Associations between KIR/KIR-ligand genotypes and clinical outcome for patients with advanced solid tumors receiving BEMPEG plus nivolumab combination therapy in the PIVOT-02 trial.

Bempegaldesleukin (BEMPEG), a CD122-preferential IL2 pathway agonist, has been shown to induce proliferation and activation of NK cells. NK activation is dependent on the balance of inhibitory and excitatory signals transmitted by NK receptors, including Fc-gamma receptors (FCγRs) and killer immunoglobulin-like receptors (KIRs) along with their KIR-ligands. The repertoire of KIRs/KIR-ligands an individual inherits and the single-nucleotide polymorphisms (SNPs) of FCγRs can influence NK function and affect responses to immunotherapies. In this retrospective analysis of the single-arm PIVOT-02 trial, 200 patients with advanced solid tumors were genotyped for KIR/KIR-ligand gene status and FCγR SNP status and evaluated for associations with clinical outcome. Patients with inhibitory KIR2DL2 and its ligand (HLA-C1) observed significantly greater tumor shrinkage (TS, median change -13.0 vs. 0%) and increased PFS (5.5 vs. 3.3 months) and a trend toward improved OR (31.2 vs. 19.5%) compared to patients with the complementary genotype. Furthermore, patients with KIR2DL2 and its ligand together with inhibitory KIR3DL1 and its ligand (HLA-Bw4) had improved OR (36.5 vs. 19.6%), greater TS (median change -16.1 vs. 0%), and a trend toward prolonged PFS (8.4 vs. 3.6 months) as compared to patients with the complementary genotype. FCγR polymorphisms did not influence OR/PFS/TS.These data show that clinical response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial may be associated with the repertoire of KIR/KIR-ligands an individual inherits. Further investigation and validation of these results may enable KIR/KIR-ligand genotyping to be utilized prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens.

Improved Neutron Lifetime Measurement with UCNτ.

We report an improved measurement of the free neutron lifetime τ_{n} using the UCNτ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38×10^{6} surviving ultracold neutrons (UCNs) after storing in UCNτ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τ_{n} from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τ_{n} measurements and by performing a global likelihood fit to all data while self-consistently incorporating the ß-decay lifetime. Both techniques achieve consistent results and find a value τ_{n}=877.75±0.28_{stat}+0.22/-0.16_{syst} s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.

Machine learning-based FDG PET-CT radiomics for outcome prediction in larynx and hypopharynx squamous cell carcinoma.

AIM: To determine whether machine learning-based radiomic feature analysis of baseline integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) computed tomography (CT) predicts disease progression in patients with locally advanced larynx and hypopharynx squamous cell carcinoma (SCC) receiving (chemo)radiotherapy. MATERIALS AND METHODS: Patients with larynx and hypopharynx SCC treated with definitive (chemo)radiotherapy at a specialist cancer centre undergoing pre-treatment PET-CT between 2008 and 2017 were included. Tumour segmentation and radiomic analysis was performed using LIFEx software (University of Paris-Saclay, France). Data were assigned into training (80%) and validation (20%) cohorts adhering to TRIPOD guidelines. A random forest classifier was created for four predictive models using features determined by recursive feature elimination: (A) PET, (B) CT, (C) clinical, and (D) combined PET-CT parameters. Model performance was assessed using area under the curve (AUC) receiver operating characteristic (ROC) analysis. RESULTS: Seventy-two patients (40 hypopharynx 32 larynx tumours) were included, mean age 61 (range 41-77) years, 50 (69%) were men. Forty-five (62.5%) had chemoradiotherapy, 27 (37.5%) had radiotherapy alone. Median follow-up 26 months (range 12-105 months). Twenty-seven (37.5%) patients progressed within 12 months. ROC AUC for models A, B, C, and D were 0.91, 0.94, 0.88, and 0.93 in training and 0.82, 0.72, 0.70, and 0.94 in validation cohorts. Parameters in model D were metabolic tumour volume (MTV), maximum CT value, minimum standardized uptake value (SUVmin), grey-level zone length matrix (GLZLM) small-zone low grey-level emphasis (SZLGE) and histogram kurtosis. CONCLUSION: FDG PET-CT derived radiomic features are potential predictors of early disease progression in patients with locally advanced larynx and hypopharynx SCC.

