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Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Vaccination is a life-saving endeavour, yet risk and uncertainty are unavoidable in science and medicine. Vaccination remains contentious in the public mind, and vaccine hesitancy is a serious public health issue. This has recently been reignited in the discussion over potential side effects of COVID-19 vaccines, and the decision by several countries to suspend measures such as the AstraZeneca vaccine. In these instances, the precautionary principle has often been invoked as a rationale, yet such heuristics do not adequately weigh potential harms against real benefits. How we analyse, communicate and react to potential harms is absolutely paramount to ensure the best decisions and outcomes for societal health, and maintaining public confidence. While balancing benefits and risks is an essential undertaking, it cannot be achieved without due consideration of several other pertinent factors, especially in the context of vaccination, where misguided or exaggerated fears have in the past imperilled public health. While well meaning, over reactions to potential hazards of vaccination and other health interventions can have unintended consequences, and cause lingering damage to public trust. In this analysis, we explore the challenges of assessing risk and benefit, and the limitations of the precautionary principle in these endeavours. When risk is unclear, cautious vigilance might be a more pragmatic and useful policy than reactionary suspensions.

Background: Malinformation is the presentation of curated facts in manner that presents a false narrative and/or creates a misleading impression by leaving out important context. Unlike its better-known relatives, misinformation and disinformation, malinformation depends not on false information, but rather on employing cherry-picked facts and deliberate omissions to mislead. While medical journals are the vanguards of new biomedical research, results and commentary published in them can be misrepresented to produce insidious malinformation, with distortions introduced by third parties interpreting the research, authors themselves, or both.Objective: To investigate the proliferation and interpretation of medical malinformation. Design: An altmetric and sentiment analysis of an article on a COVID-19 vaccine with the highest engagement score ever published in a medical journal. Setting: Worldwide.Participants: Media outlets and social media users worldwide. Measurements: Quantification of the context, spread, adoption, and interpretation of a prominent recent case study of medical malinformation.Results: This analysis suggests the selective and leading presentation made this an especially powerful piece of malinformation, in large part because the imprimatur of a respected medical journal gave it a veneer of legitimacy. Sentiment analysis suggests it has been chiefly amplified by antivaccine activists and conspiracy theorists worldwide, with negative ramifications for vaccine acceptance. The appearance of malinformation in a medical journal can adversely affect public understanding of medical science.Conclusion: To maintain public trust in medical science, authors, editors, and reviewers need be aware of the potential for malinformation and decontextualized misappropriation of bona fide results.

Vitamin D is a fat-soluble vitamin, formed in the skin under the action of UVB light and is known as sunshine vitamin with immunomodulatory as well as classical endocrine actions in calcium control. It has a role in both innate and adaptive immune responses. Intracellular synthesis of 1,25(OH)D in immunocytes promotes the production of cathelicidin and human b -defensin-2 which are …..antimicrobial peptides produced by neutrophils, macrophages, and epithelial cells that facilitate the killing of the pathogenic encapsulated viruses. Vitamin D also plays a role in inhibiting pro-inflammatory cytokines and activating anti-inflammatory cytokines. It provides antiviral immunity by promoting autophagy. Epidemiological studies have shown an association between low vitamin D levels and a variety of respiratory tract infections, both bacterial and viral. Global data correlates severe vitamin D deficiency with COVID-19 due to similar pathological processes being involved.

There is increasing awareness throughout biomedical science that many results do not withstand the trials of repeat investigation. The growing abundance of medical literature has only increased the urgent need for tools to gauge the robustness and trustworthiness of published science. Dichotomous outcome designs are vital in randomized clinical trials, cohort studies, and observational data for ascertaining differences between experimental and control arms. It has however been shown with tools like the fragility index (FI) that many ostensibly impactful results fail to materialize when even small numbers of patients or subjects in either the control or experimental arms are recoded from event to non-event. Critics of this metric counter that there is no objective means to determine a meaningful FI. As currently used, FI is not multidimensional and is computationally expensive. In this work, a conceptually similar geometrical approach is introduced, the ellipse of insignificance. This method yields precise deterministic values for the degree of manipulation or miscoding that can be tolerated simultaneously in both control and experimental arms, allowing for the derivation of objective measures of experimental robustness. More than this, the tool is intimately connected with sensitivity and specificity of the event/non-event tests, and is readily combined with knowledge of test parameters to reject unsound results. The method is outlined here, with illustrative clinical examples.Science and medicine are vital to the well-being of humankind. Yet for all the incredible advances science has made, the unfortunate reality is that a worrying fraction of biological research is not reliable. Erroneous results might arise by chance or because of scientists’ mistakes or ineptitude. Very occasionally, researchers may behave unethically and fabricate or inappropriately manipulate their data. Inevitably, this can lead to untrustworthy research that misleads scientists and the public on questions integral to our health. Indeed, a recent study showed the results of several high-profile cancer papers could not be fully replicated. This problem is not unique to cancer, and studies on various other diseases have also not stood up to scrutiny from outside investigators. Finding ways to detect dubious results is therefore essential to protect the public’s well-being and maintain public trust in science. Here, Grimes demonstrates a new tool called the ‘Ellipse of Insignificance’ for measuring the reliability of dichotomous studies which are commonly used in many branches of biomedical sciences, including clinical trials. These studies typically compare two groups: one which was subjected to a specific treatment, and a control group which was not. Statistical methods are then applied to estimate how likely it is that differences in the number of observed events between the groups are real or due to chance. The tool created by Grimes explores what would happen to seemingly strong results if some of the events in both the control and experimental arm of the study are recoded. It then assesses how much nudging is needed to change the statistical outcome of the experiment: the more interventions the result can withstand, the more robust the experiment. Grimes tested the tool and showed that a study suggesting a link between miscarriage and magnetic field exposure was likely unreliable because shifting the outcomes of less than two participants would change the result. Scientists could use the Ellipse of Insignificance tool to quickly identify misleading published results or potential research fraud. Doing this could benefit researchers and protect the public from potential harm. It may also help preserve research integrity, increase transparency, and bolster public trust in science.

