Recent advances and current challenges in CAR-T cell therapy.

Rapid advancements in the field of immunotherapy have significantly improved cancer treatments. Specifically, an individualized cell-based modality which involves the removal of some of the patient's own white blood cells, including T cells, has revolutionized research in this field. This study focuses on the recent advances and current challenges of Chimeric Antigen Receptor- T (CAR-T) cell therapy and its regulations in the United States (US) and European Union (EU). Understanding the regulatory regimes of CAR-T cell therapy is critical for researchers and manufacturers as they navigate the hurdles of bringing CAR-T cell therapy to the global market. Benefits of CAR-T cell therapy include high response rates and the potential of long-term remissions in some haematological malignancies. However, the drawbacks are still evident including high costs, adverse reactions, and limited efficacy to solid tumours. CAR-T cell therapy is rapidly advancing, with 1231 clinical trials launched globally according to www.clinicalTrial.gov . The future of CAR-T cell therapy holds enormous promise but improving its safety, effectiveness, and availability are still barriers to its successful implementation.

Major colorectal resection is feasible using a new robotic surgical platform: the first report of a case series.

BACKGROUND: The number of abdominal procedures performed via a robotic-assisted approach is increasing as potential advantages of the modality are recognised. We report the first in human case series of major colorectal resection performed using a new system, Versius®, and assess the feasibility of its use. METHODS: The initial cases performed using Versius® at a single centre in the UK were included in the study. Anonymised data were prospectively collected including patient demographics, operative details and postoperative outcomes. RESULTS: Twenty-three operations were performed, including left (n = 14) and right (n = 9)-sided colonic resections. Rectal mobilisation was performed in 13. Fifty-seven percent of the patients were male, with a malignant indication for surgery in 70% of cases. Overall mean age was 59.1 ± 15.3 (range 23-89) years. Overall mean body mass index was 28.9 ± 5.2 with a mean of 31.3 ± 4.5 for left-sided resections. The median console operating time was 166 min (range 75-320 min). All malignant cases had negative resection margins and the mean lymph node yield was 18 (SD 9.4). Only one operation (4%) was converted from robotic to open approach. Postoperative length of stay was a median of 5 days (range 3-34 days) and there were no readmissions within 30 days. CONCLUSIONS: These results compare favourably with the literature on existing robotic systems and also conventional laparoscopic surgery; hence, we believe that this series indicates the Versius® system is feasible for use in major colorectal resection. These early results from a robot-naïve centre show exciting promise for an expanding robotic market and highlight the need for further evaluation.

Patient Satisfaction With Geriatric Psychiatry Services via Video Teleconference.

OBJECTIVE: The objective for the current study is to examine patient satisfaction with geropsychiatry services provided via video telehealth. METHODS: Participants included community-dwelling older Veterans receiving geriatric psychiatry services via telehealth across regions of the Pacific Northwest and Southwestern United States. Participants completed a paper-based survey examining satisfaction with services following the completion of two medication management visits with a geropsychiatrist. RESULTS: The majority of participants (90%) reported liking or even preferring geriatric telepsychiatry, despite the experience being novel for the majority of patients. Eighty-three percent of participants reported that receiving telegeropsychiatry services was the same (n = 30) or better (n = 3) than being seen in-person. Participants saved an average of 168 driving miles (means and standard deviations = 59.2; range 2-480) each visit. CONCLUSION: The findings of the current study suggest that older adults accept and are broadly satisfied with telegeropsychiatry services. This modality of care increased access to specialty care and decreased travel hardship.

Rare structural variation of synapse and neurotransmission genes in autism.

Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.

Spot urinary protein analysis for excluding significant proteinuria in pregnancy.

