A multidisciplinary endocrinologist-led shared medical appointment (SMA) model showed statistically significant reductions in A1C from baseline over 3 years that were not significantly different from appointments with endocrinologists or primary care providers alone within a resource-poor population. Similarly, the SMA model achieved clinical outcomes on par with endocrinologist-only visits with the added benefit of improving endocrine provider productivity and specialty access for patients. Greater patient engagement with the SMA model was associated with significantly lower A1C.

Background

Positive serology for cytomegalovirus (CMV) has been associated with all-cause mortality risk but its role in COPD mortality is unknown. The objective of the present study was to assess the relationship between CMV serology and COPD mortality.

Methods

We analysed data from 806 participants in the Tucson Epidemiological Study of Airway Obstructive Disease who, at enrolment, were aged 28–70 years and had completed lung function tests. We tested CMV serology in sera from enrolment and defined "high CMV serology" as being in the highest tertile. Vital status, date and cause of death were assessed through death certificates and/or linkage with the National Death Index up to January 2017. The association of CMV serology with all-cause and cause-specific mortality risk was tested in Cox models adjusted for age, sex, level of education, body mass index, smoking status and pack-years.

Results

High CMV serology was marginally associated with all-cause mortality (p=0.071) but the effect was inversely dependent on age, with the association being much stronger among participants <55 years than among participants ≥55 years at enrolment (p-value for CMV-by-age interaction <0.001). Compared with low CMV serology, high CMV serology was associated with mortality from COPD among all subjects (adjusted hazard ratio (HR) 2.38, 95% CI 1.11–5.08; p=0.025) and particularly in subjects <55 years old at enrolment (HR 5.40, 95% CI 1.73–16.9; p=0.004). Consistent with these results, high CMV serology also predicted mortality risk among subjects who already had airflow limitation at enrolment (HR 2.10, 95% CI 1.20–3.68; p=0.009).

Conclusions

We report a strong relationship between CMV serology and the risk of dying from COPD, and thus identify a novel risk factor for COPD mortality.

Acetylation is a conserved modification used to regulate a variety of cellular pathways, such as gene expression, protein synthesis, detoxification, and virulence. Acetyltransferase enzymes transfer an acetyl moiety, usually from acetyl coenzyme A (AcCoA), onto a target substrate, thereby modulating activity or stability. Members of the GCN5-N-acetyltransferase (GNAT) protein superfamily are found in all domains of life and are characterized by a core structural domain architecture. These enzymes can modify primary amines of small molecules or of lysyl residues of proteins. From the initial discovery of antibiotic acetylation, GNATs have been shown to modify a myriad of small-molecule substrates, including tRNAs, polyamines, cell wall components, and other toxins. This review focuses on the literature on small-molecule substrates of GNATs in bacteria, including structural examples, to understand ligand binding and catalysis. Understanding the plethora and versatility of substrates helps frame the role of acetylation within the larger context of bacterial cellular physiology.

A new larger benthic porcelaneous foraminifer of soritid affinity is described as Tarburina zagrosiana n. gen., n. sp. from the late Maastrichtian of the Tarbur Formation, Zagros Zone, SW Iran. It occurs in foraminiferal–dasycladalean wackestones and packstones, in association with Loftusia ssp., dicyclinids/cuneolinids, Neobalkhania bignoti Cherchi & Schroeder, Gyroconulina columellifera Schroeder & Darmoian, Spirolina? farsiana Schlagintweit & Rashidi, Broeckina cf. dufrenoyi (d'Archiac), other benthic foraminifers, and dasycladalean algae. Due to its elongate test and marginal chamber subdivision by aligned vertical partitions, Tarburina n. gen. can be compared with representatives of the Praerhapydionininae. The interio-marginal slit-like foramina/aperture of Tarburina represents an outstanding feature in complex porcelaneous taxa. The monospecific genus Tarburina is considered a Maastrichtian newcomer within the Late Cretaceous Global Community Maturation cycle of larger benthic foraminifera. A biostratigraphic and palaeobiogeographical restriction seems possible, as reported for many other Late Cretaceous larger benthic foraminifera.