In many chemical reactions, the transformation from reactants to products is mediated by transient intermediate complexes. For gas-phase reactions involving molecules with a few atoms, these complexes typically live on the order of 10 ps or less before dissociating, and are therefore rarely influenced by external processes. Here, we demonstrate that the transient intermediate complex K2Rb2*, formed from collisions between ultracold KRb molecules, undergoes rapid photo-excitation in the presence of a continuous-wave laser source at 1,064 nm, a wavelength commonly used to confine ultracold molecules. These excitations are facilitated by the exceptionally long lifetime of the complex under ultracold conditions. Indeed, by monitoring the change in the complex population after the sudden removal of the excitation light, we directly measure the lifetime of the complex to be 360 ± 30 ns, in agreement with our calculations based on the Rice–Ramsperger–Kassel–Marcus (RRKM) statistical theory. Our results shed light on the origin of the two-body loss widely observed in ultracold molecule experiments. Additionally, the long complex lifetime, coupled with the observed photo-excitation pathway, opens up the possibility to spectroscopically probe the structure of the complex with high resolution, thus elucidating the reaction dynamics. A transient intermediate complex in a chemical reaction—formed from collisions between molecules with a few atoms—is observed under ultracold conditions. Its lifetime can be directly measured after suppression of the photo-excitation process.

Concerns over radiofrequency radiation (RFR) and carcinogenesis have long existed, and the advent of 5G mobile technology has seen a deluge of claims asserting that the new standard and RFR in general may be carcinogenic. For clinicians and researchers in the field, it is critical to address patient concerns on the topic and to be familiar with the existent evidence base.This review considers potential biophysical mechanisms of cancer induction, elucidating mechanisms of electromagnetically induced DNA damage and placing RFR in appropriate context on the electromagnetic spectrum. The existent epidemiological evidence in humans and laboratory animals to date on the topic is also reviewed and discussed.The evidence from these combined strands strongly indicates that claims of an RFR-cancer link are not supported by the current evidence base. Much of the research to date, however, has been undermined by methodological shortcomings, and there is a need for higher-quality future research endeavors. Finally, the role of fringe science and unsubstantiated claims in patient and public perception on this topic is highly relevant and must be carefully considered.

Despite the wide application of the magnetic resonance imaging (MRI) technique, there are no widely used standards on naming and describing MRI sequences. The absence of consistent naming conventions presents a major challenge in automating image processing since most MRI software require a priori knowledge of the type of the MRI sequences to be processed. This issue becomes increasingly critical with the current efforts toward open-sharing of MRI data in the neuroscience community. This manuscript reports an MRI sequence detection method using imaging metadata and a supervised machine learning technique. Three datasets from the Brain Center for Ontario Data Exploration (Brain-CODE) data platform, each involving MRI data from multiple research institutes, are used to build and test our model. The preliminary results show that a random forest model can be trained to accurately identify MRI sequence types, and to recognize MRI scans that do not belong to any of the known sequence types. Therefore the proposed approach can be used to automate processing of MRI data that involves a large number of variations in sequence names, and to help standardize sequence naming in ongoing data collections. This study highlights the potential of the machine learning approaches in helping manage health data.

Magnetic field (MF) non-ionizing radiation is widespread and everyone is exposed to some degree. This prospective cohort study of 913 pregnant women examined the association between high MF exposure and miscarriage risk. Cox (proportional hazards) regression was used to examine the association. After controlling for multiple other factors, women who were exposed to higher MF levels had 2.72 times the risk of miscarriage (hazard ratio = 2.72, 95% CI: 1.42-5.19) than those with lower MF exposure. The increased risk of miscarriage associated with high MF was consistently observed regardless of the sources of high MF. The association was much stronger if MF was measured on a typical day of participants' pregnancies. The finding also demonstrated that accurate measurement of MF exposure is vital for examining MF health effects. This study provides fresh evidence, directly from a human population, that MF non-ionizing radiation could have adverse biological impacts on human health.

Background: Few areas of health have been as insidiously influenced by misinformation as cancer. Thus, interventions that can help people impacted by cancer reduce the extent to which they are victims of misinformation are necessary. The Informed Health Choices (IHC) initiative has developed Key Concepts that can be used in the development of interventions for evaluating the trustworthiness of claims about the effects of health treatments. We are developing an online education programme called Informed Health Choices-Cancer (IHC-C) based on the IHC Key Concepts. We will provide those impacted by cancer with the knowledge and skills necessary to think critically about the reliability of health information and claims and make informed choices. Methods: We will establish a steering group (SG) of 12 key stakeholders, including oncology specialists and academics. In addition, we will establish a patient and public involvement (PPI) panel of 20 people impacted by cancer. After training the members on the Key Concepts and the prioritisation process, we will conduct a two-round prioritisation process. In the first round, 12 SG members and four PPI panel members will prioritise Key Concepts for inclusion. In the second round, the remaining 16 PPI members will undertake the prioritisation based on the prioritised Key Concepts from the first round. Participants in both rounds will use a structured judgement form to rate the importance of the Key Concepts for inclusion in the online IHC-C programme. A consensus meeting will be held, where members will reach a consensus on the Key Concepts to be included and rank the order in which the prioritised Key Concepts will be addressed in the IHC-C programme. Conclusions: At the end of this process, we will identify which Key Concepts should be included and the order in which they should be addressed in the IHC-C programme.