The aim of this research was to compare the accuracy of urinary protein/creatinine ratio (PCR) and albumin/creatinine ratio (ACR) in defining optimal cut-off points to rule-out significant proteinuria (>300 mg/24 h) in pregnancy. The secondary outcome measure was to determine the investigation of choice to evaluate proteinuria used by maternity units in the UK. PCR and ACR were calculated on first (PCR1, ACR1) void urine samples of the 24-hour urinary protein collection (24UP). Sensitivity and specificity was calculated for different cut-off points for PCR1 and ACR1 to rule-out significant proteinuria. An online survey was sent to RCOG members questioning them on their investigation of choice to evaluate proteinuria. We concluded from our results that both PCR and ACR are good rule-out tests for significant proteinuria in pregnancy using cut-off points of <20 mg/mmol and <2.5 mg/mmol. PCR is the investigation of choice in 56% of UK units studied.

Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner.

Selective blockade of CD28 is a promising therapy to inhibit pathogenic alloimmunity. However, evaluation of this approach in transplantation has been very limited. Using a novel nonactivating single-chain Fv-based reagent (α28scFv), we have investigated the role of CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) in a murine cardiac transplant model. Blockade of CD28 for 2 weeks after engraftment promoted allograft survival, and significantly attenuated chronic rejection when combined with transient CD154-blockade or calcineurin inhibition. Graft acceptance was associated with decreased alloantibody production, increased proportion of early graft infiltration by regulatory T cells and increased expression of regulatory dendritic cell genes. Blockade of CTLA-4 during α28scFv-based treatments led to prompt rejection in all animals and inhibited expression of forkhead box P3 (Foxp3), programmed death (PD)-1 and 2,3-indoleamine dioxygenase (IDO) in the graft. These results show that CD28 signaling during the first weeks after transplant is a pivotal mediator of pathogenic alloimmunity, and that selective CD28 blockade prolongs graft acceptance by at least two immunomodulatory mechanisms. Selective CD28 inhibition while sparing CTLA-4 is thus a promising approach to inhibit pathogenic alloimmunity.

The role of phenotypic plasticity in responses of hunted thinhorn sheep ram horn growth to changing climate conditions.

When phenotypic change occurs over time in wildlife populations, it can be difficult to determine to what degree it is because of genetic effects or phenotypic plasticity. Here, we assess phenotypic changes over time in horn length and volume of thinhorn sheep (Ovis dalli) rams from Yukon Territory, Canada. We considered 42 years of horn growth from over 50,000 growth measurements in over 8000 individuals. We found that weather explained a large proportion of the annual fluctuation in horn growth, being particularly sensitive to spring weather. Only 2.5% of variance in horn length growth could be explained by an individual effect, and thus any genetic changes over the time period could only have had a small effect on phenotypes. Our findings allow insight into the capacity for horn morphology to react to selection pressures and demonstrate the overall importance of climate in determining growth.

Optimisation of the mechanical and handling properties of an injectable calcium phosphate cement.

Calcium phosphate cements have the potential to be successful in minimally invasive surgical techniques, like that of vertebroplasty, due to their ability to be injected into a specific bone cavity. These bone cements set to produce a material similar to that of the natural mineral component in bone. Due to the ceramic nature of these materials they are highly brittle and it has been found that they are difficult to inject. This study was carried out to determine the factors that have the greatest effect on the mechanical and handling properties of an apatitic calcium phosphate cement with the use of a Design of Experiments (DoE) approach. The properties of the cement were predominantly influenced by the liquid:powder ratio and weight percent of di-sodium hydrogen phosphate within the liquid phase. An optimum cement composition was hypothesised and tested. The mechanical properties of the optimised cement were within the clinical range for vertebroplasty, however, the handling properties still require improvement.

Estimation of rates of births, deaths, and immigration from mark-recapture data.

