Surprising impact of stromal TIL's on immunotherapy efficacy in a real-world lung cancer study.

INTRODUCTION: Immune checkpoint inhibitors (ICI), such as anti-PD-1 agents, have become part of the standard of care treatment of advanced non-small cell lung cancer (NSCLC). Predictive biomarkers are needed to identify patients that benefit from anti-PD-1 treatments. Tumor infiltrating lymphocytes (TILs) and PD-L1 are major players in the ICI mechanism of action. In this study, we assess the impact of real-world clinicopathological variables, including TILs and PD-L1, on anti-PD-1 efficacy. METHODS: We performed a monocenter retrospective study in advanced NSCLC treated with nivolumab or pembrolizumab between January 2015 and February 2019. The impact of baseline clinical and pathological variables was assessed by univariate and multivariate models. TILs, defined as CD8+T-cells, and PD-L1 were scored in tumor and stroma, and correlated with progression free survival (PFS) and overall survival (OS). RESULTS: We included 366 patients of whom 141 were assessed for tumor and stromal TILs. The median follow-up time was 487 days. In the whole cohort, PFS was associated with high tumor PD-L1, high albumin and good performance. OS was associated with low LDH, high albumin, good performance and 'first-line treatment'. In the TILs subcohort, stromal TILs had the strongest impact on PFS and OS. Stromal TILs were a stronger marker for PFS and OS than tumoral TILs, tumoral PD-L1 or stromal PD-L1. Remaining factors for PFS and OS were albumin and albumin with LDH, respectively. CONCLUSIONS: This real-world study on clinicopathological features shows that stromal CD8 + TILs were the strongest predictor for PFS and OS in patients with advanced NSCLC on anti-PD-1 therapy. Other predictors for PFS and OS included albumin and albumin together with LDH, respectively. This study highlights the pivotal role of the stromal compartment in the mechanisms of action of ICI, and the need for further studies aiming to overcome this stromal firewall.

Turning principles into practice in Alzheimer's disease.

The prevalence of dementia is reaching epidemic proportions globally, but there remain a number of issues that prevent people with dementia, their families and caregivers, from taking control of their condition. In 2008, Alzheimer's Disease International (ADI) launched a Global Alzheimer's Disease Charter, which comprises six principles that underscore the urgency for a more ambitious approach to diagnosis, treatment and care. This review highlights some of the most important aspects and challenges of dementia diagnosis and treatment. These issues are reviewed in light of the six principles of the recent ADI Charter: promoting dementia awareness and understanding; respecting human rights; recognizing the key role of families and caregivers; providing access to health and social care; stressing the importance of optimal diagnosis and treatment; and preventing dementia through improvements in public health. The authors continue to hope that, one day, a cure for Alzheimer's disease will be found. Meanwhile, healthcare professionals need to unite in rising to the challenge of managing all cases of dementia, using the tools available to us now to work toward improved patient care.

Exploring barriers and solutions in advancing cross-centre population data science.

INTRODUCTION: It is widely acknowledged that population health and administrative data, especially when linked at the individual level, hold great value for research. Cross-centre working between data centres providing access to such data has the potential to further increase this value by effectively expanding the data available for research. However, there is limited published information on how to address the challenges and achieve success. The aim of this paper is to explore perceived barriers and solutions to inform developments in cross-centre working across data centres. METHODS: We carried out a narrative literature review on data sharing and cross centre working. We used a mixed methods approach to assess the opinions of members of the public on cross-centre data sharing, and the views and experiences of among data centre staff connected with the UK Farr Institute for Health Informatics Research. RESULTS: The literature review uncovered a myriad of practical and cultural issues. Our engagement with a public group suggested that cross-centre working involving anonymised data being moved between established centres is considered acceptable. The main themes emerging from discussions with data centre staff were dedicated resourcing, practical issues, information governance and culture. CONCLUSION: In seeking to advance cross-centre working between data centres, we conclude that there is a need for dedicated resourcing, indicators to recognise data reuse, collaboration to solve common issues, and balancing necessary barrier removal with incentivisation. This will require on-going commitment, engagement and an academic culture change.