Social media has been an effective vector for spreading disinformation about medicine and science. Informational hygiene can reduce the severity of falsehoods about health.

Objective To quantify the impact and accuracy of different screening approaches for cervical cancer, including liquid based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and their combinations via parallel co-testing and sequential triage. The secondary goal was to predict the effect of differing coverage rates of HPV vaccination on the performance of screening tests and in the interpretation of their results. Design Modelling study. Main outcomes measured Different screening modalities were compared in terms of number of cases of Cervical intra-epithelial neoplasia (CIN) grade 2 and 3 detected and missed, as well as the number of false positives leading to excess colposcopy, and number of tests required to achieve a given level of accuracy. The positive predictive value (PPV) and negative predictive value (NPV) of different modalities were simulated under varying levels of HPV vaccination. Results The model predicted that in a typical population, primary LBC screening misses 4.9 (95% Confidence Interval (CI) 3.5-CIN 2 / 3 cases per 1000 women, and results in 95 (95% CI: 93-97%) false positives leading to excess colposcopy. For primary HPV testing, 2.0 (95% CI: 1.9-2.1) cases were missed per 1000 women, with 99 (95% CI: 98-101) excess colposcopies undertaken. Co-testing markedly reduced missed cases to 0.5 (95% CI: 0.3-0.7) per 1000 women, but at the cost of dramatically increasing excess colposcopy referral to 184 per 1000 women (95% CI: 182-188). Conversely, triage testing with reflex screening substantially reduced excess colposcopy to 9.6 cases per 1000 women (95% CI: 9.3 - 10) but at the cost of missing more cases (6.4 per 1000 women, 95% CI: 5.1 - 8.0). Over a life-time of screening, women who always attend annual and 3-year co-testing were predicted to have a virtually 100% chance of falsely detecting a CIN 2 / 3 case, while 5 year co-testing has a 93.8% chance of a false positive over screening life-time. For annual, 3 year, and 5 year triage testing (either LBC with HPV reflex or vice versa), lifetime risk of a false positive is 35.1%, 13.4%, and 8.3% respectively. HPV vaccination rates adversely impact the PPV, while increasing the NPV of various screening modalities. Results of this work indicate that as HPV vaccination rates increase, HPV based screening approaches result in fewer unnecessary colposcopies than LBC approaches. Conclusion The clinical relevance of cervical cancer screening is crucially dependent upon the prevalence of cervical dysplasia and/or HPV infection or vaccination in a given population, as well as the sensitivity and specificity of various modalities. Although screening is life-saving, false negatives and positives will occur, and over-testing may cause significant harm, including potential over-treatment.

Cancer is a complex phenomenon, and the sheer variation in behaviour across different types renders it difficult to ascertain underlying biological mechanisms. Experimental approaches frequently yield conflicting results for myriad reasons, and mathematical modelling of cancer is a vital tool to explore what we cannot readily measure, and ultimately improve treatment and prognosis. Like experiments, models are underpinned by certain biological assumptions, variation of which can lead to divergent predictions. An outstanding and important question concerns contact inhibition of proliferation (CIP), the observation that proliferation ceases when cells are spatially confined by their neighbours. CIP is a characteristic of many healthy adult tissues, but it remains unclear to which extent it holds in solid tumours, which exhibit regions of hyper-proliferation, and apparent breakdown of CIP. What precisely occurs in tumour tissue remains an open question, which mathematical modelling can help shed light on. In this perspective piece, we explore the implications of different hypotheses and available experimental evidence to elucidate the implications of these scenarios. We also outline how erroneous conclusions about the nature of tumour growth may be arrived at by looking selectively at biological data in isolation, and how this might be circumvented.

Proposed molecular quantum gate takes advantage of internal coherence and resonant electric dipolar interaction with high fidelity and optical scalability., We propose a two-qubit gate based on dipolar exchange interactions between individually addressable ultracold polar molecules in an array of optical dipole traps. Our proposal treats the full Hamiltonian of the 1Σ+ molecule NaCs, utilizing a pair of nuclear spin states as storage qubits. A third rotationally excited state with rotation-hyperfine coupling enables switchable electric dipolar exchange interactions between two molecules to generate an iSWAP gate. All three states are insensitive to external magnetic and electric fields. Impacts on gate fidelity due to coupling to other molecular states, imperfect ground-state cooling, blackbody radiation and vacuum spontaneous emission are small, leading to potential fidelity above 99.99% in a coherent quantum system that can be scaled by purely optical means.