The analysis of mark-recapture data is undergoing a period of development and expansion. Here we contribute to that by presenting a model which includes both births and immigration, as well as the usual deaths. Data come from a long-term study of the willow tit (Parus montanus), where we can assume that all births are recorded, and hence immigrants can also be identified as birds captured as adults for the first time. We model the rates of immigration, birth rate per parent, and death rates of juveniles and adults. Using a hierarchical model allows us to incorporate annual variation in these parameters. The model is fitted to the data using Markov chain Monte Carlo, as a Bayesian analysis. In addition to the model fitting, we also check several aspects of the model fit, in particular whether survival varies with age or immigrant status, and whether capture probability is affected by previous capture history. The latter check is important, as independence of capture histories is a key assumption that simplifies the model considerably. Here we find that the capture probability depends strongly on whether the individual was captured in the previous year.

Lunar periodicity and the timing of river entry in Atlantic salmon Salmo salar.

Historical catch records of Atlantic salmon Salmo salar from three rivers discharging to the Baltic Sea in an area free from tides and from strong effects of the moon on illumination were analysed to investigate whether timing of S. salar river entry was associated with lunar cycles directly. Although a significant effect of lunar phase on river entry was detected, with more fish entering rivers around the full moon than other phases, the effect of the lunar cycle was very small compared with other sources of variation. Hence, the biological role of lunar cycle as a determinant of the timing of S. salar runs in the investigated populations was negligible, suggesting that lunar cycle per se does not play a role in the timing of S. salar river entry.

Climate-driven spatial dynamics of plague among prairie dog colonies.

We present a Bayesian hierarchical model for the joint spatial dynamics of a host-parasite system. The model was fitted to long-term data on regional plague dynamics and metapopulation dynamics of the black-tailed prairie dog, a declining keystone species of North American prairies. The rate of plague transmission between colonies increases with increasing precipitation, while the rate of infection from unknown sources decreases in response to hot weather. The mean annual dispersal distance of plague is about 10 km, and topographic relief reduces the transmission rate. Larger colonies are more likely to become infected, but colony area does not affect the infectiousness of colonies. The results suggest that prairie dog movements do not drive the spread of plague through the landscape. Instead, prairie dogs are useful sentinels of plague epizootics. Simulations suggest that this model can be used for predicting long-term colony and plague dynamics as well as for identifying which colonies are most likely to become infected in a specific year.

Comparative studies of quantitative trait and neutral marker divergence: a meta-analysis.

Comparative studies of quantitative genetic and neutral marker differentiation have provided means for assessing the relative roles of natural selection and random genetic drift in explaining among-population divergence. This information can be useful for our fundamental understanding of population differentiation, as well as for identifying management units in conservation biology. Here, we provide comprehensive review and meta-analysis of the empirical studies that have compared quantitative genetic (Q(ST)) and neutral marker (F(ST)) differentiation among natural populations. Our analyses confirm the conclusion from previous reviews - based on ca. 100% more data - that the Q(ST) values are on average higher than F(ST) values [mean difference 0.12 (SD 0.27)] suggesting a predominant role for natural selection as a cause of differentiation in quantitative traits. However, although the influence of trait (life history, morphological and behavioural) and marker type (e.g. microsatellites and allozymes) on the variance of the difference between Q(ST) and F(ST) is small, there is much heterogeneity in the data attributable to variation between specific studies and traits. The latter is understandable as there is no reason to expect that natural selection would be acting in similar fashion on all populations and traits (except for fitness itself). We also found evidence to suggest that Q(ST) and F(ST) values across studies are positively correlated, but the significance of this finding remains unclear. We discuss these results in the context of utility of the Q(ST)-F(ST) comparisons as a tool for inferring natural selection, as well as associated methodological and interpretational problems involved with individual and meta-analytic studies.

Bayesian approaches in evolutionary quantitative genetics.