Warmer waters masculinize wild populations of a fish with temperature-dependent sex determination.

Southern flounder (Paralichthys lethostigma) exhibit environmental sex determination (ESD), where environmental factors can influence phenotypic sex during early juvenile development but only in the presumed XX female genotype. Warm and cold temperatures masculinize fish with mid-range conditions producing at most 50% females. Due to sexually dimorphic growth, southern flounder fisheries are dependent upon larger females. Wild populations could be at risk of masculinization from ESD due to globally increasing water temperatures. We evaluated the effects of habitat and temperature on wild populations of juvenile southern flounder in North Carolina, USA. While northern habitats averaged temperatures near 23 °C and produced the greatest proportion of females, more southerly habitats exhibited warmer temperatures (>27 °C) and consistently produced male-biased sex ratios (up to 94% male). Rearing flounder in the laboratory under temperature regimes mimicking those of natural habitats recapitulated sex ratio differences observed across the wild populations, providing strong evidence that temperature is a key factor influencing sex ratios in nursery habitats. These studies provide evidence of habitat conditions interacting with ESD to affect a key demographic parameter in an economically important fishery. The temperature ranges that yield male-biased sex ratios are within the scope of predicted increases in ocean temperature under climate change.

A study of information seeking by cancer patients and their carers.

AIMS: To examine cancer patients' and carers' use of, and attitudes to, the Internet as an information source compared with other media. MATERIALS AND METHODS: The study was carried out in two phases: in phase I, interviews were used to construct a suitable instrument. In phase II, interviews were completed with 800 recently diagnosed patients and 200 carers. RESULTS: Relatively few patients (4.8%), but a high proportion of carers (48%), accessed the Internet directly for cancer information. However, around half of the patients used Internet information provided by someone else, generally a family member. The use of Internet information was uniformly low among ethnic minorities. Those who accessed Internet information reported high levels of satisfaction and generally rated it higher than booklets or leaflets. When asked who they would like to provide Internet information, overwhelmingly patients wanted the hospital doctor to do so. When this was done, there was very high compliance. Carers were much more proactive information seekers than patients. CONCLUSIONS: The Internet is an effective means of information provision in those who use it. Facilitated Internet access and directed use by health professionals would be effective ways of broadening access to this medium.

Development of a universal double-digest RAD sequencing approach for a group of nonmodel, ecologically and economically important insect and fish taxa.

The generation of genome-scale data is critical for a wide range of questions in basic biology using model organisms, but also in questions of applied biology in nonmodel organisms (agriculture, natural resources, conservation and public health biology). Using a genome-scale approach on a diverse group of nonmodel organisms and with the goal of lowering costs of the method, we modified a multiplexed, high-throughput genomic scan technique utilizing two restriction enzymes. We analysed several pairs of restriction enzymes and completed double-digestion RAD sequencing libraries for nine different species and five genera of insects and fish. We found one particular enzyme pair produced consistently higher number of sequence-able fragments across all nine species. Building libraries off this enzyme pair, we found a range of usable SNPs between 4000 and 37 000 SNPS per species and we found a greater number of usable SNPs using reference genomes than de novo pipelines in STACKS. We also found fewer reads in the Read 2 fragments from the paired-end Illumina Hiseq run. Overall, the results of this study provide empirical evidence of the utility of this method for producing consistent data for diverse nonmodel species and suggest specific considerations for sequencing analysis strategies.

Iron supplementation in preterm infants: a study comparing the effect and tolerance of a Fe2+ and a nonionic FeIII compound.

The more widely used divalent forms of iron (Fe2+) supplementation often lead to gastrointestinal symptoms in preterm infants although little is known about the use of nonionic trivalent iron preparations (FeIII) in these patients. It is especially under this nonionic form that dietary iron is available. For this reason, a randomized controlled study was undertaken to compare the efficacy and the extent of possible side effects in two groups of preterm infants. In one group, the elemental iron was given in the Fe2+ form, while the other group received a nonionic trivalent iron (FeIII) complexed with polysaccharides of low molecular weight. Both groups received 7.5 mg elemental iron daily. Measured parameters in the two study groups did not differ significantly throughout the study period of 14 weeks. Both forms of iron supplementation were well tolerated. However, vomiting, diarrhea, or constipation occurred slightly more often in the group receiving iron supplementation in the Fe2+ form without reaching statistical difference. The authors found a nonionic trivalent polysaccharide-iron complex given as iron supplementation as effective as the generally more favored ferrous sulphate. Since iron therapy is mandatory in the preterm infant, the use of trivalent iron complexes can be considered as a good alternative.

