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.

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.

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.

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.

Cognitive assessment of very low birth weight infants using the Dutch version of the PARCA-R parent questionnaire.

OBJECTIVE: Very low birth weight (VLBW) infants are at an increased risk of long-term cognitive impairment. Early identification and timely interventions are important. We aimed to validate the Dutch version of the revised Parent Report of Children's Abilities (PARCA-R) questionnaire. METHODS: The subjects were survivors from the Belgian participating centers to the NIRTURE trial. As part of a study-related follow-up, PARCA-R was sent out at the age of 2 years. As part of a normal hospital follow-up, these infants were assessed by the Bayley Scales of Infant Development - second edition (BSID-II) at the age of 9, 18 and 36 months. MRI was performed at term in the group of VLBW infants of ZOL Genk as standard care. RESULTS: PARCA-R was sent out to 193 surviving infants. BSID-II was performed in 36% (n=70) at 9 months, in 30% (n=58) at 18 months and in 12% (n=23) at 36 months. MRI was available for 32 infants. We received 86 responses to the PARCA-R. Parent report composite (PRC) scores were significantly correlated with the Mental Development Index (MDI) (p<0.0001 (9 months); p=0.003 (18 months); p=0.01 (36 months)). PRC scores were significantly lower in those with an abnormal MRI (92 vs.124; p=0.04). CONCLUSION: We support the use of the PARCA-R as a time and cost efficient alternative for identifying cognitive delay. PRACTICE IMPLICATIONS: We suggest that the combination of BSID-II, MRI at term and PARCA-R would be the ideal testing method for identifying VLBW infants at risk for cognitive developmental delay by two years of age.

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.

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.

Cardiorespiratory events recorded on home monitors: the effect of prematurity on later serious events.

OBJECTIVE: To describe severe alarms on home-documented monitoring in infants born prematurely. METHODS: In infants born at a post-menstrual age (PMA) less than 35 weeks, a polysomnography was performed before discharge. A heart rate less than 50 beats per minute (bpm) for more than 3 seconds or an apnea lasting for more than 15 seconds with a heart rate less than 60 bpm were defined as abnormal. These babies were given cardiorespiratory home monitoring with memory. Serious alarms on the home monitor were defined as heart rate less than 50 bpm for more than 3 seconds. RESULTS: Of 1058 infants, 96 infants needed cardiorespiratory home monitoring. Sixty-one infants showed alarms at home. The mean post-conceptional age (PCA) when alarms stopped was 46 weeks. Seventeen patients had serious alarms above the PCA of 50 weeks. There was a significant negative correlation (r = -0.46 and p = 0.0002 by Spearman's rank correlation) between the PMA at birth and the PCA at which the last alarm was noted CONCLUSION: Prematurely born infants with an abnormal polysomnography at discharge are at high risk for developing acute events at home. A younger PMA at birth correlates with a higher risk of alarms at a later PCA.

Nutrient composition of larval nectar secretions from three species of myrmecophilous butterflies.

A comparative chemical analysis of the larval nectar secretions and hemolymph from three unspecifically and facultatively ant-attended lycaenid species (Polyommatus coridon, P. icarus, and Zizeeria knysna) was performed by using high-performance liquid chromatography techniques. Sucrose was the main sugar component in all three species. In half of the samples of P. coridon, it was accompanied by glucose, whereas other sugars occurred only rarely. In P. icarus and Z. knysna, melezitose was the second-most important component, followed by fructose and glucose. Total sugar contents were 43.6 +/- 14.8 g/l (mean +/- SD) for P. coridon, 74.2 g/l for P. icarus, and 68.3 +/- 22.6 g/l for Z. knysna. Up to 14 different identified amino acids were found in P. coridon nectar, with a total content of 9.7 +/- 3.4 g/l. Leucine was always the major component (contributing 50% of overall amino acid content). Other important amino acids were tyrosine, proline, arginine, and phenylalanine. P. icarus nectar contained up to six amino acids with a total content of 1.2 g/l, dominated by tyrosine and phenylalanine. Z. knysna nectar contained alanine and proline, with only 0.3 +/- 0.17 g/l total content. In the hemolymph of all species, up to 16 different amino acids occurred relatively regularly, with histidine dominating, followed by serine and proline. The amino acid pattern in hemolymph was considerably different from that of the nectar secretions. Larval diet weakly influenced P. coridon nectar sugars, and with a semisynthetic diet, a more homogeneous amino acid pattern was detected. Comparison with reports from other lycaenid species shows that secretions rich in amino acids are related to intimate, often obligate ant associations, whereas facultative, unspecific myrmecophiles rely on carbohydrates.

