Dice Questions Answered

Superstitious discussion of fair and unfair dice has pervaded the tabletop gaming industry since its inception. Many of these are not based on any quantitative data or studies. Consequently, misconceptions have been spread widely. One dice float test video on Youtube currently has 925,000 views (Fisher, 2015a). To combat the flood of misconceptions we investigated the following questions: 1) Are dice cursed? 2) Are D20s (20-sided dice) less fair than D6s (6-sided dice)? 3) Do float tests tell anything about the fairness of dice? 4) Are some dice systems inherently fairer than others? 5) Are density differences or dimensions more critical to dice fairness? 6) What is the best way to test your dice for fairness? 7) How many rolls are needed to detect unfair dice? 8) Are metal dice fairer than plastic dice? Based on tens of thousands of physical dice rolls, billions of simulated dice rolls, and analysis our answer to these questions are as follows. 1) Probably plastic dice are cursed. 2) Yes, D6s are fairer than D20s. 3) Float tests tell you nothing about which side of a die will come up more often. 4) Yes, some dice systems are fairer. 5) Usually dimensions are more important except for large, off-center bubbles. 6) The running chi square goodness of fit test is the best way to test dice that we found. 7) 100 rolls are not enough except possible for loaded dice. 8) Our preliminary conclusion based on limited tests is that metal dice are not fairer than plastic dice

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8⁺ cytotoxic T lymphocytes. Chlamydia spp. are obligate intracellular bacteria and, as such, should be targeted by CD8⁺ T cells. It is likely that Chlamydia spp. have evolved mechanisms to avoid the CD8⁺ killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of various Chlamydia species to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted to defective ribosomal products, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest that Chlamydia spp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Efficacy of transoral fundoplication vs omeprazole for treatment of regurgitation in a randomized controlled trial.

Background The aim of this randomized, crossover study was to determine if transoral fundoplication (TF) could further improve clinical outcomes in partial responders to high-dose (HD) proton-pump inhibitor (PPI) therapy and to evaluate durability of TF. Methods In seven United States centers, patients with hiatal hernia ≤2 cm and abnormal esophageal acid exposure (EAE) were randomized to TF (n = 40) or HD PPIs (n = 23) group. At 6-month follow-up, PPI patients underwent crossover. We assessed clinical outcomes 6-month post TF in crossover patients (COP), as compared to 6-month of HD PPI therapy, and 12-month outcomes in patients initially randomized to TF. The primary outcome was symptom control evaluated by Reflux Disease Questionnaire and Reflux Symptom Index. Secondary outcomes included healing of esophagitis, normalization of EAE and PPI use after TF. We analyzed 21 COP and 39 TF patients. McNemar’s test or Fisher exact test was used to compare proportions. Results Of 63 randomized patients, 3 were lost to follow-up, leaving 39 TF and 21 COP for analyses. In the COP, TF further improved control of regurgitation and of atypical symptoms achieved after six months of HD PPIs. Of 20 patients with GERD symptoms after six months of high-dose PPI therapy, 65% (13/20) reported global elimination of troublesome regurgitation and atypical symptoms post TF off PPIs; 67% (6/9) reported no troublesome regurgitation. Esophagitis further healed in 75% (6/8) of patients. Seventy-one percent of COP patients were off PPIs six months following TF. Normalization of EAE decreased from 52% after HD PPIs (on PPIs) to 33% after TF (off PPIs), p =0.388. In the original TF group, 12-month post TF, 77% of patients achieved complete symptom control, 82% ceased PPI therapy, 100% healed esophagitis and 45% normalized EAE. Conclusions The results of this study indicate that in patients with incomplete symptom control on high-dose PPI therapy TF may provide further elimination of symptoms and esophagitis healing. In the original TF group, the clinical outcomes of TF remained stable between 6- and 12-month follow-up. Trial registration Clinicaltrials.gov: NCT01647958