Photodynamic action of ultraviolet A: induction of cellular hydroperoxides.

Long-wavelength ultraviolet radiation (UVA) can cause cancer. A carcinogenic mechanism involved may be the induction of harmful reactive oxygen species resulting from photodynamic effects. UVA is generally assumed to induce photodynamic effects, but evidence from experiments with viable biological materials has been indirect until present. Here we measured the induction of (lipid) hydroperoxides as direct indicators of photodynamic reactions. Cultured human fibroblasts were irradiated with 10J UVA/cm2. The induced hydroperoxides were measured by an enzymatic method using glutathione peroxidase and glutathione reductase (GR). Additionally, reduced glutathione (GSH) was determined as parameter for the constitutive antioxidant defense. UVA was found to increase lipid hydroperoxides in fibroblasts by 116% (p < 0.001), when compared to nonirradiated controls. Conversely GSH was decreased in the irradiated cells by 51% (p < 0.001). Because of the induced hydroperoxides, it is concluded that the UVA effects were mediated by a photodynamic mechanism. The photodynamic mechanism resulted in the formation of reactive oxygen species and the consumption of constitutive antioxidants. This suggests a role for antioxidants during the photodynamic mechanism. Photodynamic mechanisms may play a crucial role in carcinogenic events, especially after UVA.

Quantitative valence plasmon mapping in the TEM: viewing physical properties at the nanoscale.

Using a series of graphitising carbons heat treated at different temperatures, the peak position of the bulk (pi+sigma) plasmon was measured using electron energy loss spectroscopy and observed to shift between 22 and 27eV. Experimental data is presented and discussed showing the effects of the collection conditions and sample orientation upon the observed spectra. We present an empirical technique by which quantitative energy filtered transmission electron microscopy (EFTEM) maps with two energy windows selected in the plasmon region can be readily acquired and processed, the results of which may be interpreted as graphitisation maps and subsequently physical property maps. An experimentally established resolution of approximately 1.6nm makes this technique a very useful tool with which to examine nanoscale properties in microstructural regions of interest in TEM specimens such as fibre/matrix interfaces within carbon-carbon composites, multi-walled carbon nanotubes and graphitic inclusions in carbon steels. Also presented is data demonstrating the unsuitability of pi(*)-related chemical EFTEM maps in both the low-loss region and at the carbon K ionisation edge for mapping bonding in such highly anisotropic media due to the strong orientation dependence of the intensity of the transitions involved. This is followed by suggestions for wider application of the plasmon mapping technique within systems other than those based upon carbon.

The influence of postmenstrual age estimation on the scatter of brainstem auditory evoked potential latencies.

In normal twins the brainstem auditory evoked potential (BAEP) was recorded. The inter-individual variation of the I-V peak latency-interval within the twins appears to be of the same order of magnitude as the variation of the I-V peak latencies generally observed in infants. Consequently we conclude that in low-risk twins the inter-individual variation of the I-V peak latencies of the BAEP is maximally 0.4 msec and cannot be ascribed to a difference in postmenstrual age.

Prognostic value of early somatosensory evoked potentials for adverse outcome in full-term infants with birth asphyxia.

SEPs were examined during the first weeks of life in 34 infants with mild to severe birth asphyxia, in an attempt to provide a more accurate prediction of neurodevelopmental outcome. Normal, delayed and absent responses were compared with the infant's acute clinical condition, imaging findings using different imaging techniques and neurodevelopmental outcome. All infants with normal SEPs were normal at follow-up. All but two of the infants with a delayed or absent response died or suffered from severe neurological sequelae. A delayed or absent N1 latency carried a risk for death or severe handicap of 71 and 100%, respectively, compared with 25 and 89% for moderate or severe encephalopathy on neurological assessment, and 29 and 85% for moderate or severe changes seen using different imaging techniques. SEPs may provide useful additional information when assessing the infant with birth asphyxia.