OBJECTIVE

To investigate factors related to glycemic management among members of a professional cycling team with type 1 diabetes over a 7-day Union Cycliste Internationale World Tour stage race.

RESEARCH DESIGN AND METHODS

An observational evaluation of possible factors related to glycemic management and performance in six male professional cyclists with type 1 diabetes (HbA_1c 6.4 ± 0.6%) during the 2019 Tour of California.

RESULTS

In-ride time spent in euglycemia (3.9–10.0 mmol/L glucose) was 63 ± 11%, with a low percentage of time spent in level 1 (3.0–3.9 mmol/L; 0 ± 1% of time) and level 2 (<3.0 mmol/L; 0 ± 0% of time) hypoglycemia over the 7-day race. Riders spent 25 ± 9% of time in level 1 (10.1–13.9 mmol/L) and 11 ± 9% in level 2 (>13.9 mmol/L) hyperglycemia during races. Bolus insulin use was uncommon during races, despite high carbohydrate intake (76 ± 23 g ⋅ h^–1). Overnight, the riders spent progressively more time in hypoglycemia from day 1 (6 ± 12% in level 1 and 0 ± 0% in level 2) to day 7 (12 ± 12% in level 1 and 2 ± 4% in level 2) (²[1] > 4.78, P < 0.05).

CONCLUSIONS

Professional cyclists with type 1 diabetes have excellent in-race glycemia, but significant hypoglycemia during recovery overnight, throughout a 7-day stage race.

OBJECTIVE

Sodium–glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation.

RESEARCH DESIGN AND METHODS

Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3-³H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured.

RESULTS

Following placebo in T2D, fasting plasma glucose (FPG) (143 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 0.14 mg/kg/min) in T2D (P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 ± 0.10 to 1.78 ± 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (r = 0.824; P < 0.001) was observed.

CONCLUSIONS

Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG.

OBJECTIVE

With rising health care costs and finite health care resources, understanding the population needs of different type 2 diabetes mellitus (T2DM) patient subgroups is important. Sparse data exist for the application of population segmentation on health care needs among Asian T2DM patients. We aimed to segment T2DM patients into distinct classes and evaluate their differential health care use, diabetes-related complications, and mortality patterns.

RESEARCH DESIGN AND METHODS

Latent class analysis was conducted on a retrospective cohort of 71,125 T2DM patients. Latent class indicators included patient’s age, ethnicity, comorbidities, and duration of T2DM. Outcomes evaluated included health care use, diabetes-related complications, and 4-year all-cause mortality. The relationship between class membership and outcomes was evaluated with the appropriate regression models.

RESULTS

Five classes of T2DM patients were identified. The prevalence of depression was high among patients in class 3 (younger females with short-to-moderate T2DM duration and high psychiatric and neurological disease burden) and class 5 (older patients with moderate-to-long T2DM duration and high disease burden with end-organ complications). They were the highest tertiary health care users. Class 5 patients had the highest risk of myocardial infarction (hazard ratio [HR] 12.05, 95% CI 10.82–13.42]), end-stage renal disease requiring dialysis initiation (HR 25.81, 95% CI 21.75–30.63), stroke (HR 19.37, 95% CI 16.92–22.17), lower-extremity amputation (HR 12.94, 95% CI 10.90–15.36), and mortality (HR 3.47, 95% CI 3.17–3.80).

CONCLUSIONS

T2DM patients can be segmented into classes with differential health care use and outcomes. Depression screening should be considered for the two identified classes of patients.

OBJECTIVE

No study has reported global disability burden estimates for individual diabetes-related lower-extremity complications (DRLECs). The Global Burden of Disease (GBD) study presents a robust opportunity to address this gap.

RESEARCH DESIGN AND METHODS

GBD 2016 data, including prevalence and years lived with disability (YLDs), for the DRLECs of diabetic neuropathy, foot ulcer, and amputation with and without prosthesis were used. The GBD estimated prevalence using data from systematic reviews and DisMod-MR 2.1, a Bayesian meta-regression tool. YLDs were estimated as the product of prevalence estimates and disability weights for each DRLEC. We reported global and sex-, age-, region-, and country-specific estimates for each DRLEC for 1990 and 2016.

