Search

Purpose The rate of missing data on patient-reported health-related quality of life (HRQOL) in brain tumor clinical trials is particularly high over time. One solution to this issue is the use of proxy (i.e., partner, relative, informal caregiver) ratings in lieu of patient-reported outcomes (PROs). In this study we investigated patient–proxy agreement on HRQOL outcomes in high-grade glioma (HGG) patients. Methods Generic and disease-specific HRQOL were assessed using the EORTC QLQ-C30 and QLQ-BN20 in a sample of 501 patient–proxy dyads participating in EORTC trials 26101 and 26091. Patients were classified as impaired or intact, based on their neurocognitive performance. The level of patient–proxy agreement was measured using Lin’s concordance correlation coefficient (CCC) and the Bland–Altman limit of agreement. The Wilcoxon signed-rank test was used to evaluate differences between patients’ and proxies’ HRQOL. Results Patient–proxy agreement in all HGG patients (N = 501) ranged from 0.082 to 0.460. Only 18.8% of all patients were neurocognitively intact. Lin’s CCC ranged from 0.088 to 0.455 in cognitively impaired patients and their proxies and from 0.027 to 0.538 in cognitively intact patients and their proxies. Conclusion While patient–proxy agreement on health-related quality of life outcomes is somewhat higher in cognitively intact patients, agreement in high-grade glioma patients is low in general. In light of these findings, we suggest to cautiously consider the use of proxy’s evaluation in lieu of patient-reported outcomes, regardless of patient’s neurocognitive status.

Purpose The Working Group for Neuro-Oncology of the German Society for Radiation Oncology in cooperation with members of the Neuro-Oncology Working Group of the German Cancer Society aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS). Methods Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN including bevacizumab in clinical routine. Conclusion Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neuro-oncologist. A multistep approach as an opportunity to review as many characteristics as possible to improve diagnostic confidence is recommended. Additional information about radiotherapy (RT) techniques is crucial for the diagnosis of RN. Misdiagnosis of untreated and progressive RN can lead to severe neurological deficits. In this practice guideline, we propose a detailed nomenclature of treatment-related changes and a multistep approach for their diagnosis.

Einstein's 1905 analysis of the Brownian Motion of a pollen grain in a water droplet as due to statistical variations in the collisions of water molecules with the grain, followed up by Perrin's experiments, provided one of the most convincing demonstrations of the reality of atoms. But in 1926 Schroedinger replaced classical particles by wavefunctions, which cannot undergo collisions. Can a Schroedingerist wavefunction physics account for Perrin's observations? As systems confined to a finite box can only generate quasiperiodic signals, this seems impossible, but I argue here that the issue is more subtle. I then introduce several models of the droplet-plus-grain; unfortunately, no explicit solutions are available (related is the remarkable fact that the harmonics of a general right triangle are still unknown). But from generic features of the models I conclude that: (a) wavefunction models may generate trajectories resembling those of a stochastic process; (b) diffusive behavior may appear for a restricted time interval; and (c) additional ``Wave Function Energy", by restricting ``cat" formation, can render the observations more ``classical". But completing the Einstein program of linking diffusion to viscosity and temperature in wavefunction models is still challenging.

Background Maintenance of functioning and well-being during the progression-free survival (PFS) period is important for glioma patients. This study aimed to determine whether health-related quality of life (HRQoL) can be maintained during progression-free time, and factors associated with HRQoL deterioration in this period. Methods We included longitudinal HRQoL data from previously published clinical trials in glioma. The percentage of patients with stable HRQoL until progression was determined per scale and at the individual patient level (i.e. considering all scales simultaneously). We assessed time to a clinically relevant deterioration in HRQoL, expressed in deterioration-free survival and time-to-deterioration (the first including progression as an event). We also determined the association between sociodemographic and clinical factors and HRQoL deterioration in the progression-free period. Results Five thousand five hundred and thirty-nine patients with at least baseline HRQoL scores had a median time from randomization to progression of 7.6 months. Between 9–29% of the patients deteriorated before disease progression on the evaluated HRQoL scales. When considering all scales simultaneously, 47% of patients deteriorated on ≥1 scale. Median deterioration-free survival period ranged between 3.8–5.4 months, and median time-to-deterioration between 8.2–11.9 months. For most scales, only poor performance status was independently associated with clinically relevant HRQoL deterioration in the progression-free period. Conclusions HRQoL was maintained in only 53% of patients in their progression-free period, and treatment was not independently associated with this deterioration in HRQoL. Routine monitoring of the patients’ functioning and well-being during the entire disease course is therefore important, so that interventions can be initiated when problems are signaled.

