A current perspective on cancer immune therapy: Step‑by‑step approach to constructing the magic bullet

Immunotherapy is the new trend in cancer treatment due to the selectivity, long lasting effects, and demonstrated improved overall survival and tolerance, when compared to patients treated with conventional chemotherapy. Despite these positive results, immunotherapy is still far from becoming the perfect magic bullet to fight cancer, largely due to the facts that immunotherapy is not effective in all patients nor in all cancer types. How and when will immunotherapy overcome these hurdles? In this review we take a step back to walk side by side with the pioneers of immunotherapy in order to understand what steps need to be taken today to make immunotherapy effective across all cancers. While early scientists, such as Coley, elicited an unselective but effective response against cancer, the search for selectivity pushed immunotherapy to the side in favor of drugs focused on targeting cancer cells. Fortunately, the modern era would revive the importance of the immune system in battling cancer by releasing the brakes or checkpoints (anti-CTLA-4 and anti-PD-1/PD-L1) that have been holding the immune system at bay. However, there are still many hurdles to overcome before immunotherapy becomes a universal cancer therapy. For example, we discuss how the redundant and complex nature of the immune system can impede tumor elimination by teeter tottering between different polarization states: one eliciting anti-cancer effects while the other promoting cancer growth and invasion. In addition, we highlight the incapacity of the immune system to choose between a fight or repair action with respect to tumor growth. Finally we combine these concepts to present a new way to think about the immune system and immune tolerance, by introducing two new metaphors, the “push the accelerator” and “repair the car” metaphors, to explain the current limitations associated with cancer immunotherapyThis work was supported by NIH R00 CA154605 and Louisiana Board of Regents LEQSF(2016-17)-RD-C-14 (H.L.M.), a Rámon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain (B.S.Jr) and a Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY (B.S.Jr)

Caesarean Section among Referred and Self-Referred Birthing Women: A Cohort Study from a Tertiary Hospital, Northeastern Tanzania.

The inequity in emergency obstetric care access in Tanzania is unsatisfactory. Despite an existing national obstetric referral system, many birthing women bypass referring facilities and go directly to higher-level care centres. We wanted to compare Caesarean section (CS) rates among women formally referred to a tertiary care centre versus self-referred women, and to assess the effect of referral status on adverse outcomes after CS. We used data from 21,011 deliveries, drawn from the birth registry of a tertiary hospital in northeastern Tanzania, during 2000-07. Referral status was categorized as self-referred if the woman had bypassed or not accessed referral, or formally-referred if referred by a health worker. Because CS indications were insufficiently registered, we applied the Ten-Group Classification System to determine the CS rate by obstetric group and referral status. Associations between referral status and adverse outcomes after CS delivery were analysed using multiple regression models. Outcome measures were CS, maternal death, obstetric haemorrhage ≥ 750 mL, postpartum stay > 9 days, neonatal death, Apgar score < 7 at 5 min and neonatal ward transfer. Referral status contributed substantially to the CS rate, which was 55.0% in formally-referred and 26.9% in self-referred birthing women. In both groups, term nulliparous singleton cephalic pregnancies and women with previous scar(s) constituted two thirds of CS deliveries. Low Apgar score (adjusted OR 1.42, 95% CI 1.09-1.86) and neonatal ward transfer (adjusted OR 1.18, 95% CI 1.04-1.35) were significantly associated with formal referral. Early neonatal death rates after CS were 1.6% in babies of formally-referred versus 1.2% in babies of self-referred birthing women, a non-significant difference after adjusting for confounding factors (adjusted OR 1.37, 95% CI 0.87-2.16). Absolute neonatal death rates were > 2% after CS in breech, multiple gestation and preterm deliveries in both referral groups. Women referred for delivery had higher CS rates and poorer neonatal outcomes, suggesting that the formal referral system successfully identifies high-risk birth, although low volume suggests underutilization. High absolute rates of post-CS adverse outcomes among breech, multiple gestation and preterm deliveries suggest the need to target self-referred birthing women for earlier professional intrapartum care