Characteristics of respiratory syncytial virus-related apnoea in three infants.

UNLABELLED: Apnoea is a common sign in respiratory syncytial virus (RSV) infections in young infants and can be the first presentation of an acquired RSV infection. We describe polysomnographic recordings of three infants revealing prolonged RSV-related apnoea before RSV infection was diagnosed. The apnoeas were of central origin. The caregivers had not noted any apparent life-threatening events (ALTE) prior to the polysomnography. Cardiorespiratory monitoring after the acute infection did not reveal any further apnoeas. CONCLUSION: Central, prolonged apnoea can be the first sign of an acquired RSV infection in young infants in the absence of other respiratory symptoms and without any previous observation of apnoea by the caregivers.

[Manipulation of the step borer as cause of too shallow boring depth in the femoral neck with the gamma nail system]. / Handhabung des Stufenbohrers als Ursache für eine zu geringe Bohrtiefe im Schenkelhals beim Gamma-Nagelsystem.

The gamma nail step drill has been sold over 500,000 times worldwide. Depending on the construction used and the way it is handled, it can lead to a drill depth in the femoral head that is too shallow if the anatomic dimension of the femoral neck is rather long. Whenever the relationship between rotational speed and drive force is unfavorable, as it is by hand reaming, the triple-bladed drill only produces a triangular hole in the lateral cortical bone. Subsequently, it draws itself through this hole like a screw, without forming the hole into a complete circle. The drill shaft expands conically along its length preventing it from passing through the hole in the cortical bone at a depth of 90 mm. Until now, this phenomenon has been traced back to blunt drills or perhaps curved guide wires. Since the lag screws that have been used could not be screwed into undrilled cancellus bone, screws have sometimes been implanted at a sub-optimal length. The problem was noticed, however, and documented in experiments, and potential solutions were proposed.

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.

Effects of non-nutritive sucking on heart rate, respiration and oxygenation: a model-based signal processing approach.

Several studies support the idea that the use of pacifiers can reduce the risk of Sudden Infant Death Syndrome. To investigate the effect of non-nutritive sucking (NNS), we measured heart rate, abdominal respiration, EMG and arterial oxygen saturation of 20 neonates. Also, in 10 of these neonates, changes in cerebral hemoglobin concentrations were acquired by means of near-infrared spectroscopy. Using a parametric technique to model the heart rate as a sum of exponentially damped sinusoids, two main frequency components were found in the heart rate during NNS: a frequency of approximately 0.08 Hz due to the alternation of sucking bursts and pauses, and a frequency of approximately 0.8 Hz that reflects the influence of the respiration. Our analysis shows that it is the alternation of bursts and pauses itself that causes the increased heart rate variability, and that this is not due to increased effort. This suggests that the neuronal mechanism regulating NNS also stimulates the heart rate. From our measurements, no effect of NNS on cerebral or peripheral oxygenation could be found. Furthermore, we show that our model-based signal processing technique is well suited for the analysis of non-stationary biomedical signals.

In vitro studies on the immunomodulatory effects of extracts of Osbeckia aspera.

