We introduce a new computer aided detection and diagnosis system for lung cancer screening with low-dose CT scans that produces meaningful probability assessments. Our system is based entirely on 3D ...convolutional neural networks and achieves state-of-the-art performance for both lung nodule detection and malignancy classification tasks on the publicly available LUNA16 and Kaggle Data Science Bowl challenges. While nodule detection systems are typically designed and optimized on their own, we find that it is important to consider the coupling between detection and diagnosis components. Exploiting this coupling allows us to develop an end-to-end system that has higher and more robust performance and eliminates the need for a nodule detection false positive reduction stage. Furthermore, we characterize model uncertainty in our deep learning systems, a first for lung CT analysis, and show that we can use this to provide well-calibrated classification probabilities for both nodule detection and patient malignancy diagnosis. These calibrated probabilities informed by model uncertainty can be used for subsequent risk-based decision making towards diagnostic interventions or disease treatments, as we demonstrate using a probability-based patient referral strategy to further improve our results.
Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined ...the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.
•IL-33 is upregulated by cigarette smoke and released in response to virus infection•Smoke dampens ST2 expression on ILC2s but enhances ST2 on NK cells and macrophages•IL-33 drives an exacerbated Th1-cell-like inflammatory response to virus infection•IL-33 might play a critical role in pathogen-induced exacerbations of COPD
Smoking is thought to be central to the altered responsiveness to infection in patients with chronic obstructive pulmonary disease (COPD). Humbles and colleagues show that mice lacking interleukin-33 (IL-33) are protected from smoke-induced exaggerated inflammatory responses to virus infection, suggesting that IL-33 is a critical mediator in acute exacerbations of COPD.
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and ...quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
Background. Candida species are the fourth most common cause of bloodstream infection and are the leading cause of invasive fungal infection among hospitalized patients in the United States. However, ...the frequency and outcomes attributable to the infection are uncertain. This retrospective study set out to estimate the incidence of candidemia in hospitalized adults and children in the United States and to determine attributable mortality, length of hospital stay, and hospital charges related to candidemia. Methods. We used the Nationwide Inpatient Sample 2000 for adult patients and the Kids' Inpatient Database 2000 for pediatric patients. We matched candidemia-exposed and candidemia-unexposed patients by the propensity scores for the probability of candidemia exposure, which were derived from patient characteristics. Attributable outcomes were calculated as the differences in estimates of outcomes between propensity score–matched patients with and without candidemia. Results. In the United States in 2000, candidemia was diagnosed in an estimated 1118 hospital admissions of pediatric patients and 8949 hospital admissions of adult patients, yielding a frequency of 43 cases per 100,000 pediatric admissions (95% confidence interval CI, 35–52 cases per 100,000 pediatric admissions) and 30 cases per 100,000 adult admissions (95% CI, 26–34 cases per 100,000 adult admissions). In pediatric patients, candidemia was associated with a 10.0% increase in mortality (95% CI, 6.2%–13.8%), a mean 21.1-day increase in length of stay (95% CI, 14.4–27.8 days), and a mean increase in total per-patient hospital charges of $92,266 (95% CI, $65,058–$119,474). In adult patients, candidemia was associated with a 14.5% increase in mortality (95% CI, 12.1%–16.9%), a mean 10.1-day increase in length of stay (95% CI, 8.9–11.3 days), and a mean increase in hospital charges of $39,331 (95% CI, $33,604–$45,602). Conclusion. The impact of candidemia on excess mortality, increased length of stay, and the burden of cost of hospitalization underscores the need for improved means of prevention and treatment of candidemia in adults and children.
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Task Force recently introduced a new clinical score termed quick Sequential (Sepsis-related) Organ Failure ...Assessment (qSOFA) for identification of patients at risk of sepsis outside the intensive care unit (ICU). We attempted to compare the discriminatory capacity of the qSOFA versus the Systemic Inflammatory Response Syndrome (SIRS) score for predicting mortality, ICU-free days, and organ dysfunction-free days in patients with suspicion of infection outside the ICU.
The Weill Cornell Medicine Registry and Biobank of Critically Ill Patients is an ongoing cohort of critically ill patients, for whom biological samples and clinical information (including vital signs before and during ICU hospitalization) are prospectively collected. Using such information, qSOFA and SIRS scores outside the ICU (specifically, within 8 hours before ICU admission) were calculated. This study population was therefore comprised of patients in the emergency department or the hospital wards who had suspected infection, were subsequently admitted to the medical ICU and were included in the Registry and Biobank.
