humans and mice. Recently, high expression of Siglecs was found on several immune cells within the tumor microenvironment (TME).Recent studies, using human samples and mouse models, indicate that sialoglycan–Siglec interactions in the TME can suppress effector immune cell activity and modulate myeloid cell functions, thus contributing to tumor immune evasion and sustained tumor growth.The individual contribution of the 14 Siglec family members to immune evasion and their precise sialoglycan ligands in the TME remain to be elucidated.Sialoglycans and Siglecs might represent immune ‘checkpoints’ that should be further explored as potential targets for cancer immunotherapy.
This paper describes the anatomy of the posterior cruciate ligament (PCL) and the meniscofemoral ligaments (MFLs). The fibres of the PCL may be split into two functional bundles; the anterolateral ...bundle (ALB) and the posteromedial bundle (PMB), relating to their femoral attachments. The tibial attachment is relatively compact, with the ALB anterior to the PLB. These bundles are not isometric: the ALB is tightest in the mid-arc of knee flexion, the PMB is tight at both extension and deep flexion. At least one MFL is present in 93% of knees. On the femur, the anterior MFL attaches distal to the PCL, close to the articular cartilage; the posterior MFL attaches proximal to the PCL. They both attach distally to the posterior horn of the lateral meniscus. Their slanting orientation allows the MFLs to resist tibial posterior drawer.
Knowledge of which physical activity programs are most effective for older adults in different sub-populations and contexts is limited. The objectives of this rapid review were to: 1) Overview ...evidence evaluating physical activity programs/services for older adults; and 2) Describe impact on physical activity, falls, intrinsic capacity (physical domain), functional ability (physical, social, and cognitive/emotional domains), and quality of life. We conducted a rapid review of primary studies from 350 systematic reviews identified in a previous scoping review (March 2021: PEDro, MEDLINE, CINAHL, Cochrane Database). For Objective 1, we included intervention studies investigating physical activity programs/services in adults greater than or equal to 60 years. Of these, we included good quality (greater than or equal to 6/10 PEDro scale) randomised controlled trials (RCTs) with greater than or equal to 50 participants per group in Objective 2. Evidence supporting physical activity for older adults is positive. We outline which activity types are most effective in different populations and settings.
Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and ...the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.
Immune therapy is a successful cancer treatment coming into its own. This is because checkpoint molecules, adoptive specific lymphocyte transfer and chimeric antigen T-cell (CAR-T) therapy are able ...to induce more durable responses in an increasing number of malignancies compared to chemotherapy. In addition, immune therapies are able to treat bulky disease, whereas standard cytotoxic therapies cannot treat large tumour burdens. Checkpoint inhibitor monoclonal antibodies are becoming widely used in the clinic and although more complex, adoptive lymphocyte transfer and CAR-T therapies show promise. We are learning that there are nuances to predicting the successful use of the checkpoint inhibitors as well as to specific-antigen adoptive and CAR-T therapies. We are also newly aware of a here-to-fore unrealised natural force, the status of the microbiome. However, despite better understanding of mechanisms of action of the new immune therapies, the best responses to the new immune therapies remain 20-30%. Likely the best way to improve this somewhat low response rate for patients is to increase the patient's own immune response. Thermal therapy is a way to do this. All forms of thermal therapy, from fever-range systemic thermal therapy, to high-temperature HIFU and even cryotherapy improve the immune response pre-clinically. It is time to test the immune therapies with thermal therapy in vivo to test for optimal timing of the combinations that will best enhance tumour response and then to begin to test the immune therapies with thermal therapy in the clinic as soon as possible.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant ...prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10
6
, 12.5 × 10
6
and 25 × 10
6
cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.
The distributional ranges of many species are contracting with habitat conversion and climate change. For vertebrates, informed strategies for translocations are an essential option for decisions ...about their conservation management. The pygmy bluetongue lizard, Tiliqua adelaidensis, is an endangered reptile with a highly restricted distribution, known from only a small number of natural grassland fragments in South Australia. Land‐use changes over the last century have converted perennial native grasslands into croplands, pastures and urban areas, causing substantial contraction of the species' range due to loss of essential habitat. Indeed, the species was thought to be extinct until its rediscovery in 1992. We develop coupled‐models that link habitat suitability with stochastic demographic processes to estimate extinction risk and to explore the efficacy of potential climate adaptation options. These coupled‐models offer improvements over simple bioclimatic envelope models for estimating the impacts of climate change on persistence probability. Applying this coupled‐model approach to T. adelaidensis, we show that: (i) climate‐driven changes will adversely impact the expected minimum abundance of populations and could cause extinction without management intervention, (ii) adding artificial burrows might enhance local population density, however, without targeted translocations this measure has a limited effect on extinction risk, (iii) managed relocations are critical for safeguarding lizard population persistence, as a sole or joint action and (iv) where to source and where to relocate animals in a program of translocations depends on the velocity, extent and nonlinearities in rates of climate‐induced habitat change. These results underscore the need to consider managed relocations as part of any multifaceted plan to compensate the effects of habitat loss or shifting environmental conditions on species with low dispersal capacity. More broadly, we provide the first step towards a more comprehensive framework for integrating extinction risk, managed relocations and climate change information into range‐wide conservation management.
Abstract The acromial tracker is used to measure scapular rotations during dynamic movements. The method has low accuracy in high elevations and is sensitive to its attachment location on the ...acromion. The aim of this study was to investigate the effect of the attachment position and shoulder orientation during calibration on the tracker accuracy. The tracker was attached to one of three positions: near the anterior edge of the acromion process, just above the acromial angle and the meeting point between the acromion and the scapular spine. The scapula locator was used to track the scapula during bilateral abduction simultaneously. The locator was used to calibrate the tracker at: no abduction, 30°, 60°, 90° and 120° humerothoracic abduction. ANOVA tests compared RMS errors for different attachment positions and calibration angles. The results showed that attaching the device at the meeting point between the acromion and the scapular spine gave the smallest errors and it was best to calibrate the device at 60° for elevations ≤90°, at 120° for elevations >90° and at 90°or 120° for the full range of abduction. The accuracy of the tracker is significantly improved if attached appropriately and calibrated for the range of movement being measured.
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