Key Points Question As human papillomavirus (HPV)–based cervical screening modalities change and HPV vaccination becomes more widespread, what are the likely outcomes for the interpretation of screening modalities? Findings In this decision analytical model with a simulated population of women aged 25 years and older, HPV-based screening modalities detected more abnormal cervical cells than traditional liquid-based cytology (LBC) approaches, but they did so at the cost of increased false positives. However, as HPV vaccination increased, HPV-based modalities resulted in fewer unnecessary colposcopies than LBC methods. Meaning These findings suggest that the ideal screening modality for a given population should account for HPV vaccination status to maximize the efficiency of screening., This decision analytical model estimates the likely outcomes of different screening modalities and models the effect of growing uptake of the human papillomavirus (HPV) vaccine on the interpretation of screening results., Importance Cervical cancer screening is a lifesaving intervention, with an array of approaches, including liquid-based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and combinations via parallel cotesting or sequential triage. Maximizing screening efficacy while minimizing overtreatment is vital, especially when considering how the HPV vaccine will affect the interpretation of results. Objectives To estimate the likely outcomes of different screening modalities and to model how the increasing uptake of the HPV vaccine could affect the interpretation of screening results. Design, Setting, and Participants This decision analytic model established a simple Markov model to compare the outcomes of different cervical cancer screening modalities on a simulated population of women (aged ≥25 years), considering different levels of HPV vaccination. Main Outcomes and Measures The number of cases of cervical intraepithelial neoplasia (CIN) grade 2 and 3 detected and missed, the number of false positives, and the number of tests required to achieve a given level of accuracy. Positive and negative predictive values of different modalities were simulated under varying levels of HPV vaccination and therefore HPV prevalence. Results In a simulated population of 1000 women aged 25 years and older with an HPV prevalence of 2%, HPV-based modalities outperformed LBC-based approaches, detecting 19% more true positives (HPV test sensitivity, 89.9% [95% CI, 88.6%-91.1%]; LBC test sensitivity, 75.5% [95% CI, 66.6%-82.7%]). While cotesting markedly reduced missed cases, detecting 29% more true positives than LBC alone (19.5 [95% CI, 19.3-19.7] per 1000 women screened vs 15.1 [95% CI, 13.3-16.5] per 1000 women screened), it unacceptably increased excess colposcopy referral by 94% (184.4 [95% CI, 181.8-188.0] false positives per 1000 women screened vs 95.1 [95% CI, 93.1-97.0] false positives per 1000 women screened). By contrast, triage testing with reflex screening substantially reduced false positives by a factor of approximately 10 (eg, HPV with LBC triage, 9.6 [95% CI, 9.3-10.0] per 1000 women screened). Over a lifetime of screening, reflex approaches with appropriate test intervals maximized therapeutic efficacy; as HPV vaccination rates increased, HPV-based screening approaches resulted in fewer unnecessary colposcopies than LBC approaches (HPV testing, 80% vaccine coverage: 44.1 [95% CI, 40-45.9] excess colposcopies; LBC testing, 80% vaccine coverage: 96.9 [95% CI, 96.8-97.0] excess colposcopies). Conclusions and Relevance In this decision analytic model, the effectiveness of cervical cancer screening was dependent on the prevalence of cervical dysplasia and/or HPV infection or vaccination in a population as well as the sensitivity and specificity of various modalities. Although screening is lifesaving, overtesting or modalities inappropriate to the target population may cause significant harm, including overtreatment.

Editor – Weir and colleagues timidly state that ‘If vitamin D does in fact reduce the severity of COVID-19 … [then] supplements would offer a relatively easy option to decrease the impact of the pandemic.’[1][1] This reticence ignores about 40 years of developing scientific knowledge of the

The transformative effect of oxygen on conventional x-ray radiotherapy has long been known, with the presence of molecular oxygen boosting treatment efficacy multi-fold. This effect is present too in charged particle therapy, but the boosting potential decreases with increasing linear energy transfer of the incident radiation. With particle modalities such as proton therapy becoming common-place and emerging technologies like carbon-ion therapy on the horizon, it is pertinent to address the additive dose boost gained from molecular oxygen with high energy radiation, and the implications of this for dose planning. This work establishes an empirical model for oxygen enhancement across the radiotherapy energy spectrum, and discusses implications of this for therapy.

ObjectivesDisinformation on medical matters has become an increasing public health concern. Public engagement by scientists, clinicians and patient advocates can contribute towards public understanding of medicine. However, depth of feeling on many issues (notably vaccination and cancer) can lead to adverse reactions for those communicating medical science, including vexatious interactions and targeted campaigns. Our objective in this work is to establish a taxonomy of common negative experiences encountered by those communicating medical science, and suggest guidelines so that they may be circumvented.DesignWe establish a taxonomy of the common negative experiences reported by those communicating medical science, informed by surveying medical science communicators with public platforms.Participants142 prominent medical science communicators (defined as having >1000 Twitter followers and experience communicating medical science on social and traditional media platforms) were invited to take part in a survey, with 101 responses.Results101 responses were analysed. Most participants experienced abusive behaviour (91.9%), including persistent harassment (69.3%) and physical violence and intimidation (5.9%). A substantial number (38.6%) received vexatious complaints to their employers, professional bodies or legal intimidation. The majority (62.4%) reported negative mental health sequelae due to public outreach, including depression, anxiety and stress. A significant minority (19.8%) were obligated to seek police advice or legal counsel due to actions associated with their outreach work. While the majority targeted with vexatious complaints felt supported by their employer/professional body, 32.4% reported neutral, poor or non-existent support.ConclusionsThose engaging in public outreach of medical science are vulnerable to negative repercussions, and we suggest guidelines for professional bodies and organisations to remedy some of these impacts on front-line members.