Cerebral hyperperfusion following episodes of bradycardia in the preterm infant.

The alterations in cerebral hemodynamics during and following 39 episodes with bradycardia of different severity have been studied by analysis of Doppler flow velocity waveforms amongst 16 stable preterm infants (range of conceptional age at the time of study 33-39 weeks; weight 1730-2820 g). Each episode with bradycardia has been classified as mild on seven occasions (heart rate between 100-120 beats/min), moderate on 15 occasions (80-100), or severe on 17 occasions (heart rate below 80) Depending on the severity of the bradycardia, the time-averaged mean flow velocity (V) could decrease by 80% below the preexistent baseline value and the end-diastolic velocity (D) dropped towards the zero line, whereas peak systolic velocities did not change The magnitude of the percentage decrease of V correlated positively with the severity of bradycardia, indicating a progressive decline of cerebral blood flow (CBF). Following bradycardia, V could increase up to 75% above the preexistent baseline value. Simultaneously, an increase of mean arterial blood pressure and D could be documented. Peak systolic velocities remained unaltered. The magnitude of the percentage increase of V following bradycardia depended both on the severity of bradycardia as well as on the drop in transcutaneous oxygen during the preceding bradycardia. Interpretation of these findings suggested that the transient cerebral hyperperfusion following bradycardia compensates for the hypoxic-ischemic episode, sustained during the preceding epoch of apnea and bradycardia.

The influence of blood transfusion on brain blood flow autoregulation among stable preterm infants.

Prior to and 24 h following blood transfusion serial determinations of both cerebral artery flow velocity waveforms and mean arterial blood pressure have been used to reconstruct the autoregulatory curve and its upper blood pressure limit among five stable preterm infants. Prior to transfusion the autoregulatory range of cerebral blood flow (CBF) was narrow due to a relatively low-set upper blood pressure limit. At 24 h after transfusion each individual has been re-examined. Following correction of anemia both a significant reduction of CBF velocities as well as a concomitant rise of the Pulsatility Index (PI) occurred over the entire range of blood pressures indicating a reduction of CBF after transfusion. In addition a right-sided shift of the upper limit towards higher mean blood pressures occurred after transfusion and resulted in an extension of the autoregulatory plateau of CBF. These favourable effects of blood transfusion ameliorating autoregulation of brain blood flow particularly at higher blood pressures might well bear important therapeutic perspectives in our effort to prevent intracranial haemorrhage among sick preterm infants.

The influence of behavioural states on cerebral blood flow velocity patterns in stable preterm infants.

Previous Doppler ultrasound studies assessing cerebral blood flow velocities in the anterior cerebral artery (ACA) among healthy term and preterm infants, showed a widespread range for the calculated flow indices. However, only one of these studies accounted for the infant's behavioural state. In the present study a stable pattern of the cerebral blood flow velocity tracings and of the Pulsatility Index (PI) was observed during state 1, whereas marked fluctuations in cerebral blood flow velocity and PI were found during state 4 or active wakefulness. During state 2, minor variations of cerebral blood flow velocity and PI occurred though tended to be less pronounced than during active wakefulness. Thus at the time of Doppler assessment the cerebral blood flow velocity pattern and its variability will be better understood by taking into account the behavioural state of the infant.

Feeding behaviour in preterm neonates.

In 100 bottle-fed preterm infants feeding efficiency was studied by quantifying the volume of milk intake per minute and the number of teat insertions per 10 ml of milk intake. These variables were related to gestational age and to number of weeks of feeding experience. Feeding efficiency was greater in infants above 34 weeks gestational age than in those below this age. There was a significant correlation between feeding efficiency and the duration of feeding experience at most gestational ages between 32 and 37 weeks. A characteristic adducted and flexed arm posture was observed during feeding: it changed along with feeding experience. A neonatal feeding score was devised that allowed the quantification of the early oral feeding behavior. The feeding score correlated well with some aspects of perinatal assessment, with some aspects of the neonatal neurological evaluation and with developmental assessment at 7 months of age. These findings are a stimulus to continue our study into the relationships between feeding behaviour and other aspects of early development, especially of neurological development.