RESULTS

In 2016, an estimated 131 million people (1.8% of the global population) had DRLECs. An estimated 16.8 million YLDs (2.1% global YLDs) were caused by DRLECs, including 12.9 million (95% uncertainty interval 8.30–18.8) from neuropathy only, 2.5 million (1.7–3.6) from foot ulcers, 1.1 million (0.7–1.4) from amputation without prosthesis, and 0.4 million (0.3–0.5) from amputation with prosthesis. Age-standardized YLD rates of all DRLECs increased by between 14.6% and 31.0% from 1990 estimates. Male-to-female YLD ratios ranged from 0.96 for neuropathy only to 1.93 for foot ulcers. The 50- to 69-year-old age-group accounted for 47.8% of all YLDs from DRLECs.

CONCLUSIONS

These first-ever global estimates suggest that DRLECs are a large and growing contributor to the disability burden worldwide and disproportionately affect males and middle- to older-aged populations. These findings should facilitate policy makers worldwide to target strategies at populations disproportionately affected by DRLECs.

Pharmacokinetic-based prophylaxis of replacement factor VIII (FVIII) products has been encouraged in recent years, but the relationship between exposure (factor VIII activity) and response (bleeding frequency) remains unclear. The aim of this study was to characterize the relationship between FVIII dose, plasma FVIII activity, and bleeding patterns and individual characteristics in severe hemophilia A patients. Pooled pharmacokinetic and bleeding data during prophylactic treatment with BAY 81-8973 (octocog alfa) were obtained from the three LEOPOLD trials. The population pharmacokinetics of FVIII activity and longitudinal bleeding frequency, as well as bleeding severity, were described using non-linear mixed effects modeling in NONMEM. In total, 183 patients [median age 22 years (range, 1-61); weight 60 kg (11-124)] contributed with 1,535 plasma FVIII activity observations, 633 bleeds and 11 patient/study characteristics [median observation period 12 months (3.1-13.1)]. A parametric repeated time-to-categorical bleed model, guided by plasma FVIII activity from a 2-compartment population pharmacokinetic model, described the time to the occurrence of bleeds and their severity. Bleeding probability decreased with time of study, and a bleed was not found to affect the time of the next bleed. Several covariate effects were identified, including the bleeding history in the 12-month pre-study period increasing the bleeding hazard. However, unexplained inter-patient variability in the phenotypic bleeding pattern remained large (111%CV). Further studies to translate the model into a tool for dose individualization that considers the individual bleeding risk are required. Research was based on a post-hoc analysis of the LEOPOLD studies registered at clinicaltrials.gov identifiers: 01029340, 01233258 and 01311648.

As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3⁺ Treg-cell expansion in the spleen of wild-type mice but not in Gitr^–/– mice. G3C/cps also induced the expansion of nonconventional Cd4⁺Cd25^–/lowFoxp3^lowGitr^int/high (GITR single-positive [sp]) Tregs. Both Cd4⁺Cd25⁺Gitr^highFoxp3⁺ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.

We conducted a 7-year case–control study of people ≥30 years of age on the prevalence of influenza, gastroenteritis, hepatitis, and pneumonia infections to indirectly examine whether these infections correlated to malignant cancer formation. Data were extracted from a large medical claims database of a Japanese social health insurance system; the case group included 2,354 people with their first cancer diagnosis in the 7th year of this study, and the control group included 48,395 people with no cancer diagnosis by the 7th year. The yearly prevalence rates of influenza, gastroenteritis, hepatitis, and pneumonia infections increased throughout the study period. Age-adjusted ORs and 95% confidence intervals (CI) in cases 1 year before cancer detection were significantly higher—for influenza 1.29 (95% CI, 1.14–1.46), for gastroenteritis 1.60 (95% CI, 1.41–1.82), for hepatitis 3.38 (95% CI, 2.12–5.37), for pneumonia 2.36 (95% CI, 1.79–3.13), and for any of these four diseases 1.55 (95% CI, 1.40–1.70). In influenza infections, significant ORs were found only in the 2nd and 6th years before cancer diagnosis. For each cancer site, an increased rate of infection prior to cancer diagnosis was observed. Here, we showed that increased infections during the precancerous stage, a possible surrogate for tumor-induced immune suppression, correlated to eventual cancer development.