One hundred fifty-two patients (67% from the emergency department) were included in this study. Sixty-seven percent had positive cultures and 19% died in the hospital. Discrimination of in-hospital mortality using qSOFA area under the receiver operating characteristic curve (AUC), 0.74; 95% confidence intervals (CI), 0.66-0.81 was significantly greater compared with SIRS criteria (AUC, 0.59; 95% CI, 0.51-0.67; p = 0.03). The qSOFA performed better than SIRS regarding discrimination for ICU-free days (p = 0.04), but not for ventilator-free days (p = 0.19), any organ dysfunction-free days (p = 0.13), or renal dysfunction-free days (p = 0.17).
In patients with suspected infection who eventually required admission to the ICU, qSOFA calculated before their ICU admission had greater accuracy than SIRS for predicting mortality and ICU-free days. However, it may be less clear whether qSOFA is also better than SIRS criteria for predicting ventilator free-days and organ dysfunction-free days. These findings may help clinicians gain further insight into the usefulness of qSOFA.
Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and ...reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events.
This meta-analysis included studies from the 2006 Cochrane meta-analysis, studies published/updated since the 2006 Cochrane report, and unpublished trial data from Amgen and Centocor Ortho Biotech. The 60 studies analysed (15 323 patients) were conducted in the settings of chemotherapy/radiochemotherapy, radiotherapy only treatment or anaemia of cancer. Data were summarised using odds ratios (ORs) with 95% confidence intervals (CIs).
Results indicated that ESA use did not significantly affect mortality (60 studies: OR=1.06; 95% CI: 0.97-1.15) or disease progression (26 studies: OR=1.01; 95% CI: 0.90-1.14), but increased the risk for venous-thromoboembolic events (44 studies: OR=1.48; 95% CI: 1.28-1.72).
Though this meta-analysis showed no significant effect of ESAs on survival or disease progression, prospectively designed, future randomised clinical trials will further examine the safety and efficacy of ESAs when used according to the revised labelling information.
With the establishment and maturation of the experimental programs searching for new physics with sizeable couplings at the LHC, there is an increasing interest in the broader particle and ...astrophysics community for exploring the physics of light and feebly-interacting particles as a paradigm complementary to a New Physics sector at the TeV scale and beyond. FIPs 2020 has been the first workshop fully dedicated to the physics of feebly-interacting particles and was held virtually from 31 August to 4 September 2020. The workshop has gathered together experts from collider, beam dump, fixed target experiments, as well as from astrophysics, axions/ALPs searches, current/future neutrino experiments, and dark matter direct detection communities to discuss progress in experimental searches and underlying theory models for FIPs physics, and to enhance the cross-fertilisation across different fields. FIPs 2020 has been complemented by the topical workshop “Physics Beyond Colliders meets theory”, held at CERN from 7 June to 9 June 2020. This document presents the summary of the talks presented at the workshops and the outcome of the subsequent discussions held immediately after. It aims to provide a clear picture of this blooming field and proposes a few recommendations for the next round of experimental results.
Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural ...processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.
Although many patients with end-stage cancer are offered chemotherapy to improve quality of life (QOL), the association between chemotherapy and QOL amid progressive metastatic disease has not been ...well-studied. American Society for Clinical Oncology guidelines recommend palliative chemotherapy only for solid tumor patients with good performance status.
To evaluate the association between chemotherapy use and QOL near death (QOD) as a function of patients' performance status.
A multi-institutional, longitudinal cohort study of patients with end-stage cancer recruited between September 2002 and February 2008. Chemotherapy use (n = 158 50.6%) and Eastern Cooperative Oncology Group (ECOG) performance status were assessed at baseline (median = 3.8 months before death) and patients with progressive metastatic cancer (N = 312) following at least 1 chemotherapy regimen were followed prospectively until death at 6 outpatient oncology clinics in the United States.
Patient QOD was determined using validated caregiver ratings of patients' physical and mental distress in their final week.
Chemotherapy use was not associated with patient survival controlling for clinical setting and patients' performance status. Among patients with good (ECOG score = 1) baseline performance status, chemotherapy use compared with nonuse was associated with worse QOD (odds ratio OR, 0.35; 95% CI, 0.17-0.75; P = .01). Baseline chemotherapy use was not associated with QOD among patients with moderate (ECOG score = 2) baseline performance status (OR, 1.06; 95% CI, 0.51-2.21; P = .87) or poor (ECOG score = 3) baseline performance status (OR, 1.34; 95% CI, 0.46-3.89; P = .59).
Although palliative chemotherapy is used to improve QOL for patients with end-stage cancer, its use did not improve QOD for patients with moderate or poor performance status and worsened QOD for patients with good performance status. The QOD in patients with end-stage cancer is not improved, and can be harmed, by chemotherapy use near death, even in patients with good performance status.
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