From the point of view of Schr\"odingerism, a wavefunction-only philosophy, thermodynamics must be recast in terms of an ensemble of wavefunctions, rather than classical particle configurations or "found" values of Copenaghen Quantum Mechanics. Recapitulating the historical sequence, we consider here several models of magnets that classically can exhibit a phase transition to a low-temperature magnetized state. We formulate wavefunction analogues including a "Schr\"odingerist QUantum Ising Model" (SQUIM), a "Schr\"odingerist Curie-Weiss Model"(SCWM), and others. We show that the SQUIM with free boundary conditions and distinguishable "spins" has no finite-temperature phase transition, which we attribute to entropy swamping energy. The SCWM likewise, even assuming exchange symmetry in the wavefunction (in this case the analytical argument is not totally satisfactory and we helped ourself with a computer analysis). But a variant model with "Wavefunction Energy" (introduced in prior communications about Schr\"odingerism and the Measurement Problem) does have a phase transition to a magnetised state. The three results together suggest that magnetization in large wavefunction spin chains appears if and only if we consider indistinguishable particles and block macroscopic dispersion (i.e. macroscopic superpositions) by energy conservation. Our principle technique involves transforming the problem to one in probability theory, then applying results from Large Deviations, particularly the G\"artner-Ellis Theorem. Finally, we discuss Gibbs vs. Boltzmann/Einstein entropy in the choice of the quantum thermodynamic ensemble, as well as open problems. PhySH: quantum theory, quantum statistical mechanics, large deviation & rare event statistics., Comment: A correction related to the ellipse figure, some conceptual comments and improvements in the proof of Theorem Two are added with respect to previous versions

PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.

Background Different analytical methods may lead to different conclusions about the impact of treatment on health-related quality of life (HRQoL). This study aimed to examine 3 different methods to evaluate change in HRQoL and to study whether these methods result in different conclusions. Methods HRQoL data from 15 randomized clinical trials were combined (CODAGLIO project). Change in HRQoL scores, measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and BN20 questionnaires, was analyzed in 3 ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms, (2) at the patient level per scale/item, calculating the percentage of patients that deteriorated, improved, or remained stable per scale/item, and (3) at the individual patient level, combining all scales/items. Results Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level, only the item “hair loss” showed a significant and clinically relevant change (ie, ≥10 points) over time, whereas change scores on the other scales/items were statistically significant only (all P Conclusions Different analytical methods of changes in HRQoL result in distinct conclusions of treatment effects, all of which may be relevant for informing clinical decision making.

In previous papers I expounded non-linear Schrodingerist quantum mechanics as a solution of the Measurement Problem. Here I show that NLQM is compatible with Einstein's theory of General Relativity. The extension to curved space-times presumes adoption of "space-time wavefunctions" (sometimes called "multi-time wavefunctions") and some additional algebraic structure: a "bitensor" supplementing Einstein's metric tensor. This kind of matter may violate the Strong Energy Condition even without a mass term, possibly with implications for the formation of singularities within Black Holes.