The Consortium has produced these medical and service delivery guidelines about oral emergency contraceptive pills to assist family planning programs and providers in assuring that the women they serve can use these regimens effectively and safely. This document reflects the latest available evidence and has been reviewed by internationally recognized reproductive health experts. Local programs are welcome to adapt these guidelines as needed to comply with national or other requirements. These guidelines do not discuss the use of the copper-bearing intrauterine device for emergency contraception. This device is the most effective emergency contraceptive option and should be offered to women when appropriate. Some of the new research and data updated include: New details on the hormone UPA and new studies on the influence of BMI on effectiveness are briefly discussed as well as how ECP regimens work their efficacy and safety guidelines on repeat use and considerations for starting or resuming regular contraceptives following ECP regimens. This update includes a Clinical Summary document (https://www.cecinfo.org/wp-content/uploads/2018/12/18-209_ICEC-Clinical-Summary_121918.pdf) which highlights essential takeaways.

Oxygen plays a central role in cellular metabolism, in both healthy and tumour tissue. The presence and concentration of molecular oxygen in tumours has a substantial effect on both radiotherapy response and tumour evolution, and as a result the oxygen micro-environment is an area of intense research interest. Multi-cellular tumour spheroids closely mimic real avascular tumours, and in particular they exhibit physiologically relevant heterogeneous oxygen distribution. This property has made them a vital part of in vitro experimentation. For ideal spheroids, their heterogeneous oxygen distributions can be predicted from theory, allowing determination of cellular oxygen consumption rate (OCR) and anoxic extent. However, experimental tumour spheroids often depart markedly from perfect sphericity. There has been little consideration of this reality. To date, the question of how far an ellipsoid can diverge from perfect sphericity before spherical assumptions break down remains unanswered. In this work, we derive equations governing oxygen distribution (and, more generally, nutrient and drug distribution) in both prolate and oblate tumour ellipsoids, and quantify the theoretical limits of the assumption that the spheroid is a perfect sphere. Results of this analysis yield new methods for quantifying OCR in ellipsoidal spheroids, and how this can be applied to markedly increase experimental throughput and quality.

Random assignment of individual participants in clinical trials entails two steps: (i) generating an unbiased treatment allocation schedule; and (ii) applying the schedule without foreknowledge of upcoming allocations. These two steps were implicit in the famous randomized trial of streptomycin for pulmonary tuberculosis in 1948, and were recognized explicitly in some early books on controlled trials. However, half a century later, no widely accepted term denoting the process of concealing upcoming allocations had been adopted. In 1983 Thomas Chalmers and colleagues termed that process “randomization blinding,” and showed that blinded randomization and unblinded randomization were associated with differing estimates of treatment effects; however, their terminology was subsequently rarely used. In the mid-1990s we suggested that the term “allocation concealment” would be preferable to “blinded randomization,” particularly to avoid terminology that might be confused with blinding of treatments after random allocation. After controlling for more factors than had been accounted for by Chalmers and colleagues, we demonstrated an association between allocation concealment and estimates of treatment effects. Moreover, as further indication of bias, inadequately concealed trials displayed more heterogeneity than adequately concealed trials. Notably, our modeling and methodological approach to examine the associations between trial quality and estimates of treatment effects has gained recognition and achieved replication. A PubMed search for the term “allocation concealment” between 1972 and 1993 in “any field” yielded no instances, compared with 1471 between 1995 and 2016. Google Scholar found 25 matches before 1994 and over 30,000 matches after. Although the term might still be improved to avoid occasional misconceptions about its meaning, we assume that it has been widely adopted by authors and editors because they find the term useful.

BackgroundLow oxygen in tumours have long been associated with poor prognosis and metastatic disease, precise reasons for which remain poorly understood. Somatic evolution drives cancer progression and treatment resistance. This process is fuelled not only by genetic and epigenetic mutation, but by selection resulting from the interactions between tumour cells, normal cells and physical microenvironment. The ecological habitat tumour cells inhabit influences evolutionary dynamics but impact on tempo of evolution is less clear.MethodsWe explored this complex dialogue with a combined clinical-theoretical approach. Using an agent-based-model, we simulated proliferative hierarchy under heterogeneous oxygen availability. Predictions were compared against clinical data derived from histology samples taken from glioblastoma patients, stained to elucidate areas of hypoxia / necrosis, and p53 expression heterogeneity.ResultsSimulation results indicate cell division in hypoxic environments is effectively upregulated, and that low-oxygen niches provide new avenues for tumour cells to spread. Analysis of human data indicates cell division isn’t decreased in low-oxygen regions, despite evidence of significant physiological stress. This is consistent with simulation, suggesting hypoxia is a crucible that effectively warping evolutionary velocity, making deleterious mutations more likely than in well-oxygenated regions.ConclusionsResults suggest hypoxic regions alter evolutionary tempo, driving mutations which fuel tumour heterogeneity..

Exposure to nonionizing radiation used in wireless communication remains a contentious topic in the public mind-while the overwhelming scientific evidence to date suggests that microwave and radio frequencies used in modern communications are safe, public apprehension remains considerable. A recent article in Child Development has caused concern by alleging a causative connection between nonionizing radiation and a host of conditions, including autism and cancer. This commentary outlines why these claims are devoid of merit, and why they should not have been given a scientific veneer of legitimacy. The commentary also outlines some hallmarks of potentially dubious science, with the hope that authors, reviewers, and editors might be better able to avoid suspect scientific claims.