Prediction of outcome in anal squamous cell carcinoma using radiomic feature analysis of pre-treatment FDG PET-CT.

PURPOSE: Incidence of anal squamous cell carcinoma (ASCC) is increasing, with curative chemoradiotherapy (CRT) as the primary treatment of non-metastatic disease. A significant proportion of patients have locoregional treatment failure (LRF), but distant relapse is uncommon. Accurate prognostication of progression-free survival (PFS) would help personalisation of CRT regimens. The study aim was to evaluate novel imaging pre-treatment features, to prognosticate for PFS in ASCC. METHODS: Consecutive patients with ASCC treated with curative intent at a large tertiary referral centre who underwent pre-treatment FDG-PET/CT were included. Radiomic feature extraction was performed using LIFEx software on baseline FDG-PET/CT. Outcome data (PFS) was collated from electronic patient records. Elastic net regularisation and feature selection were used for logistic regression model generation on a randomly selected training cohort and applied to a validation cohort using TRIPOD guidelines. ROC-AUC analysis was used to compare performance of a regression model encompassing standard clinical prognostic factors (age, sex, tumour and nodal stage-model A), a radiomic feature model (model B) and a combined radiomic/clinical model (model C). RESULTS: A total of 189 patients were included in the study, with 145 in the training cohort and 44 in the validation cohort. Median follow-up was 35.1 and 37. 9 months, respectively for each cohort, with 70.3% and 68.2% reaching this time-point with PFS. GLCM entropy (a measure of randomness of distribution of co-occurring pixel grey-levels), NGLDM busyness (a measure of spatial frequency of changes in intensity between nearby voxels of different grey-level), minimum CT value (lowest HU within the lesion) and SMTV (a standardized version of MTV) were selected for inclusion in the prognostic model, alongside tumour and nodal stage. AUCs for performance of model A (clinical), B (radiomic) and C (radiomic/clinical) were 0.6355, 0.7403, 0.7412 in the training cohort and 0.6024, 0.6595, 0.7381 in the validation cohort. CONCLUSION: Radiomic features extracted from pre-treatment FDG-PET/CT in patients with ASCC may provide better PFS prognosis than conventional staging parameters. With external validation, this might be useful to help personalise CRT regimens in the future.

Search for the Neutron Decay n→X+γ, Where X is a Dark Matter Particle.

Fornal and Grinstein recently proposed that the discrepancy between two different methods of neutron lifetime measurements, the beam and bottle methods, can be explained by a previously unobserved dark matter decay mode, n→X+γ. We perform a search for this decay mode over the allowed range of energies of the monoenergetic γ ray for X to be dark matter. A Compton-suppressed high-purity germanium detector is used to identify γ rays from neutron decay in a nickel-phosphorous-coated stainless-steel bottle. A combination of Monte Carlo and radioactive source calibrations is used to determine the absolute efficiency for detecting γ rays arising from the dark matter decay mode. We exclude the possibility of a sufficiently strong branch to explain the lifetime discrepancy with 97% confidence.

Emersion behaviour underlies variation in gill morphology and aquatic respiratory function in the amphibious fish Kryptolebias marmoratus.

Fishes acclimated to hypoxic environments often increase gill surface area to improve O2 uptake. In some species, surface area is increased via reduction of an interlamellar cell mass (ILCM) that fills water channels between gill lamellae. Amphibious fishes, however, may not increase gill surface area in hypoxic water because these species can, instead, leave water and breathe air. To differentiate between these possibilities, we compared wild amphibious mangrove rivulus Kryptolebias marmoratus from two habitats that varied in O2 availability - a hypoxic freshwater pool versus nearly anoxic crab burrows. Fish captured from crab burrows had less gill surface area (as ILCMs were enlarged by ∼32%), increased rates of normoxic O2 consumption and increased critical O2 tension compared with fish from the freshwater pool. Thus, wild mangrove rivulus do not respond to near-anoxic water by decreasing metabolism or increasing O2 extraction. Instead, fish from the crab burrow habitat spent three times longer out of water, which probably caused the observed changes in gill morphology and respiratory phenotype. We also tested whether critical O2 tension is influenced by genetic heterozygosity, as K. marmoratus is one of only two hermaphroditic vertebrate species that can produce both self-fertilized (inbred) or out-crossed (more heterozygous) offspring. We found no evidence for inbreeding depression, suggesting that self-fertilization does not impair respiratory function. Overall, our results demonstrate that amphibious fishes that inhabit hypoxic aquatic habitats can use a fundamentally different strategy from that used by fully aquatic water-breathing fishes, relying on escape behaviour rather than metabolic depression or increased O2 extraction ability.