To better understand how associated microorganisms ("microbiota") influence organismal aging, we focused on the model organism Drosophila melanogaster. We conducted a metagenome-wide association (MGWA) as a screen to identify bacterial genes associated with variation in the D. melanogaster life span. The results of the MGWA predicted that bacterial cysteine and methionine metabolism genes influence fruit fly longevity. A mutant analysis, in which flies were inoculated with Escherichia coli strains bearing mutations in various methionine cycle genes, confirmed a role for some methionine cycle genes in extending or shortening fruit fly life span. Initially, we predicted these genes might influence longevity by mimicking or opposing methionine restriction, an established mechanism for life span extension in fruit flies. However, follow-up transcriptome sequencing (RNA-seq) and metabolomic experiments were generally inconsistent with this conclusion and instead implicated glucose and vitamin B₆ metabolism in these influences. We then tested if bacteria could influence life span through methionine restriction using a different set of bacterial strains. Flies reared with a bacterial strain that ectopically expressed bacterial transsulfuration genes and lowered the methionine content of the fly diet also extended female D. melanogaster life span. Taken together, the microbial influences shown here overlap with established host genetic mechanisms for aging and therefore suggest overlapping roles for host and microbial metabolism genes in organismal aging.

IMPORTANCE Associated microorganisms ("microbiota") are intimately connected to the behavior and physiology of their animal hosts, and defining the mechanisms of these interactions is an urgent imperative. This study focuses on how microorganisms influence the life span of a model host, the fruit fly Drosophila melanogaster. First, we performed a screen that suggested a strong influence of bacterial methionine metabolism on host life span. Follow-up analyses of gene expression and metabolite abundance identified stronger roles for vitamin B₆ and glucose than methionine metabolism among the tested mutants, possibly suggesting a more limited role for bacterial methionine metabolism genes in host life span effects. In a parallel set of experiments, we created a distinct bacterial strain that expressed life span-extending methionine metabolism genes and showed that this strain can extend fly life span. Therefore, this work identifies specific bacterial genes that influence host life span, including in ways that are consistent with the expectations of methionine restriction.

Background:

The negative effect of adverse childhood experiences (ACEs) on physical and mental health has led to calls for routine screening for ACEs in primary care settings. We aimed to examine the association between maternal ACEs and children’s behaviour problems (externalizing and internalizing) at age 5 in the context of other known predictors.

Methods:

We analyzed data from mother-and-child dyads participating in the All Our Families cohort in Calgary, Canada, between 2011 and 2017. Data were collected for factors related to the individual child (sex, age, temperament and behaviour), the mother (adverse childhood experiences, mental health, personality and parenting) and sociodemographic characteristics (family income, ethnicity and family structure) when the children were 3 and 5 years of age. We used logistic regression models to estimate crude and adjusted associations between maternal ACEs and children’s externalizing (hyperactivity and aggression) and internalizing (anxiety, depression and somatization) behaviours.

Results:

Data were available for 1688 mother-and-child dyads. In the crude models, the presence of 4 or more maternal ACEs was associated with children’s externalizing and internalizing behaviours at age 5. However, these associations were attenuated with adjustment. Persistent maternal mental health symptoms were associated with both externalizing and internalizing behaviours at age 5 (adjusted odds ratio [OR] 4.20, 95% confidence interval [CI] 2.50–7.05, and adjusted OR 2.52, 95% CI 1.66–3.81, respectively). High levels of ineffective parenting behaviours were also associated with both externalizing and internalizing behaviours at age 5 (adjusted OR 6.27, 95% CI 4.30–9.14, and adjusted OR 1.43, 95% CI 1.03–1.99, respectively).