The study of evolutionary quantitative genetics has been advanced by the use of methods developed in animal and plant breeding. These methods have proved to be very useful, but they have some shortcomings when used in the study of wild populations and evolutionary questions. Problems arise from the small size of data sets typical of evolutionary studies, and the additional complexity of the questions asked by evolutionary biologists. Here, we advocate the use of Bayesian methods to overcome these and related problems. Bayesian methods naturally allow errors in parameter estimates to propagate through a model and can also be written as a graphical model, giving them an inherent flexibility. As packages for fitting Bayesian animal models are developed, we expect the application of Bayesian methods to evolutionary quantitative genetics to grow, particularly as genomic information becomes more and more associated with environmental data.

Bias and precision in QST estimates: problems and some solutions.

Comparison of population differentiation in neutral marker genes and in genes coding quantitative traits by means of F(ST) and Q(ST) indexes has become commonplace practice. While the properties and estimation of F(ST) have been the subject of much interest, little is known about the precision and possible bias in Q(ST) estimates. Using both simulated and real data, we investigated the precision and bias in Q(ST) estimates and various methods of estimating the precision. We found that precision of Q(ST) estimates for typical data sets (i.e., with <20 populations) was poor. Of the methods for estimating the precision, a simulation method, a parametric bootstrap, and the Bayesian approach returned the most precise estimates of the confidence intervals.

Spatial test for agricultural pesticide "blow-in" effect on prevalence of Parkinson's disease.

The current study used Department of Veteran's Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson's disease patients, and pesticide applications to determine if there was evidence for "blow-in" of pesticides as a factor in explaining the prevalence of Central Valley Parkinson's disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.

Genetic variability of encephalomyocarditis virus (EMCV) isolates.

In order to evaluate the variability of encephalomyocarditis virus (EMCV), field isolates originating from different European regions and inducing different clinical pictures in pigs have been molecularly characterised. The regions targeted were the poly(C) tract, a part of the 5'-UTR (360 nucleotides), the Leader gene (201 nucleotides), the complete capsid coding region (2502 nucleotides), the 2A gene (403 nucleotides), the end of the 3D polymerase gene (305 nucleotides) and the 3'-UTR (123 nucleotides). Analyses have also been performed on a virulent field isolate, which had been subjected to serial passages in vivo and in vitro resulting, in the case of the in vitro passaged virus, in attenuation, as demonstrated by animal experiments. The present study shows that different clinical pictures, such as acute fatal myocarditis or reproductive failure, may not only be caused by EMCV isolates which are genetically diverse but also by the same isolate. Thus no correlation could be demonstrated between genotype and clinical disease. However, the European isolate which showed the highest genetic divergence also gave rise to a more complex clinical picture. Despite EMCV having been isolated from cases of acute fatal myocarditis in pigs in certain areas of the world for many years, clinical disease, including a variety of clinical pictures and pathogenicity, has only been recognised in Europe since 1986 and thus it can be considered an emerging disease in this region. These findings, associated with the reported phenotype changes of the virus under environmental changes (passages), along with its wide distribution among vertebrate species (including higher primates), shows the validity of considering EMCV as a potential pathogen for recipients in xenotransplantation.

Comparing the effects of genetic drift and fluctuating selection on genotype frequency changes in the scarlet tiger moth.

One of the recurring arguments in evolutionary biology is whether evolution occurs principally through natural selection or through neutral processes such as genetic drift. A 60-year-long time series of changes in the genotype frequency of a colour polymorphism of the scarlet tiger moth, Callimorpha dominula, was used to compare the relative effects of genetic drift and variable natural selection. The analysis showed that most of the variation in frequency was the result of genetic drift. In addition, although selection was acting, mean fitness barely increased. This supports the 'Red Queen's hypothesis' that long-term improvements in fitness may not occur, because populations have to keep pace with changes in the environment.

Advanced colorectal cancer is associated with impaired interleukin 12 and enhanced interleukin 10 production.