How confident are general practitioners in interpreting neuroradiology reports?

AIM: To determine the level of confidence general practitioners (GPs) have in radiology reports provided by neuroradiologists and to elicit the preferences of GPs regarding report format and level of detail. MATERIALS AND METHODS: Electronic surveys comprising anonymised neuroradiology reports were sent to GP practices served by a tertiary neuroscience centre. After reviewing the reports, GPs were asked to complete a two-part questionnaire. Firstly, GPs indicated their level of confidence, using a five-tiered Likert scale, in their understanding of: (a) the body of text; (b) the meaning of the report; and (c) the significance of the report. Secondly, GPs provided free-text suggestions for improving the report and highlighted any phrases that they did not understand. RESULTS: One hundred GPs responded from a group of 439 that received a survey (response rate 23%). Although the majority of GPs were fairly confident in their understanding of reports, fewer than one-third of GPs were entirely confident. Approximately 10% of GPs were not confident at all in their understanding of the reports. Causes of confusion included the use of detailed anatomy, acronyms, radiological terminology, and a lack of a conclusion and an action plan. CONCLUSION: General practice is a time-sensitive discipline that demands clear communication. In neuroradiology reports, GPs do not find detailed anatomy, acronyms, or radiological terminology helpful. Rather, GPs want a clear conclusion and action plan.

An audit of Cryptosporidium and Giardia detection in Scottish National Health Service Diagnostic Microbiology Laboratories.

Giardia duodenalis and Cryptosporidium species are protozoan parasites capable of causing gastrointestinal disease in humans and animals through the ingestion of infective faeces. Whereas Cryptosporidium species can be acquired locally or through foreign travel, there is the mis-conception that giardiasis is considered to be largely travel-associated, which results in differences in laboratory testing algorithms. In order to determine the level of variation in testing criteria and detection methods between diagnostic laboratories for both pathogens across Scotland, an audit was performed. Twenty Scottish diagnostic microbiology laboratories were invited to participate with questions on sample acceptance criteria, testing methods, testing rates and future plans for pathogen detection. Reponses were received from 19 of the 20 laboratories representing each of the 14 territorial Health Boards. Detection methods varied between laboratories with the majority performing microscopy, one using a lateral flow immunochromatographic antigen assay, another using a manually washed plate-based enzyme immunoassay (EIA) and one laboratory trialling a plate-based EIA automated with an EIA plate washer. Whereas all laboratories except one screened every stool for Cryptosporidium species, an important finding was that significant variation in the testing algorithm for detecting Giardia was noted with only four laboratories testing all diagnostic stools. The most common criteria were 'travel history' (11 laboratories) and/or 'when requested' (14 laboratories). Despite only a small proportion of stools being examined in 15 laboratories for Giardia (2%-18% of the total number of stools submitted), of interest is the finding that a higher positivity rate was observed for Giardia than Cryptosporidium in 10 of these 15 laboratories. These findings highlight that the underreporting of Giardia in Scotland is likely based on current selection and testing algorithms.

Under-reporting giardiasis: time to consider the public health implications.