INvestigational Vertebroplasty Efficacy and Safety Trial (INVEST): a randomized controlled trial of percutaneous vertebroplasty

Background: The treatment of painful osteoporotic vertebral compression fractures has historically been limited to several weeks of bed rest, anti-inflammatory and analgesic medications, calcitonin injections, or external bracing. Percutaneous vertebroplasty (the injection of bone cement into the fractured vertebral body) is a relatively new procedure used to treat these fractures. There is increasing interest to examine the efficacy and safety of percutaneous vertebroplasty and to study the possibility of a placebo effect or whether the pain relief is from local anesthetics placed directly on the bone during the vertebroplasty procedure. Methods/Designs: Our goal is to test the hypothesis that patients with painful osteoporotic vertebral compression fractures who undergo vertebroplasty have less disability and pain at 1 month than patients who undergo a control intervention. The control intervention is placement of local anesthesia near the fracture, without placement of cement. One hundred sixty-six patients with painful osteoporotic vertebral compression fractures will be recruited over 5 years from US and foreign sites performing the vertebroplasty procedure. We will exclude patients with malignant tumor deposit (multiple myeloma), tumor mass or tumor extension into the epidural space at the level of the fracture. We will randomly assign participants to receive either vertebroplasty or the control intervention. Subjects will complete a battery of validated, standardized measures of pain, functional disability, and health related quality of life at baseline and at post-randomization time points (days 1, 2, 3, and 14, and months 1, 3, 6, and 12). Both subjects and research interviewers performing the follow-up assessments will be blinded to the randomization assignment. Subjects will have a clinic visit at months 1 and 12. Spine X-rays will be obtained at the end of the study (month 12) to determine subsequent fracture rates. Our co-primary outcomes are the modified Roland score and pain numerical rating scale at 1 month. Discussion: Although extensively utilized throughout North America for palliation of pain, vertebroplasty still has not undergone rigorous study. The study outlined above represents the first randomized, controlled study that can account for a placebo effect in the setting of vertebroplasty. Trial Registration: Current Controlled Trials ISRCTN81871888.The source of funding for the study and all authors for this publication was National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

A Novel Human Cytomegalovirus Locus Modulates Cell Type-Specific Outcomes of Infection

Clinical strains of HCMV encode 20 putative ORFs within a region of the genome termed ULb′ that are postulated to encode functions related to persistence or immune evasion. We have previously identified ULb′-encoded pUL138 as necessary, but not sufficient, for HCMV latency in CD34+ hematopoietic progenitor cells (HPCs) infected in vitro. pUL138 is encoded on polycistronic transcripts that also encode 3 additional proteins, pUL133, pUL135, and pUL136, collectively comprising the UL133-UL138 locus. This work represents the first characterization of these proteins and identifies a role for this locus in infection. Similar to pUL138, pUL133, pUL135, and pUL136 are integral membrane proteins that partially co-localized with pUL138 in the Golgi during productive infection in fibroblasts. As expected of ULb′ sequences, the UL133-UL138 locus was dispensable for replication in cultured fibroblasts. In CD34+ HPCs, this locus suppressed viral replication in HPCs, an activity attributable to both pUL133 and pUL138. Strikingly, the UL133-UL138 locus was required for efficient replication in endothelial cells. The association of this locus with three context-dependent phenotypes suggests an exciting role for the UL133-UL138 locus in modulating the outcome of viral infection in different contexts of infection. Differential profiles of protein expression from the UL133-UL138 locus correlated with the cell-type dependent phenotypes associated with this locus. We extended our in vitro findings to analyze viral replication and dissemination in a NOD-scid IL2Rγcnull-humanized mouse model. The UL133-UL138NULL virus exhibited an increased capacity for replication and/or dissemination following stem cell mobilization relative to the wild-type virus, suggesting an important role in viral persistence and spread in the host. As pUL133, pUL135, pUL136, and pUL138 are conserved in virus strains infecting higher order primates, but not lower order mammals, the functions encoded likely represent host-specific viral adaptations