Online-Abonnement-Vermarktung. Erfolgreicher Marketingmix für die Abonnement- Vermarktung von Konsumgütern

Die Online-Abonnement(Abo)-Vermarktung für Konsumgüter gilt als lukrativer Nischenmarkt im E-Commerce. Obwohl etablierte Firmen sowie Start-ups neue Konzepte erarbeiten, bleibt der Erfolg von Unternehmen eine Unbekannte. Davon ausgehend wurden im Rahmen des vorliegenden Beitrags die Schlüsselfaktoren des kuratierten Online-Abo-Marktes untersucht, die den Erfolg fördern. Bisher wurden keine branchenspezifischen Analysen durchgeführt, welche sich auf den Marketingmix im Online-Abo-Bereich beziehen. Aufgrund der identifizierten Lücken wird der Frage nachgegangen, wie Unternehmen anhand des Marketingmix-Ansatzes eine erfolgreiche Online-Abo-Vermarktung für Konsumgüter gestalten können. Im Mittelpunkt steht daher der kuratierte Online-Abomarkt. Im ersten Teil dieses Beitrages werden die Themen „Subscription economy“ und der Marketingmix behandelt. Im zweiten Teil des Beitrages folgt eine qualitative Bestandsaufnahme von vier untersuchten Fallstudien. Anhand einer Cross-Case-Untersuchung mit Bezug auf prozentuale Umsatz- und Abonnentenentwicklungen werden Schlüsselfaktoren für eine erfolgreiche Abo-Vermarktung herauskristallisiert. Die Kombination von konzeptioneller und empirischer Analyse erlaubt es, wichtige Schlüsselfaktoren für eine erfolgreiche Online-Abo-Vermarktung aufzuzeigen, welche auch für andere Online-Abo-Anbieter relevant sein dürften

Electronic voting to encourage interactive lectures: a randomised trial

Background: Electronic Voting Systems have been used for education in a variety of disciplines. Outcomes from these studies have been mixed. Because results from these studies have been mixed, we examined whether an EVS system could enhance a lecture's effect on educational outcomes. Methods: A cohort of 127 Year 5 medical students at the University of Adelaide was stratified by gender, residency status and academic record then randomised into 2 groups of 64 and 63 students. Each group received consecutive 40-minute lectures on two clinical topics. One group received the EVS for both topics. The other group received traditional teaching only. Evaluation was undertaken with two, 15-question multiple-choice questionnaires (MCQ) assessing knowledge and problem solving and undertaken as a written paper immediately before and after the lectures and repeated online 8–12 weeks later. Standardised institutional student questionnaires were completed for each lecture and independent observers assessed student behaviour during the lectures. Lecturer's opinions were assessed by a questionnaire developed for this study. Results: Two-thirds of students randomised to EVS and 59% of students randomised to traditional lectures attended. One-half of the students in the EVS group and 41% in the traditional group completed all questionnaires. There was no difference in MCQ scores between EVS and traditional lectures (p = 0.785). The cervical cancer lectures showed higher student ranking in favour of EVS in all parameters. The breast cancer lectures showed higher ranking in favour of traditional lectures in 5 of 7 parameters (p < 0.001). The observed higher-order lecturer-students interactions were increased in the EVS lecture for one lecturer and reduced for the other. Both lecturers felt that the EVS lectures were difficult to prepare, that they were able to keep to time in the traditional lectures, that the educational value of both lecture styles was similar, and that they were neutral-to-slightly favourably disposed to continue with the EVS technology. The 2 lecturers disagreed regarding the ease of preparation of the traditional lecture, their ability to keep to time in the EVS lecture, and personal satisfaction with the EVS lecture. The lecturers felt that EVS encouraged student participation and helped identify where students were having difficulty. Conclusion: In this setting, EVS technology used in large group lectures did not offer significant advantages over the more traditional lecture format.Paul M Duggan, Edward Palmer and Peter Devit