Interleukin 12 (IL-12) is a heterodimeric cytokine that has been demonstrated to have a major role in stimulating a cell-mediated antitumor response. IL-10, a product of T helper 2 lymphocytes, is its most potent inhibitor. The aim of this study was to investigate whether patients with colorectal cancer had an imbalance in production of IL-12 and IL-10 preoperatively, and whether this was associated with advanced disease at surgery. Blood was obtained before surgery from 60 patients with colorectal cancer and from 30 controls. Peripheral blood mononuclear cells were incubated with Staphylococcus aureus Cowan's strain 1 in vitro for 24 h to assess IL-12 expression after stimulation, and serum was used for IL-10 measurement. IL-12 and IL-10 levels were assessed by ELISA. A single pathologist staged the tumors according to the tumor-node-metastasis (TNM) and Dukes' classifications. Patients with colorectal cancer had significantly lower levels of IL-12 (P <0.001) and higher levels of IL-10(P = 0.004) compared to controls. In addition, lower levels of IL-12 were detected in those patients who were node positive (P<0.05), had Dukes' C lesions (P < or = 0.001), and T3 or T4 lesions (P<0.033) when compared to controls. Patients with Dukes' B and C lesions (P<0.01) and T3 and T4 lesions (P<0.05) also had higher levels of IL-10 compared to controls. This study is the first to demonstrate that patients with colorectal cancer have decreased IL-12 production and increased serum IL-10. This suggests an impaired T helper 1 cell-mediated antitumor response and provides some justification for exogenous IL-12 therapy or anti-IL-10 therapy in these patients.

Treatment Planning for Image-Guided Neuro-Vascular Interventions Using Patient-Specific 3D Printed Phantoms.

Minimally invasive endovascular image-guided interventions (EIGIs) are the preferred procedures for treatment of a wide range of vascular disorders. Despite benefits including reduced trauma and recovery time, EIGIs have their own challenges. Remote catheter actuation and challenging anatomical morphology may lead to erroneous endovascular device selections, delays or even complications such as vessel injury. EIGI planning using 3D phantoms would allow interventionists to become familiarized with the patient vessel anatomy by first performing the planned treatment on a phantom under standard operating protocols. In this study the optimal workflow to obtain such phantoms from 3D data for interventionist to practice on prior to an actual procedure was investigated. Patient-specific phantoms and phantoms presenting a wide range of challenging geometries were created. Computed Tomographic Angiography (CTA) data was uploaded into a Vitrea 3D station which allows segmentation and resulting stereo-lithographic files to be exported. The files were uploaded using processing software where preloaded vessel structures were included to create a closed-flow vasculature having structural support. The final file was printed, cleaned, connected to a flow loop and placed in an angiographic room for EIGI practice. Various Circle of Willis and cardiac arterial geometries were used. The phantoms were tested for ischemic stroke treatment, distal catheter navigation, aneurysm stenting and cardiac imaging under angiographic guidance. This method should allow for adjustments to treatment plans to be made before the patient is actually in the procedure room and enabling reduced risk of peri-operative complications or delays.

Impact of 5-HTTLPR on hippocampal subregional activation in older adults.

Studies have shown that a functional polymorphism of the serotonin transporter gene (5-HTTLPR) impacts performance on memory-related tasks and the hippocampal structures that subserve these tasks. The short (s) allele of 5-HTTLPR has been linked to greater susceptibility for impaired memory and smaller hippocampal volume compared to the long allele (l). However, previous studies have not examined the associations between 5-HTTLPR allele and activation in subregions of the hippocampus. In this study, we used functional magnetic resonance imaging (fMRI) to measure activation in hippocampal and temporal lobe subregions in 36 elderly non-clinical participants performing a face-name encoding and recognition task. Although there were no significant differences in task performance between s allele carriers and l homozygotes, right CA1 and right parahippocampal activation during recognition errors was significantly greater in individuals bearing the s allele. In an exploratory analysis, we determined that these effects were more pronounced in s allele carriers with the apolipoprotein ɛ4 allele. Our results suggest that older individuals with the s allele inefficiently allocate neural resources while making errors in recognizing face-name associations, which could negatively impact memory performance during more challenging tasks.