Background Chemical exchange saturation transfer (CEST) is a novel MRI technique applied to brain tumor patients. Purpose To investigate the anatomic location dependence of CEST MRI obtained at 7T and histopathological/molecular parameters in WHO IV° glioma patients. Study Type Analytic prospective study. Population Twenty‐one patients with newly diagnosed WHO IV° gliomas were studied prior to surgery; 11 healthy volunteers were investigated. Field Strength/Sequence Conventional MRI (contrast‐enhanced, T2w and diffusion‐weighted imaging) at 3T and T2w and CEST MRI at 7T was performed for patients and both patients and volunteers. Assessment Mean CEST signal intensities (nuclear‐Overhauser‐enhancement [NOE], amide‐proton‐transfer [APT], downfield NOE‐suppressed APT [dns‐APT]), ADC values, and histopathological/molecular parameters were evaluated with regard to hemisphere location and contact with the subventricular zone. CEST signal intensities of cerebral tissue of healthy volunteers were evaluated with regard to hemisphere discrimination. Statistical Tests Spearman correlation, Mann–Whitney U‐test, Wilcoxon signed‐rank‐test, Fisher's exact test, and area under the receiver operating curve. Results Maximum APT and dns‐APT signal intensities were significantly different in right vs. left hemisphere gliomas (P = 0.037 and P = 0.007), but not in right vs. left hemisphere cerebral tissue of healthy subjects (P = 0.062‐0.859). Mean ADC values were significantly decreased in right vs. left hemisphere gliomas (P = 0.044). Mean NOE signal intensity did not differ significantly between gliomas of either hemisphere (P = 0.820), but in case of subventricular zone contact (P = 0.047). A significant correlation was observed between APT and dns‐APT and ADC signal intensities (rs = –0.627, P = 0.004 and rs = –0.534, P = 0.019), but not between NOE and ADC (rs = –0.341, P = 0.154). Histopathological/molecular parameters were not significantly different concerning the tumor location (P = 0.104–1.000, P = 0.286–0.696). Data Conclusion APT, dns‐APT, and ADC were inversely correlated and depended on the gliomas' hemisphere location. NOE showed significant dependence on subventricular zone contact. Location dependency of APT‐ and NOE‐mediated CEST effects should be considered in clinical investigations of CEST MRI.

I discuss three proposed experiments that could in principle locate the boundary between the classical and quantum worlds, as well as distinguish the Hamiltonian theory presented in the first paper of this series from the spontaneous-collapse theories.

BACKGROUND The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations. MATERIAL AND METHODS We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

Paper I of this series introduced a nonlinear version of quantum mechanics that blocks cats, and paper II postulated a random part of the wavefunction to explain outcomes in experiments such as Stern-Gerlach or EPRB. However, an ad hoc extra parameter was assumed for the randomness. Here I provide some analytic and simulation evidence that the nonlinear theory exhibits sensitive dependence on initial conditions in measurement scenarios, perhaps implying that the magnitude of randomness required is determined by structural features of the model, and does not require a free parameter.

© 2017 Elsevier Ltd Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m2for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour

BACKGROUND Temporal muscle thickness (TMT) was described as surrogate marker of skeletal muscle mass and prognostic parameter in brain metastasis patients. This study aimed to evaluate the prognostic relevance of TMT in patients with progressive glioblastoma. MATERIAL AND METHODS TMT was analyzed on the baseline cranial magnetic resonance (MR) images of 596 patients with progression of glioblastoma after radio-chemotherapy enrolled in the EORTC 26101 trial. An optimal TMT cutoff for overall survival (OS) and progression free survival (PFS) was defined in the training cohort (n=260 patients enrolled in phase 2 part of EORTC 26101). Patients were grouped as “below” or “above” the TMT cutoff and associations with OS and PFS were tested using the Cox model. The findings were validated in a test cohort (n=308 patients enrolled in phase 3 part of EORTC 26101). RESULTS An optimal baseline TMT cutoff of 7.2 mm was obtained in the training cohort for both OS and PFS (AUC=0.64). Univariate analyses estimated a hazard ratio (HR) of 0.54 (95% CI:0.42, 0.70, p1, HR of 2.47, 95% CI: 1.38, 4,41, p = 0.002). Similar results were obtained in the validation cohort. CONCLUSION TMT is an independent prognostic parameter in patients with progressive glioblastoma. This parameter is easily assessable on routine MR images and may help to better define frail patient populations and thus facilitate patient management by supporting patient stratification for therapeutic interventions or clinical trials.