Objective: We conducted a systematic review of the literature on the effectiveness of medical abortion “reversal” treatment. Since the usual care for women seeking to continue pregnancies after ingesting mifepristone is expectant management with fetal surveillance, we also performed a systematic review of continuing pregnancy after mifepristone alone. Study design: We searched PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Scopus and the Cochrane Library for articles published through March 2015 reporting the proportion of pregnancies continuing after treatment with either mifepristone alone or after an additional treatment following mifepristone aimed at reversing its effect. Results: From 1115 articles retrieved, 1 study met inclusion criteria for abortion reversal, and 13 studies met criteria for continuing pregnancy after mifepristone alone. The one report of abortion reversal was a case series of 7 patients receiving varying doses of progesterone in oil intramuscularly or micronized progesterone orally or vaginally; 1 patient was lost to follow-up. The study was of poor quality and lacked clear information on patient selection. Four of six women continued the pregnancy to term [67%, 95% confidence interval (CI) 30– 90%]. Assuming the lost patient aborted resulted in a continuing pregnancy proportion of 57% (95% CI 25–84%). The proportion of pregnancies continuing 1–2 weeks after mifepristone alone varied from 8% (95% CI 3–22%) to 46% (95% CI 37–56%). Continuing pregnancy was more common with lower mifepristone doses and advanced gestational age. Conclusions: In the rare case that a woman changes her mind after starting medical abortion, evidence is insufficient to determine whether treatment with progesterone after mifepristone results in a higher proportion of continuing pregnancies compared to expectant management. Implications: Legislation requiring physicians to inform patients about abortion reversal transforms an unproven therapy into law and represents legislative interference in the patient–physician relationship. © 2015 Elsevier Inc. All rights reserved.

In 1994, Altman (1994) startled themedical world by declaring that poor research is as unethical as fraudulent research. His reasoning was simple: both kinds of research mislead which, in turn, harms patients. A decade later, others (von Elm and Egger, 2004) found that the problem had persisted. With the growing indiscriminate use of administrative databases for epidemiologic research (Grimes, 2010) the problem has only gottenworse since then. The record-linkage studyof assisted reproductive technologies (ART) and cancer in this issue (Reigstad et al., 2015a) illustrates the problem.

Ultraviolet radiation (UVR) has been an effective treatment for a number of chronic skin disorders, and its ability to alleviate these conditions has been well documented. Although nonionizing, exposure to ultraviolet (UV) radiation is still damaging to deoxyribonucleic acid integrity, and has a number of unpleasant side effects ranging from erythema (sunburn) to carcinogenesis. As the conditions treated with this therapy tend to be chronic, exposures are repeated and can be high, increasing the lifetime probability of an adverse event or mutagenic effect. Despite the potential detrimental effects, quantitative ultraviolet dosimetry for phototherapy is an underdeveloped area and better dosimetry would allow clinicians to maximize biological effect whilst minimizing the repercussions of overexposure. This review gives a history and insight into the current state of UVR phototherapy, including an overview of biological effects of UVR, a discussion of UVR production, illness treated by this modality, cabin design and the clinical implementation of phototherapy, as well as clinical dose estimation techniques. Several dose models for ultraviolet phototherapy are also examined, and the need for an accurate computational dose estimation method in ultraviolet phototherapy is discussed.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are among the most frequently prescribed groups of drugs worldwide. The use of NSAIDs is associated with a high number of significant adverse effects. Recently, the safety of PPIs has also been challenged. Capsule endoscopy studies reveal that even low-dose NSAIDs are responsible for gut mucosal injury and numerous clinical adverse effects, for example, bleeding and anemia, that might be difficult to diagnose. The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota. Thus, the use of PPI is considered to be an independent risk factor associated with NSAID-associated enteropathy. In this review, we discuss this important clinical problem and review relevant aspects of epidemiology, pathophysiology, and management. We also present the hypothesis that even minor and subclinical injury to the intestinal mucosa can result in significant, though delayed, metabolic consequences, which may seriously affect the health of an individual. PubMed was searched using the following key words (each key word alone and in combination): gut microbiota, microbiome, non-steroidal anti inflammatory drugs, proton pump inhibitors, enteropathy, probiotic, antibiotic, mucosal injury, enteroscopy, and capsule endoscopy. Google engine search was also carried out to identify additional relevant articles. Both original and review articles published in English were reviewed.

Ultraviolet light has long been used to alleviate a number of skin conditions, and its efficacy is well known. However, over-exposure to ultraviolet radiation has a number of detrimental effects and thus it is vital to maintain a dose to skin within the therapeutic window. To maximise treatment gain whilst circumventing potential side-effects of over-exposure requires accurate determination of irradiance and skin-dose. This is complicated by the fact that ultraviolet radiation is essentially absorbed at the skin surface, which means that changing orientation of the patient and source can modulate dose received. In addition, irregular patient shapes mean dose must be carefully calibrated. This chapter focuses on methods of determination of dose, clinical protocols for quantifying radiation dose received and mathematical models for estimating these quantities.

Acquired therapy resistance to cancer treatment is a common and serious clinical problem. The classic U-shape model for the emergence of resistance supposes that: (1) treatment changes the selective pressure on the treatment-naive tumour; (2) this shifting pressure creates a proliferative or survival difference between sensitive cancer cells and either an existing or de novo mutant; (3) the resistant cells then out-compete the sensitive cells and – if further interventions (like drug holidays or new drugs or dosage changes) are not pursued – take over the tumour: returning it to a state dangerous to the patient. The emergence of ruxolitinib resistance in chronic myelomonocytic leukemia (CMML) seems to challenge the classic model: we see the global properties of resistance, but not the drastic change in clonal architecture expected with the selection bottleneck. To study this, we explore three population-level models as alternatives to the classic model of resistance. These three effective models are designed in such a way that they are distinguishable based on limited experimental data on the time-progression of resistance in CMML. We also propose a candidate reductive implementation of the proximal cause of resistance to ground these effective theories. With these reductive implementations in mind, we also explore the impact of oxygen diffusion and spatial structure more generally on the dynamics of CMML in the bone marrow concluding that, even small fluctuations in oxygen availability can seriously impact the efficacy of ruxolitinib. Finally, we look at the ability of spatially distributed cytokine signaling feedback loops to produce a relapse in symptoms similar to what we observe in the clinic.