Suboptimal clinical response to ciprofloxacin in patients with enteric fever due to Salmonella spp. with reduced fluoroquinolone susceptibility: a case series

BACKGROUND: Salmonella spp. with reduced susceptibility to fluoroquinolones have higher than usual MICs to these agents but are still considered "susceptible" by NCCLS criteria. Delayed treatment response to fluoroquinolones has been noted, especially in cases of enteric fever due to such strains. We reviewed the ciprofloxacin susceptibility and clinical outcome of our recent enteric fever cases. METHODS: Salmonella enterica Serotype Typhi (S. Typhi) and Serotype Paratyphi (S. Paratyphi) blood culture isolates (1998–2002) were tested against nalidixic acid by disk diffusion (DD) and agar dilution (AD) and to ciprofloxacin by AD using NCCLS methods and interpretive criteria. Reduced fluoroquinolone susceptibility was defined as a ciprofloxacin MIC of 0.125–1.0 mg/L. The clinical records of patients treated with ciprofloxacin for isolates with reduced fluoroquinolone susceptibility were reviewed. RESULTS: Seven of 21 (33%) S. Typhi and S. Paratyphi isolates had reduced susceptibility to fluoroquinolones (MIC range 0.125–0.5 mg/L). All 7 were nalidixic acid resistant by DD (no zone) and by AD (MIC 128- >512 mg/L). The other 14 isolates were nalidixic acid susceptible and fully susceptible to ciprofloxacin (MIC range 0.015–0.03 mg/L). Five of the 7 cases were treated initially with oral ciprofloxacin. One patient remained febrile on IV ciprofloxacin until cefotaxime was added, with fever recurrence when cefotaxime was discontinued. Two continued on oral or IV ciprofloxacin alone but had prolonged fevers of 9–10 days duration, one was switched to IV beta-lactam therapy after remaining febrile for 3 days on oral/IV ciprofloxacin and one was treated successfully with oral ciprofloxacin. Four of the 5 required hospitalization. CONCLUSIONS: Our cases provide further evidence that reduced fluoroquinolone susceptibility of S. Typhi and S. Paratyphi is clinically significant. Laboratories should test extra-intestinal Salmonella spp. for reduced fluoroquinolone susceptibility

Clinician-facilitated physical activity intervention versus pulmonary rehabilitation for improving physical activity in COPD: a feasibility study

Pulmonary rehabilitation (PR) may not suit all individuals with chronic obstructive pulmonary disease (COPD) and may not result in increased physical activity. Higher levels of physical activity are associated with reduced mortality and morbidity. The aim of this study was to assess the feasibility of conducting a trial to investigate the effectiveness of a clinician-facilitated physical activity intervention (PAI) versus PR in improving physical activity in patients with COPD referred to PR. In this randomised controlled mixed methods feasibility study, all patients referred to PR who were eligible and willing were assessed at baseline and then randomised to the PAI or to PR. The assessments were repeated post-intervention and at 3-month follow-up. The main outcome was step count measured by Actigraph. Semi-structured interviews were conducted post-intervention. The N = 50 patients; mean (SD) age, 64.1(8.6) years, 24M were recruited and randomised; N = 23 (PAI) and n = 26 (PR): one patient was excluded from the analysis as that person did not meet the GOLD diagnostic criteria. Key feasibility criteria were met; recruitment was 11%, dropouts in PAI were 26% (n = 6) and 50% (n = 13/26) PR. Participants in both groups experienced a range of health benefits from their respective programmes. The PAI appears to be effective in increasing step counts in people with COPD: mean change (standard deviation) [confidence interval] for the PAI group was 972.0(3230.3)[–1080.3 to 3024.4], n = 12 and 4.3(662.7)[-440.9 to 449.5], n = 11 for the PR group. The PAI met all domains of fidelity. This study provides key information to inform a future-randomised controlled trial in physical activity