Working entirely within the Schroedinger paradigm, meaning wavefunction only, I present a modification of his theory that prevents formation of macroscopic dispersion (MD; "cats"). The proposal is to modify the Hamiltonian based on a method introduced by Steven Weinberg in 1989, as part of a program to test quantum mechanics at the atomic or nuclear level. By contrast, the intent here is to eliminate MD without affecting the predictions of quantum mechanics at the microscopic scale. This restores classical physics at the macro level. Possible experimental tests are indicated and the differences from previous theories discussed. In a second paper, I will address the other difficulty of wavefunction physics without the statistical (Copenhagen) interpretation: how to explain random outcomes in experiments such as Stern-Gerlach, and whether a Schroedingerist theory with a random component can violate Bell's inequality.

Gliomatosis cerebri is a rare, diffusely growing neuroepithelial tumor characterized by extensive brain infiltration involving more than two cerebral lobes. Among 13 patients with gliomatosis cerebri (median age, 46 years), biopsies showed features of diffuse astrocytoma (n = 4), oligoastrocytoma (n = 1), anaplastic astrocytoma (n = 5), anaplastic oligoastrocytoma (n = 1), or glioblastoma (n = 2). Molecular genetic investigation showed TP53 mutations in three of seven tumors and both PTEN mutation and epidermal growth factor receptor overexpression in one tumor. Amplification of CDK4 or MDM2 or homozygous deletion of CDKN2A was not detected. Three of 10 patients receiving radiotherapy showed a partial response (one patient) or had stable disease (two patients) lasting for more than 1 year. Four of six patients treated with procarbazine, carmustine, vincristine chemotherapy demonstrated partial remission (one patient), minor response (two patients), or stable disease (one patient). Median survival time from diagnosis was 14 months (range, 4-91+ months). Infratentorial involvement was associated with shorter survival. We conclude that (1) the molecular genetic alterations in gliomatosis cerebri resemble those in diffuse astrocytomas; (2) the prognosis of gliomatosis cerebri is variable but for at least 50% of patients as poor as for glioblastoma; and (3) some patients respond to radiotherapy and/or procarbazine, carmustine, vincristine chemotherapy.

Background: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. Methods: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. Results and conclusions: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progression-free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress.

© 2015 The Author(s). A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR systems.

BACKGROUND: Molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, mutations and (consequently) loss of expression of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, improve prognostication and may even guide treatment decisions in patients with anaplastic gliomas. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) allow the determination of large-scale methylation profiles and genome-wide DNA copy number changes, enabling molecular subgrouping of tumors. In addition, algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion and MGMT promoter methylation using this assay. METHODS: In the biomarker cohort of the NOA-04 trial, the diagnostic and prognostic performance of these molecular markers using single tests, HM450 data and HM450-based algorithms has been investigated to propose biological subgroups, which reflect outcomes and potentially influence treatment decisions. RESULTS: Loss of ATRX expression was detected in 45% of anaplastic astrocytomas (AA), 27% of anaplastic oligoastrocytomas (AOA) and 10% of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. In tumors with IDH1 mutation, MGMT promoter methylation was associated with prolonged progression-free survival (PFS) with chemotherapy or radiotherapy (RT), and thus prognostic. In tumors without IDH1 mutation, MGMT promoter methylation was associated with increased PFS in patients treated with chemotherapy, too, but not in those who received RT alone as the first-line treatment, and is thus chemotherapy-predictive. Comparisons of single assays and HM450-based algorithms revealed a high concordance for IDH and 1p/19q status. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of cases as conventional methylation-specific PCR, with 87/91 G-CIMP-positive tumors predicted as MGMT promoter-methylated. CONCLUSIONS: ATRX loss is a hallmark and favorable prognosticator of astrocytic tumors allowing a better definition of the clinically and morphologically mixed group of AOA. MGMT promoter methylation is a predictive biomarker for benefit from alkylating agent chemotherapy in patients with IDH1-wildtype, but not IDH1-mutant malignant gliomas of WHO grades III/IV. Combined IDH1/ MGMT assessment may help to individualize clinical decision making in neurooncology. G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and associated with prognosis in the NOA-04 trial. HM450 arrays allowed clustering of anaplastic gliomas into relevant subgroups.