Ultraviolet light has long been used to alleviate a number of skin conditions, and its efficacy is well known. However, over-exposure to ultraviolet radiation has a number of detrimental effects and thus it is vital to maintain a dose to skin within the therapeutic window. To maximise treatment gain whilst circumventing potential side-effects of over-exposure requires accurate determination of irradiance and skin-dose. This is complicated by the fact that ultraviolet radiation is essentially absorbed at the skin surface, which means that changing orientation of the patient and source can modulate dose received. In addition, irregular patient shapes mean dose must be carefully calibrated. This chapter focuses on methods of determination of dose, clinical protocols for quantifying radiation dose received and mathematical models for estimating these quantities.

Beginning in the 1960s depot medroxyprogesterone acetate (DMPA) injectable contraception has been widely used in family planning programs abroad especially in Africa and Southeast Asia [1]. Approved in the US for the treatment of endometrial cancer in the mid-1960s it was also used off-label for contraception [2]. In 1992 DMPA received Food and Drug Administration (FDA) approval for contraception and began to have a noticeable impact in preventing unintended pregnancies in the US particularly among teens. By 2002 some 2 million US women used injectable contraception [3]. Whereas US teen births increased 23% from 1986 peaking in 1991 rates then declined 35% by 2005 [4]. The authors of the 2002 National Survey of Family Growth (NSFG) reported that “Teens were more likely in 2002 to use contraception at first sex and at most recent sex than in 1995 and were more likely to have used highly effective methods such as injectable contraception” [5]. Copyright © 2014 Elsevier Inc. All rights reserved.

Clinical Opinion www. AJOG .org GENERAL GYNECOLOGY A statement on abortion by 100 professors of obstetrics: 40 years later One Hundred Professors of Obstetrics and Gynecology F orty years ago, leaders in obstetrics and gynecology published a com- pelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade (Supplementary Data available at www.AJOG.org). 1 They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. 1 They wrote to ex- press their concern for women’s health in a new legal and medical era of re- productive control and to define the responsibilities of academic obstetrician- gynecologists. Since then, we have advanced the fields of reproduction and family planning. Thanks to these developments, women can now prevent pregnancy with safer and more effective forms of contracep- tion (most recently long-acting revers- ible methods), with simple and sensitive hormonal and sonographic methods to determine pregnancy status and dura- tion, and with new methods of infer- tility treatment and prenatal testing that rely on the option of terminating inten- ded pregnancies that are diagnosed as abnormal. To terminate pregnancies, cli- nicians now use misoprostol and mife- pristone for “medical abortion” (which in 2009 accounted for 16.5% of termina- tions in the United States and can be office-based) and use sonographic guid- ance of intrauterine procedures along with new methods for inducing cervical From the 100 Professors (Appendix). Received Dec. 3, 2012; revised Jan. 23, 2013; accepted March 7, 2013. The author reports no conflict of interest. Reprints not available from the authors. a 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.03.007 In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women’s health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists. Key words: abortion, law, teaching hospital dilation and uterine contraction; patients benefit from innovations in counseling and new approaches to pain control. 2-6 Studies of abortion practice and out- comes are also much more sophisticated than they were 40 years ago. 7,8 We have had 40 years of medical progress but have witnessed political regression that the 100 professors did not anticipate. In 2011 alone, 24 states passed 92 legislative restrictions on abortion. 9 Waiting periods after consent are now law in 26 states. Alabama, Arizona, Florida, Kansas, Louisiana, North Car- olina, Oklahoma, and Texas require pa- tients to view ultrasound images and, in Arizona, Louisiana, Mississippi, and Texas, to listen to fetal heart beats. 10 Laws in 27 states force physicians to provide deceptive counseling including false statements about risks of breast cancer, infertility, and mental health. They include laws to limit second-trimester abortion under the guise of protecting the fetus from pain (Alabama, Idaho, Indiana, Kansas, Louisiana, Nebraska, and Oklahoma). 11 Laws directed specif- ically at medical education in Arizona, Kansas, and Texas prohibit abortion training in public institutions and another 7 states ban abortion in public hospitals, precluding training in them. 12 What vision of the future of legalized abortion did the 100 professors have? How accurately did they estimate the need for safe, legal abortion and antici- pate their colleagues’ willingness and commitment to meeting it? They wrote, “In view of the impending change in abortion practices generated by new state legislation and federal court de- cisions, we believe it helpful to [respond] to this increasingly liberal course of events.by contributing to the solution of an imminent problem.” 1 Forty years later, the change is not liberal. Its effects will threaten, not improve, women’s health and already obstruct physicians’ evidence-based and patient-centered practices. We review our predecessors’ 1972 statement and judge how it com- ports with what actually occurred and with legislation that has been adopted over the 40 years since their writing and the passage of Roe v Wade. The 100 professors were remarkably prescient in anticipating the need for 1 million legal abortions and today’s abortion rate of 1 in 4 pregnancies. 13,14 They predicted that teaching hospitals with specialized outpatient facilities could meet the demand and believed that abortions were the responsibility of hospitals. But today, 90% of abortions, which include the 10% that are in the second trimester, are done away from hospitals. 15 Many hospitals enforce fetal and maternal health restrictions that SEPTEMBER 2013 American Journal of Obstetrics & Gynecology