Interpretation:

The association between maternal ACEs and children’s behaviour at age 5 was weakened in the presence of other maternal and family-level factors. Assessments of maternal mental health and parenting behaviours may be better targets for identifying children at risk of behavioural problems.

Background:

Deaths from respiratory tract infections (RTIs) in children are preventable through timely access to public health and medical interventions. We aimed to assess whether socioeconomic disparities in mortality related to pediatric RTI persisted after accounting for health status at birth.

Methods:

We compared the prevalence of and risk factors for RTI-related death in singletons aged 28 days to 4 years across Ontario (Canada), Scotland and England (jurisdictions with universal health care) using linked administrative data for 2003–2013. We estimated rates of RTI-related mortality for children living in deprived areas and those born to teenage girls; we estimated both crude rates and those adjusted for health status at birth.

Results:

A total of 1 299 240 (Ontario), 547 556 (Scotland) and 3 910 401 (England) children were included in the study. Across all jurisdictions, children born in the most deprived areas experienced the highest rates of RTI-related mortality. After adjustment for high-risk chronic conditions and prematurity, we observed differences in mortality according to area-level deprivation in Ontario and England but not in Scotland. In Ontario, teenage motherhood was also an independent risk factor for RTI-related mortality.

Interpretation:

Socioeconomic disparities played a substantial role in child mortality related to RTI in all 3 jurisdictions. Context-specific investigations around the mechanisms of this increased risk and development of programs to address socioeconomic disparities are needed.

Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain.We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk.We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR.We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

Purpose:

Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown.

Experimental Design:

Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients.

Results:

A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity [hazard ratio (HR_adj) = 0.77; 95% confidence interval (CI), 0.63–0.93]. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF ± steroids for steroid-refractory toxicity compared with patients who were managed with steroids only (HR_adj = 1.61; 95% CI, 1.03–2.51), with a median OS of 17 and 27 months, respectively.

Conclusions:

Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy.

See related commentary by Weber and Postow, p. 2085

Purpose:

To provide a better understanding of the interplay between the immune system and brain metastases to advance therapeutic options for this life-threatening disease.

Experimental Design:

Tumor-infiltrating lymphocytes (TIL) were quantified by semiautomated whole-slide analysis in brain metastases from 81 lung adenocarcinomas. Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single-cell resolution. Molecular determinants of the extent of TILs in brain metastases were analyzed by transcriptomics in a subset of 63 patients. Findings in lung adenocarcinoma brain metastases were related to published multi-omic primary lung adenocarcinoma The Cancer Genome Atlas data (n = 230) and single-cell RNA-sequencing (scRNA-seq) data (n = 52,698).

Results:

TIL numbers within tumor islands was an independent prognostic marker in patients with lung adenocarcinoma brain metastases. Comparative transcriptomics revealed that expression of three surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) was closely associated with TIL numbers. Their expression was not only prognostic in brain metastasis but also in primary lung adenocarcinoma. Correlation with scRNA-seq data revealed that brain metastases with high expression of surfactant genes might originate from tumor cells resembling alveolar type 2 cells. Methylome-based estimation of immune cell fractions in primary lung adenocarcinoma confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment.

Conclusions:

The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) defines an inflamed subtype of lung adenocarcinoma brain metastases characterized by high abundance of TILs in close vicinity to tumor cells, a prolonged survival, and a tumor microenvironment which might be more accessible to immunotherapeutic approaches.

Purpose:

The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the cerebrospinal fluid (CSF) from patients with LMM to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells.

Experimental Design:

A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (<4 months) and one was an extraordinary responder (still alive with survival >35 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells that were subjected to RNA sequencing (RNA-seq) analysis. Functional assays were performed to validate the pathways identified.

Results:

Mass spectrometry analyses showed the CSF of most patients with LMM to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anticorrelated in the extraordinary responder. RNA-seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGFβ, and oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGFβ expression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays.

Conclusions:

These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from patients with LMM has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.