Giardiasis is a treatable disease, caused by the flagellated protozoan parasite, Giardia duodenalis (G. duodenalis). It is one of the most common enteric parasites found globally to cause gastrointestinal disturbances, and infections may result in long-term irritable bowel syndrome-like symptoms. It is a common misconception that giardiasis is associated with foreign travel, which results in locally acquired cases in the UK being underdiagnosed. This report highlights the findings from one large Scottish Health Board, arising from a change in testing methodology, which resulted in the screening of all stools submitted for enteric investigations for G. duodenalis. Previous selection criteria were restricted to patients with a travel history to specific regions of the world, or on the basis of certain clinical details. In this report, clinical details were recorded from samples shown to be positive using two methods: an ELISA-based antigen detection assay and microscopy. Clinical details were assessed for a total of 28 laboratory-confirmed positive cases against the original selection criteria. Twenty-six cases (93%) would have been excluded from Giardia testing if the previous selection criteria had been applied. Although nine cases stated foreign travel, only two had been to regions deemed to be 'high risk'. Therefore, those seven cases that travelled to perceived 'low-risk' regions would have been excluded from testing for this reason. This summary highlights the need for significant improvements to the selection criteria for Giardia testing. Laboratories should be encouraged towards the testing of all routinely submitted stools for this neglected pathogen to ensure cases that are acquired locally are properly identified and treated effectively.

Fish in hot water: hypoxaemia does not trigger catecholamine mobilization during heat shock in rainbow trout (Oncorhynchus mykiss).

Rainbow trout (Oncorhynchus mykiss) exposed to an acute heat shock (1 h at 25 °C after raising water temperature from 13 °C to 25 °C over 4 h) mount a significant catecholamine response. The present study investigated the proximate mechanisms underlying catecholamine mobilization. Trout exposed to heat shock in vivo exhibited a significant reduction in arterial O(2) tension, but arterial O(2) concentration was not affected by heat shock, nor was catecholamine release during heat shock prevented by prior and concomitant exposure to hyperoxia (to prevent the fall in arterial O(2) tension). Thus, catecholamine mobilization probably was not triggered by impaired blood O(2) transport. Heat-shocked trout also exhibited an elevation of arterial CO(2) tension coupled with a fall in arterial pH, but these factors are not expected to trigger catecholamine release. The changes in blood O(2) and CO(2) tension occurred despite a significant hyperventilatory response to heat shock. Future studies should investigate whether catecholamine mobilization during heat shock in rainbow trout is triggered by a specific effect of high temperature activating the sympathetic nervous system via a thermosensitive transient receptor potential channel.

Specialist Palliative Care and Dementia: Staff Challenges and Learning Needs.

Objective: This study explored the perspectives of specialist palliative care (SPC) teams in Ireland, in relation to personal learning needs and education regarding dementia care. Methods: This mixed-methods study involved a survey and focus group. SPC staff were recruited through a professional palliative care society and via hospices in 4 regions. Survey items included challenges in clinical care, personal learning needs, and preferred modes of educational delivery. Quantitative data analysis was descriptive; open-answer survey questions and the focus group transcript underwent thematic analysis. Results: In total, 76 staff completed surveys and rated the following as most challenging: timely access to community agency and specialist support; and managing the needs of people with dementia (PwD). Respondents volunteered additional challenges around the timing/duration of SPC involvement, prognostication, and inadequate knowledge of local services. Staff ranked learning needs as highest in: nonpharmacological management of noncognitive and cognitive symptoms; differentiation of dementia subtypes; and pharmacological management of cognitive symptoms. The focus group (n = 4) gave deeper perspectives on these topics. Overall, 79.2% of staff preferred formal presentations by dementia-care specialists and 76.6% preferred e-learning. Conclusion: Several dementia-care challenges and learning needs are identified by SPC staff, as above. These can inform the design and delivery of tailored education programs for SPC staff. There is also a need for closer working between dementia services and SPC services to provide integrated, holistic care for PwD. One aspect of achieving this is greater awareness of local dementia-care services among SPC staff, and vice versa.

Predictors of 1-year outcomes of major depressive disorder among individuals with a lifetime diagnosis: a population-based study.