A habituation account of change detection in same/different judgments

We investigated the basis of change detection in a short-term priming task. In two experiments, participants were asked to indicate whether or not a target word was the same as a previously presented cue. Data from an experiment measuring magnetoencephalography failed to find different patterns for “same” and “different” responses, consistent with the claim that both arise from a common neural source, with response magnitude defining the difference between immediate novelty versus familiarity. In a behavioral experiment, we tested and confirmed the predictions of a habituation account of these judgments by comparing conditions in which the target, the cue, or neither was primed by its presentation in the previous trial. As predicted, cue-primed trials had faster response times, and target-primed trials had slower response times relative to the neither-primed baseline. These results were obtained irrespective of response repetition and stimulus–response contingencies. The behavioral and brain activity data support the view that detection of change drives performance in these tasks and that the underlying mechanism is neuronal habituation

Chronic non-specific low back pain - sub-groups or a single mechanism?

Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches. Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient. An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention. Summary: The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed

Geomorphological evolution of a debris‐covered glacier surface

There exists a need to advance our understanding of debris‐covered glacier surfaces over relatively short timescales due to rapid, climatically induced areal expansion of debris cover at the global scale, and the impact debris has on mass balance. We applied unpiloted aerial vehicle structure‐from‐motion (UAV‐SfM) and digital elevation model (DEM) differencing with debris thickness and debris stability modelling to unravel the evolution of a 0.15 km2 region of the debris‐covered Miage Glacier, Italy, between June 2015 and July 2018. DEM differencing revealed widespread surface lowering (mean 4.1 ± 1.0 m a‐1; maximum 13.3 m a‐1). We combined elevation change data with local meteorological data and a sub‐debris melt model, and used these relationships to produce high resolution, spatially distributed maps of debris thickness. These maps were differenced to explore patterns and mechanisms of debris redistribution. Median debris thicknesses ranged from 0.12 to 0.17 m and were spatially variable. We observed localized debris thinning across ice cliff faces, except those which were decaying, where debris thickened. We observed pervasive debris thinning across larger, backwasting slopes, including those bordered by supraglacial streams, as well as ingestion of debris by a newly exposed englacial conduit. Debris stability mapping showed that 18.2–26.4% of the survey area was theoretically subject to debris remobilization. By linking changes in stability to changes in debris thickness, we observed that slopes that remain stable, stabilize, or remain unstable between periods almost exclusively show net debris thickening (mean 0.07 m a‐1) whilst those which become newly unstable exhibit both debris thinning and thickening. We observe a systematic downslope increase in the rate at which debris cover thickens which can be described as a function of the topographic position index and slope gradient. Our data provide quantifiable insights into mechanisms of debris remobilization on glacier surfaces over sub‐decadal timescales, and open avenues for future research to explore glacier‐scale spatiotemporal patterns of debris remobilization

Functional Divergence in the Genus Oenococcus as Predicted by Genome Sequencing of the Newly-Described Species, Oenococcus kitaharae

Oenococcus kitaharae is only the second member of the genus Oenococcus to be identified and is the closest relative of the industrially important wine bacterium Oenococcus oeni. To provide insight into this new species, the genome of the type strain of O. kitaharae, DSM 17330, was sequenced. Comparison of the sequenced genomes of both species show that the genome of O. kitaharae DSM 17330 contains many genes with predicted functions in cellular defence (bacteriocins, antimicrobials, restriction-modification systems and a CRISPR locus) which are lacking in O. oeni. The two genomes also appear to differentially encode several metabolic pathways associated with amino acid biosynthesis and carbohydrate utilization and which have direct phenotypic consequences. This would indicate that the two species have evolved different survival techniques to suit their particular environmental niches. O. oeni has adapted to survive in the harsh, but predictable, environment of wine that provides very few competitive species. However O. kitaharae appears to have adapted to a growth environment in which biological competition provides a significant selective pressure by accumulating biological defence molecules, such as bacteriocins and restriction-modification systems, throughout its genome