See related commentary by Glitza Oliva and Tawbi, p. 2083

Purpose:

In the phase III DUO trial, duvelisib, an oral dual PI3K-, inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.

Patients and Methods:

Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.

Results:

As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).

Conclusions:

Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.

Cefazolin has become a prominent therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections. However, an important concern is the cefazolin inoculum effect (CzIE), a phenomenon mediated by staphylococcal β-lactamases. Four variants of staphylococcal β-lactamases have been described based on serological methodologies and limited sequence information. Here, we sought to reassess the classification of staphylococcal β-lactamases and their correlation with the CzIE. We included a large collection of 690 contemporary bloodstream MSSA isolates recovered from Latin America, a region with a high prevalence of the CzIE. We determined cefazolin MICs at standard and high inoculums by broth microdilution. Whole-genome sequencing was performed to classify the β-lactamase in each isolate based on the predicted full sequence of BlaZ. We used the classical schemes for β-lactamase classification and compared it to BlaZ allotypes found in unique sequences using the genomic information. Phylogenetic analyses were performed based on the BlaZ and core-genome sequences. The overall prevalence of the CzIE was 40%. Among 641 genomes, type C was the most predominant β-lactamase (37%), followed by type A (33%). We found 29 allotypes and 43 different substitutions in BlaZ. A single allotype, designated BlaZ-2, showed a robust and statistically significant association with the CzIE. Two other allotypes (BlaZ-3 and BlaZ-5) were associated with a lack of the CzIE. Three amino acid substitutions (A9V, E112A, and G145E) showed statistically significant association with the CzIE (P = <0.01). CC30 was the predominant clone among isolates displaying the CzIE. Thus, we provide a novel approach to the classification of the staphylococcal β-lactamases with the potential to more accurately identify MSSA strains exhibiting the CzIE.

Imipenem-relebactam (I-R) is a recently developed carbapenem–beta-lactamase inhibitor combination agent that can overcome carbapenem resistance, which has now emerged in Escherichia coli, including sequence type 131 (ST131) and its fluoroquinolone-resistant H30R subclone, the leading cause of extraintestinal E. coli infections globally. To clarify the likely utility of I-R for carbapenem-resistant (CR) E. coli infections in the United States, we characterized 203 recent CR clinical E. coli isolates from across the United States (years 2002 to 2017) for phylogroup, clonal group (including ST131, H30R, and the CTX-M-15-associated H30Rx subset within H30R), relevant beta-lactamase genes, and broth microdilution MICs for I-R and 11 comparator agents. Overall, I-R was highly active (89% susceptible), more so than all comparators except tigecycline and colistin (both 99% susceptible). I-R’s activity varied significantly in relation to phylogroup, clonal background, resistance genotype, and region. It was greatest among phylogroup B2, ST131-H30R, H30Rx, Klebsiella pneumoniae carbapenemase (KPC)-positive, and northeast U.S. isolates and lowest among phylogroup C, New Delhi metallo-β-lactamase (NDM)-positive, and southeast U.S. isolates. Relebactam improved imipenem’s activity against CR isolates within each phylogroup—especially groups A, B1, and B2—and particularly against isolates containing KPC. I-R remained substantially active against isolates coresistant to comparator agents, albeit somewhat less so than against the corresponding susceptible isolates. These findings suggest that I-R should be useful for treating most CR E. coli infections in the United States, largely independent of coresistance, although this likely will vary in relation to the local prevalence of specific E. coli lineages and carbapenem resistance mechanisms.