BACKGROUND: Examining predictors of the outcomes of major depressive disorder (MDD) is important for clinical practice and population health. There are few population-based longitudinal studies on this topic. The objectives of this study were to (1) estimate the proportions of persistent and recurrent MDD among those with MDD over 1 year, and (2) identify demographic, socio-economic, workplace psychosocial and clinical factors associated with the outcomes. METHOD: From a population-based longitudinal study of the working population, participants with a lifetime diagnosis of MDD were selected (n=834). They were classified into two groups: those with and those without current MDD. The proportions of 1-year persistence and recurrence of MDD were estimated. MDD was assessed by the World Health Organization (WHO) Composite International Diagnostic Interview, CIDI-Auto 2.1, by telephone. RESULTS: The proportions of persistent and recurrent MDD in 1 year were 38.5% [95% confidence interval (CI) 31.1-46.5] and 13.3% (95% CI 10.2-17.1) respectively. Long working hours, negative thinking and having co-morbid social phobia were predictive of persistence of MDD. Perceived work-family conflict, the severity of a major depressive episode and symptoms of depressed mood were significantly associated with the recurrence of MDD. CONCLUSIONS: Clinical and psychosocial factors are important in the prognosis of MDD. The factors associated with persistence and recurrence of MDD may be different. More large longitudinal studies on this topic are needed so that clinicians may predict potential outcomes based on the clinical profile and provide interventions accordingly. They may also take clinical action to change relevant psychosocial factors to minimize the chance of persistence and/or recurrence of MDD.

Disordered gambling among higher-frequency gamblers: who is at risk?

BACKGROUND: When gambling opportunities are made available to the public in a given jurisdiction, some individuals participate occasionally and others more frequently. Among frequent gamblers, some individuals develop problematic involvement and some do not. This study addresses the association among demographic and social risk factors, frequency of gambling and gambling disorders. METHOD: Data from an adult community sample (n=1372) were used to identify risk factors for higher-frequency gambling and disordered gambling involvement. RESULTS: Individuals with higher intelligence, older individuals and more religious individuals were less frequent gamblers. Males, single individuals and those exposed to gambling environments (friends and family who gamble) and those who started to gamble at a younger age were more frequent gamblers. Excitement-seeking personality traits were also higher among more frequent gamblers. A different set of risk factors was associated with the likelihood of gambling disorder among these higher-frequency gamblers. These variables included mental health indicators, childhood maltreatment and parental gambling involvement. Among higher-frequency gamblers, individuals who smoke cigarettes, those with a diagnosis of alcohol or drug dependence or obsessive-compulsive disorder, those with higher anxiety or depression and those with higher impulsivity and antisocial personality traits were more likely to report gambling-related problems. These individuals were also more likely to report gambling on electronic gambling machines (e.g. slot machines). CONCLUSIONS: These data suggest a model in which higher-frequency gambling, particularly with electronic gambling machines, when combined with any type of emotional vulnerability increased the likelihood of gambling disorder.

Psychosocial health care needs assessment of adult cancer patients: a consensus-based guideline.

PURPOSE: Although recommended as an essential part of cancer care, there is limited evidence regarding the optimum approach to psychosocial health care needs assessment in this setting. To address this gap, the Cancer Journey Action Group of the Canadian Partnership Against Cancer (CPAC) and the Canadian Association of Psychosocial Oncology (CAPO) partnered to develop consensus-based recommendations regarding the routine assessment of psychosocial and supportive care needs. The purpose of this paper is to summarize the evidence that informed the guideline and disseminate the recommendations developed by the expert panel. METHODS: Clinical practice recommendations were developed by a panel comprised of psychosocial and interdisciplinary experts. Recommendations were informed by a review of oncology clinical practice guidelines, systematic reviews, and primary research, through to May 2008. Following expert consensus on the recommendations, the clinical practice guideline was externally reviewed by a purposively selected sample of national and international interdisciplinary experts. RESULTS: A total of nine clinical practice guidelines, three systematic reviews, and 14 primary studies were included in the review. Overall, this body of literature suggested that routine collection of psychosocial health care data has an influence on communication with oncologists and other study specific outcomes, but the evidence was limited by heterogeneity and methodological limitations. Based on the interpretation of this body of evidence by clinical experts, research methodologists, and external reviewers, 12 substantive recommendations were developed regarding the process and parameters of psychosocial needs assessment in adult cancer patients. CONCLUSION: Given the limitations in the current body of evidence, there remains a need for rigorous empirical research regarding the optimal approach to psychosocial needs assessment, including the specific characteristics that influence effectiveness on patient outcomes. This guideline fills an important gap in psychosocial care, regarding the routine assessment of psychosocial health care needs.