Ayruvedic medical practitioners in Sri Lanka use aqueous extracts of the mature leaves of Osbeckia aspera to treat liver disease. The extract has been shown to have hepatoprotective effects in vitro and in vivo, and to have inhibitory effects on the complement system and on in vitro phagocytosis by polymorphonuclear cells. The aim of this study was to investigate the effect of an aqueous extract of Osbeckia on lymphocyte proliferation stimulated by mitogens and antigen. In control peripheral blood mononuclear cells (PBMC), high concentrations of the Osbeckia extract were inhibitory to proliferation stimulated by phytohaemagglutinin (PHA) and tuberculin purified protein derivative (PPD). On stimulation by phorbol myristate acetate and ionomycin (PMA+I) the extract showed stimulation of proliferation at low concentrations (<10 microg/ml) with inhibition at higher concentrations. A similar inhibitory pattern on mitogen/antigen stimulation was seen with PBMC from patients with chronic hepatitis C virus (HCV) infection. These results suggest that the inhibitory agent(s) in the aqueous extract of Osbeckia may have an effect on antigen-presenting cell function. The combined hepatoprotective and immunosuppressive effects of the extract are more likely to be beneficial in acute hepatitis rather than chronic hepatitis viral infection.

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.

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.

Polysomnography and home documented monitoring of cardiorespiratory pattern.

Polysomnographic findings were compared with data obtained subsequently from home documented monitoring in order to study the diagnostic value of both techniques. Polysomnography was performed in 1274 infants born prematurely and in 422 patients admitted because of apparent life threatening events (ALTEs). In 72 of the infants, home documented monitoring of the cardiorespiratory pattern, including QRS complexes, was performed. Subsequent documented episodes of heart rate < 50 beats/min were considered as "serious life threatening events". It was confirmed that polysomnographic findings correlated well with subsequent events as registered by home documented monitoring. Especially in the ALTE group where both infants with and without abnormal polysomnography were home monitored, the single polysomnography significantly predicted subsequent life threatening events. Home documented monitoring of the cardiorespiratory pattern has a distinctive advantage over simple cardiorespiratory monitoring as a means to identify and document life threatening events, in addition to its value as a rescue device.

Lymphoblastoid interferon alfa with or without steroid pretreatment in children with chronic hepatitis B: a multicenter controlled trial.

The comparative efficacy of prednisolone followed by interferon alfa (IFN-alpha) versus IFN-alpha alone in enhancing the rate of antibody to hepatitis B e antigen (anti-HBe) seroconversion has not been evaluated in a large cohort of white children. To determine this, a multicenter-controlled trial was conducted in 95 hepatitis B virus (HBV)-DNA/hepatitis B e antigen (HBeAg)-positive children (median age, 9 years [range, 2-16 years]; 56 boys; 84 [89 percent] white), all having inflammatory changes on liver biopsy. Patients were randomized to receive either prednisolone followed by IFN-alpha (n = 34); placebo followed by IFN-alpha (n = 30); or no treatment (n = 31). The prednisolone/placebo was given on a double-blind basis. Lymphoblastoid IFN-alpha was given at 5 MU/m(2) three times a week for 12 weeks. Baseline clinical, biochemical, and histological features were similar for the three groups. The majority (85 percent) had a baseline aspartate aminotransferase (AST) level < or = 100 IU/L. On follow-up between 12 and 18 months (median, 15 months) after treatment, the loss of HBeAg with anti-HBe seroconversion was more common in patients pretreated with steroids (12 of 34 [35 percent]) or placebo [12 of 30 (40 percent)] as against controls (4 of 31 [13 percent], P< .05). Factors predictive of anti-HBe seroconversion were baseline HBV-DNA concentration of < or = 1,000 pg/mL and a greater degree of portal tract inflammation on pretrial biopsy. Our results show that in white children treatment with IFN-alpha, at the dose and duration used in this study, improves the rate of anti-HBe seroconversion. Steroid priming does not potentiate the effect of IFN-alpha.