Delamanid (DLM), a nitro-dihydroimidazooxazole derivative currently approved for pulmonary multidrug-resistant tuberculosis (TB) therapy, is a prodrug activated by mycobacterial 7,8-didemethyl-8-hydroxy 5-deazaflavin electron transfer coenzyme (F₄₂₀)-dependent nitroreductase (Ddn). Despite inhibiting the biosynthesis of a subclass of mycolic acids, the active DLM metabolite remained unknown. Comparative liquid chromatography-mass spectrometry (LC-MS) analysis of DLM metabolites revealed covalent binding of reduced DLM with a nicotinamide ring of NAD derivatives (oxidized form) in DLM-treated Mycobacterium tuberculosis var. Bacille de Calmette et Guérin. Isoniazid-resistant mutations in the type II NADH dehydrogenase gene (ndh) showed a higher intracellular NADH/NAD ratio and cross-resistance to DLM, which were restored by complementation of the mutants with wild-type ndh. Our data demonstrated for the first time the adduct formation of reduced DLM with NAD in mycobacterial cells and its importance in the action of DLM.

BRAF^V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAF^V600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort "basket" study of the BRAF inhibitor vemurafenib in non-melanoma BRAF^V600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized.

Significance:

These data suggest that BRAF^V600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care.

See related commentary by Ribas and Lo, p. 640.

This article is highlighted in the In This Issue feature, p. 627

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc. (ACP), and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an initiative of the Cleveland Clinic’s internal medicine residents to improve diabetes care and outcomes within an underserved patient population at an East Cleveland, OH, health center.

Background:

Sex steroid hormones and sex hormone–binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma in situ (DCIS) of the breast, remain unclear.

Methods:

We used Cox proportional hazards regression models to estimate the associations of serum levels of estradiol (premenopausal women only), testosterone, and/or SHBG with DCIS risk among 182,935 women. After a median follow-up of 7.1 years, 186 and 531 DCIS cases were ascertained in premenopausal and postmenopausal women, respectively.

Results:

Total and free estradiol were positively associated with risk of DCIS among premenopausal women. The HRs for the highest versus the lowest tertiles were 1.54 (1.06–2.23) and 1.72 [95% confidence interval (CI), 1.15–2.57], respectively. Among postmenopausal women, elevated levels of free testosterone (FT), and to a lesser extent, total testosterone, were positively associated with DCIS risk. The HRs for the highest versus the lowest quartiles were 1.42 (95% CI, 1.09–1.85) and 1.16 (95% CI, 0.91–1.48), respectively. Serum SHBG levels were inversely associated with risk of DCIS among postmenopausal women (HR_{q4 vs. q1}: 0.75; 95% CI, 0.56–0.99).

Conclusions:

This study suggests that elevated levels of estradiol are associated with increased risk of DCIS among premenopausal women, and that among postmenopausal women, elevated levels of testosterone, and particularly those of FT, are associated with increased DCIS risk, while elevated levels of SHBG are associated with reduced risk.

Impact:

These findings may be helpful in developing prevention strategies aimed at reducing breast cancer risk among premenopausal and postmenopausal women.

Background:

Reduction in breast density may be a biomarker of endocrine therapy (ET) efficacy. Our objective was to assess the impact of race on ET-related changes in volumetric breast density (VBD).

Methods:

This retrospective cohort study assessed longitudinal changes in VBD measures in women with estrogen receptor–positive invasive breast cancer treated with ET. VBD, the ratio of fibroglandular volume (FGV) to breast volume (BV), was measured using Volpara software. Changes in measurements were evaluated using a multivariable linear mixed effects model.

Results:

Compared with white women (n = 191), black women (n = 107) had higher rates of obesity [mean ± SD body mass index (BMI) 34.5 ± 9.1 kg/m² vs. 30.6 ± 7.0 kg/m², P < 0.001] and premenopausal status (32.7% vs. 16.7%, P = 0.002). Age- and BMI-adjusted baseline FGV, BV, and VBD were similar between groups. Modeled longitudinal changes were also similar: During a follow-up of 30.7 ± 15.0 months (mean ± SD), FGV decreased over time in premenopausal women (slope = –0.323 cm³; SE = 0.093; P = 0.001), BV increased overall (slope = 2.475 cm³; SE = 0.483; P < 0.0001), and VBD decreased (premenopausal slope = –0.063%, SE = 0.011; postmenopausal slope = –0.016%, SE = 0.004; P < 0.0001). Race was not significantly associated with these longitudinal changes, nor did race modify the effect of time on these changes. Higher BMI was associated with lower baseline VBD (P < 0.0001). Among premenopausal women, VBD declined more steeply for women with lower BMI (time x BMI, P = 0.0098).