In two previous papers, I introduced SuperSpreader (SS) epidemic models, offered some theoretical discussion of prevention issues, and fitted some models to data derived from published accounts of the ongoing MERS epidemic (concluding that a pandemic is likely). Continuing on this theme, here I discuss prediction: whether, in a disease outbreak driven by superspreader events, a rigorous decision point---meaning a declaration that a pandemic is imminent---can be defined. I show that all sources of prediction bias contribute to generating false negatives (i.e., discounting the chance of a pandemic when it is looming or has already started). Nevertheless, the statistical difficulties can be overcome by improved data gathering and use of known techniques that decrease bias. One peculiarity of the SS epidemic is that the prediction can sometimes be made long before the actual pandemic onset, generating lead time to alert the medical community and the public. Thus modeling is useful to overcome a false sense of security arising from the long "kindling times" characteristic of SS epidemics and certain political/psychological factors, as well as improve the public health response.

In a paper of August 2013, I discussed the so-called SuperSpreader (SS) epidemic model and emphasized that it has dynamics differing greatly from the more-familiar uniform (or Poisson) textbook model. In that paper, SARS in 2003 was the representative instance and it was suggested that MERS may be another. In April 2014, MERS incident cases showed a spectacular spike (going from a handful in the previous April to more than 260 in that month of 2014) reminiscent of a figure I published nine months earlier. Here I refit the two-level and several variant SS models to incident data from January 1, 2013--April 30, 2014 and conclude that MERS will go pandemic (all other factors remaining the same). In addition, I discuss a number of model-realism and fitting methodology issues relevant to analysing SS epidemics.

I discuss the so-called SuperSpreader epidemic, for which SARS is the canonical examples (and, perhaps, MERS will be another). I use simulation by an agent-based model as well as the mathematics of multi-type branching-processes to illustrate how the SS epidemic differs from the more familiar uniform epidemic (e.g., caused by influenza). The conclusions may surprise the reader: (a) The SS epidemic must be described by at least two numbers, such as the mean reproductive number (of "secondary" cases caused by a "primary case"), R0, and the variance of same, call it V0; (b) Even if R0 > 1, if V0 >> R0 the probability that an infection-chain caused by one primary case goes extinct without intervention may be close to one (e.g., 0.97); (c) The SS epidemic may have a long "kindling period" in which sporadic cases appear (transmitted from some unknown host) and generate a cluster of cases, but the chains peter out, perhaps generating a false sense of security that a pandemic will not occur; (d) Interventions such as isolation (or contact-tracing and secondary case isolation) may prove efficacious even without driving R0 below one; (e) The efficacy of such interventions diminishes, but slowly, with increasing V0 at fixed R0. From these considerations, I argue that the SS epidemic has dynamics sufficiently distinct from the uniform case that efficacious public-health interventions can be designed even in the absence of a vaccine or other form of treatment.

The disappointing outcomes of cellular immune-based vaccines against HIV-1 despite strong evidence for the protective role of CD8⁺ T lymphocytes (CTLs) has prompted revisiting the mechanisms of cellular immunity. Prior data from experiments examining the kinetics of Simian Immunodeficiency Virus (SIV) clearance in infected macaques with or without in vivo CD8 depletion were interpreted as refuting the concept that CTLs suppress SIV/HIV by direct killing of infected cells. Here we briefly review the biological evidence for CTL cytolytic activity in viral infections, and utilize biologically-directed modeling to assess the possibility of a killing mechanism for the antiviral effect of CTLs, taking into account the generation, proliferation, and survival of activated CD4⁺ and CD8⁺ T lymphocytes, as well as the life cycle of the virus. Our analyses of the published macaque data using these models support a killing mechanism, when one considers T lymphocyte and HIV-1 lifecycles, and factors such as the eclipse period before release of virions by infected cells, an exponential pattern of virion production by infected cells, and a variable lifespan for acutely infected cells. We conclude that for SIV/HIV pathogenesis, CTLs deserve their reputation as being cytolytic.