MRI characteristics of tuberculous spondylitis.

Spondylitis is the most common osseous manifestation of Mycobacterium tuberculosis infection. Although treatable, it continues to cause significant mortality and morbidity. Early diagnosis through familiarity with its imaging characteristics is essential to permit rapid treatment and prevent potential life-limiting consequences. In this review, we demonstrate the key magnetic resonance imaging features of this disease.

Ultracold neutron properties of the Eljen-299-02D deuterated scintillator.

In this paper, we report studies of the Fermi potential and loss per bounce of ultracold neutrons (UCNs) on a deuterated scintillator (Eljen-299-02D). These UCN properties of the scintillator enable its use in a wide variety of applications in fundamental neutron research.

Determination of the axial-vector weak coupling constant with ultracold neutrons.

A precise measurement of the neutron decay ß asymmetry A0 has been carried out using polarized ultracold neutrons from the pulsed spallation ultracold neutron source at the Los Alamos Neutron Science Center. Combining data obtained in 2008 and 2009, we report A0 = -0.119 66±0.000 89{-0.001 40}{+0.001 23}, from which we determine the ratio of the axial-vector to vector weak coupling of the nucleon g{A}/g{V}=-1.275 90{-0.004 45}{+0.004 09}.

Toxicity and Efficacy of Stereotactic Ablative Body Radiotherapy for Moderately Central Non-small Cell Lung Cancers Using 50 Gy in Five Fractions.

AIMS: Stereotactic ablative body radiotherapy doses for peripheral lung lesions caused high toxicity when used for central non-small cell lung cancer (NSCLC). To determine a safe stereotactic ablative body radiotherapy dose for central tumours, the phase I/II Radiation Therapy Oncology Group RTOG 0813 trial used 50 Gy/five fractions as a baseline. From 2013, 50 Gy/five fractions was adopted at the Beatson West of Scotland Cancer Centre for inoperable early stage central NSCLC. We report our prospectively collected toxicity and efficacy data. MATERIALS AND METHODS: Patient and treatment characteristics were obtained from electronic medical records. Tumours were classed as moderately central or ultra-central tumours using published definitions. Toxicity was assessed in a centralised follow-up clinic at 2 weeks, 6 weeks, 3 months, 6 months, 1 year and 2 years after treatment. RESULTS: Fifty patients (31 women, 19 men, median age 75.1 years) were identified with T1-2N0M0 moderately central NSCLC; one patient had both an ultra-central and a moderately central tumour. Eighty-four per cent were medically unfit for surgery. Forty per cent had biopsy-proven NSCLC and 60% were diagnosed radiologically using 18-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Fifty-six per cent of patients were Eastern Cooperative Oncology Group (ECOG) performance status 2 or worse. All patients received 50 Gy/five fractions on alternate days on schedule. Two patients died within 90 days of treatment, one from a chest infection, the other cause of death was unknown. There was one episode of early grade 3 oesophagitis and one grade 3 late dyspnoea. There was no grade 4 toxicity. Over a median follow-up of 25.2 months (range 1-70 months), there were 34 deaths: 18 unrelated to cancer and 16 due to cancer recurrence. The median overall survival was 27.0 months (95% confidence interval 20.6-35.9) and cancer-specific survival was 39.8 months (95% confidence interval 28.6, not reached). CONCLUSION: This study has shown that 50 Gy/five fractions is a safe dose and fractionation for early stage inoperable moderately central NSCLC, with outcomes comparable with other series, even with patients with a poor performance status.

Which behavior does the lamprey central motor program mediate?

The isolated lamprey spinal cord, when bathed in 2 millimolar D-glutamic acid, will generate a pattern of motor neuron discharge that has generally been assumed to represent the central motor program for swimming. Motion pictures of behaving lampreys were analyzed by a computer algorithm to estimate undulatory movement parameters that could be directly compared with those generated during D-glutamate--induced undulations. The D-glutamate--induced movement parameters were significantly different from those observed during normal behaviors, including swimming, but accurately predicted the undulations produced by spinally transected adult lampreys.