Correctly diagnosing pelvic inflammatory disease (PID) using noninvasive clinical criteria remains challenging. Current guidelines for initiating treatment, based on minimal criteria (sensitive but not specific), are justified for public health purposes but inadequate and misleading for scientific purposes. Previous research on the link between the intrauterine device (IUD) and PID was controversial and subject to many limitations. Even today, these limitations still exist and include uncertainty of the PID diagnosis, unfair contraceptive comparisons, selection and diagnostic bias, and confounding. For example, IUD users are on heightened alert for PID relative to users of other methods. In addition, IUD users with pelvic pain may be more likely to seek physician consultation and consequently receive a PID diagnosis (true-positive or false-positive). Confounding factors such as higher coital frequency, multiple sexual partners, and low condom use may explain any finding that shows a higher PID rate among IUD users compared with other contraceptive users. Good evidence on how or whether the IUD changes the etiology of PID is lacking. In the past 10 years, use of the intrauterine device in the United States has increased markedly. Thus today, researchers may now have sufficient population-level exposure (IUD use) and disease (PID) to search for a connection and repeat past mistakes. Any new findings using observational research should be interpreted with caution. More rigorous research designs may not be pragmatic or feasible.

The in situ oxygen partial pressure in normal and tumor tissues is in the range of a few percent. Therefore, when studying cell growth in 3D culture systems, it is essential to consider how the physiological oxygen concentration, rather than the one in the ambient air, influences the proliferation parameters. Here, we investigated the effect of reducing oxygen partial pressure from 21% to 5% on cell proliferation rate and regionalization in a 3D tumor spheroid model. We found that 5% oxygen concentration strongly inhibited spheroid growth, changed the proliferation gradient and reduced the 50% In Depth Proliferation index (IDP50), compared with culture at 21% oxygen. We then modeled the oxygen partial pressure profiles using the experimental data generated by culturing spheroids in physioxic and normoxic conditions. Although hypoxia occurred at similar depth in spheroids grown in the two conditions, oxygen partial pressure was a major rate-limiting factor with a critical effect on cell proliferation rate and regionalization only in spheroids grown in physioxic condition and not in spheroids grown at atmospheric normoxia. Our findings strengthen the need to consider conducting experiment in physioxic conditions (i.e., tissue normoxia) for proper understanding of cancer cell biology and the evaluation of anticancer drugs in 3D culture systems.

Regions of hypoxia in tumours can be modelled in vitro in 2D cell cultures with a hypoxic chamber or incubator in which oxygen levels can be regulated. Although this system is useful in many respects, it disregards the additional physiological gradients of the hypoxic microenvironment, which result in reduced nutrients and more acidic pH. Another approach to hypoxia modelling is to use three-dimensional spheroid cultures. In spheroids, the physiological gradients of the hypoxic tumour microenvironment can be inexpensively modelled and explored. In addition, spheroids offer the advantage of more representative modelling of tumour therapy responses compared with 2D culture. Here, we review the use of spheroids in hypoxia tumour biology research and highlight the different methodologies for spheroid formation and how to obtain uniformity. We explore the challenge of spheroid analyses and how to determine the effect on the hypoxic versus normoxic components of spheroids. We discuss the use of high-throughput analyses in hypoxia screening of spheroids. Furthermore, we examine the use of mathematical modelling of spheroids to understand more fully the hypoxic tumour microenvironment.

The oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertainin situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to insitutumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model.

The presence of oxygen in tumours has substantial impact on treatment outcome; relative to anoxic regions, well-oxygenated cells respond better to radiotherapy by a factor 2.5–3. This increased radio-response is known as the oxygen enhancement ratio. The oxygen effect is most commonly explained by the oxygen fixation hypothesis, which postulates that radical-induced DNA damage can be permanently ‘fixed’ by molecular oxygen, rendering DNA damage irreparable. While this oxygen effect is important in both existing therapy and for future modalities such a radiation dose-painting, the majority of existing mathematical models for oxygen enhancement are empirical rather than based on the underlying physics and radiochemistry. Here we propose a model of oxygen-enhanced damage from physical first principles, investigating factors that might influence the cell kill. This is fitted to a range of experimental oxygen curves from literature and shown to describe them well, yielding a single robust term for oxygen interaction obtained. The model also reveals a small thermal dependency exists but that this is unlikely to be exploitable.

Regions of hypoxia in tumours can be modelled in vitro in 2D cell cultures with a hypoxic chamber or incubator in which oxygen levels can be regulated. Although this system is useful in many respects, it disregards the additional physiological gradients of the hypoxic microenvironment, which result in reduced nutrients and more acidic pH. Another approach to hypoxia modelling is to use three-dimensional spheroid cultures. In spheroids, the physiological gradients of the hypoxic tumour microenvironment can be inexpensively modelled and explored. In addition, spheroids offer the advantage of more representative modelling of tumour therapy responses compared with 2D culture. Here, we review the use of spheroids in hypoxia tumour biology research and highlight the different methodologies for spheroid formation and how to obtain uniformity. We explore the challenge of spheroid analyses and how to determine the effect on the hypoxic versus normoxic components of spheroids. We discuss the use of high-throughput analyses in hypoxia screening of spheroids. Furthermore, we examine the use of mathematical modelling of spheroids to understand more fully the hypoxic tumour microenvironment.