Upper limits of brain blood flow autoregulation in stable infants of various conceptional age.

In healthy adults cerebral blood flow is autoregulated and kept constant over a wide range of mean arterial blood pressures (MAP) between 60 and 150 mmHg. In 27 stable infants with different conceptional ages ranging from 33 to 50 weeks, Doppler measurements of mean flow velocity at the anterior cerebral artery have been recorded simultaneously with mean arterial blood pressures (MAP) during a period of 6 h. The range of autoregulation and its upper limit could thus be determined. The upper limit was found to increase with advancing age. In the infants with conceptional ages between 33 and 35 weeks, the upper limit of autoregulation varied between 45 and 60 mmHg, while the upper limit shifted to a MAP of 100 mmHg at 47 weeks conceptional age. A significant positive linear relationship existed between the upper limit of autoregulation and conceptional age.

Three-dimensional imaging of acetabular dysplasia: diagnostic value and impact on surgical type classification.

OBJECTIVE: To investigate the diagnostic value and the impact on surgical type classification of three-dimensional (3D) images for pre-surgical evaluation of dysplastic hips. MATERIALS AND METHODS: Three children with a different surgical type of hip dysplasia were investigated with helical computed tomography. For each patient, two-dimensional (2D) images, 3D, and a stereolithographic model of the dysplastic hip were generated. In two separate sessions, 40 medical observers independently analyzed the 2D images (session 1), the 2D and 3D images (session 2), and tried to identify the corresponding stereolithographic hip model. The influence of both image presentation (2D versus 3D images) and observer (degree of experience, radiologist versus orthopedic surgeon) were statistically analyzed. The SL model choice reflected the impact on surgical type classification. RESULTS: Image presentation was a significant factor whereas the individual observer was not. Three-dimensional images scored significantly better than 2D images (P=0.0003). Three-dimensional imaging increased the correct surgical type classification by 35%. CONCLUSION: Three-dimensional images significantly improve the pre-surgical diagnostic assessment and surgical type classification of dysplastic hips.

[Hamartoma of the breast. Comparative mammographic and histopathological studies]. / Das Hamartom der Mamma. Vergleichende mammographische und histopathologische Untersuchung.

Hamartomas of the breast are well circumscribed tumour-like lesions composed of fibroadipose and glandular tissue in variable degrees, depending on the patients' age. The nodules have a pseudocapsule and can easily be enucleated surgically. They may be recognised on mammography by their contours and density. Clinically they appear as painless areas of induration most frequently in the fourth and fifth decade of life. Pathogenetically it is assumed that they are an additional sprout of the breast, comparable to an "intra-glandular polymastia".

Chronic ethanol alters CNS cholinergic and cerebellar development in chick embryos.

Chick embryos were given daily injections of ethanol (approximately 30 mg/day) either chronically from embryonic days 4 to 15 (E4-E15) or E18, or acutely from E15 to E18. Untreated and saline-injected embryos served as controls. Although morphological indicators of developmental age were not different among groups, chronic ethanol reduced weights of several brain regions. Similar to rodent models of prenatal ethanol exposure, chronic ethanol treatment reduced cerebellar Purkinje cell numbers compared to controls. Chronic but not acute ethanol exposure resulted in a significant reduction in choline acetyltransferase activity in the optic tectum (OT) and forebrain (FB) compared with controls. This study demonstrates that the chick embryo is a viable model to investigate the effects of ethanol exposure on CNS development. Unlike the mammalian fetus, the avian embryo is isolated from maternal interactions and may prove more useful in investigating the mechanisms by which ethanol directly influences brain development.

The "deterministic simple epidemic" unmasked.

We derive a simple but surprising connection between the "deterministic epidemic with recovery" and the spatial birth-and-death process, and discuss its implications for the use of nonlinear differential equation models for the spatial spread of epidemics. This paper consists of a manuscript dating back to 1977, which has been widely referred to in the literature but not previously published, and its more recent extension to include recovery/death in the processes considered, with some additional comments. To aid reference, we retain the original title.