Conclusions:

Race does not appear to impact ET-related longitudinal changes in VBD.

Impact:

Racial disparities in estrogen receptor–positive breast cancer recurrence and mortality may not be explained by differential declines in breast density due to ET.

Background:

Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood.

Methods:

We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis.

Results:

Alcohol use was positively associated with PD (P_trend = 0.01), unassociated with DA (P_trend = 0.23), and inversely associated with NDA (P_trend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (P_trend = 0.0008), unassociated with DA (P_trend = 0.93), and positively associated with NDA (P_trend<0.0001). These trends were stronger in normal and overweight women than in obese women.

Conclusions:

These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA.

Impact:

PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.

Background:

Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case–control study.

Methods:

Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose–response relationships and to analyze their shape.

Results:

Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39–2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11–1.99) or chest (OR = 1.33; 95% CI, 1.12–1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10–2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31–3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01–2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03–1.49). Dose–response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely.

Conclusions:

This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations.

Impact:

This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.

Background:

New technologies are being developed for early detection of multiple types of cancer simultaneously. To quantify the potential benefit, we estimated reductions in absolute cancer–related deaths that could occur if cancers diagnosed after metastasis (stage IV) were instead diagnosed at earlier stages.

Methods:

We obtained stage-specific incidence and survival data from the Surveillance, Epidemiology, and End Results Program for 17 cancer types for all persons diagnosed ages 50 to 79 years in 18 geographic regions between 2006 and 2015. For a hypothetical cohort of 100,000 persons, we estimated cancer-related deaths under assumptions that cancers diagnosed at stage IV were diagnosed at earlier stages.

Results:

Stage IV cancers represented 18% of all estimated diagnoses but 48% of all estimated cancer-related deaths within 5 years. Assuming all stage IV cancers were diagnosed at stage III, 51 fewer cancer-related deaths would be expected per 100,000, a reduction of 15% of all cancer-related deaths. Assuming one third of metastatic cancers were diagnosed at stage III, one third diagnosed at stage II, and one third diagnosed at stage I, 81 fewer cancer-related deaths would be expected per 100,000, a reduction of 24% of all cancer-related deaths, corresponding to a reduction in all-cause mortality comparable in magnitude to eliminating deaths due to cerebrovascular disease.

Conclusions:

Detection of multiple cancer types earlier than stage IV could reduce at least 15% of cancer-related deaths within 5 years, affecting not only cancer-specific but all-cause mortality.

Impact:

Detecting cancer before stage IV, including modest shifts to stage III, could offer substantial population benefit.

BACKGROUND AND PURPOSE:

Endolymphatic hydrops in patients with Menière disease relies on delayed postcontrast 3D-FLAIR sequences. The purpose of this study was to compare the degree of perilymphatic enhancement and the detection rate of endolymphatic hydrops using constant and variable flip angles sequences.

MATERIALS AND METHODS:

This was a retrospective study performed in 16 patients with Menière disease who underwent 3T MR imaging 4 hours after gadolinium injection using two 3D-FLAIR sequences with a constant flip angle at 140° for the first and a heavily-T2 variable flip angle for the second. The signal intensity ratio was measured using the ROI method. We graded endolymphatic hydrops and evaluated the cochlear blood-labyrinth barrier impairment.

RESULTS:

Both for symptomatic and asymptomatic ears, the median signal intensity ratio was significantly higher with the constant flip angle than with the heavily-T2 variable flip angle (7.16 versus 1.54 and 7.00 versus 1.45, P < .001). Cochlear blood-labyrinth barrier impairment was observed in 4/18 symptomatic ears with the heavily-T2 variable flip angle versus 8/19 with constant flip angle sequences. With heavily-T2 variable flip angle sequences, endolymphatic hydrops was observed in 7–10/19 symptomatic ears versus 12/19 ears with constant flip angle sequences. We found a significant association between the clinical symptomatology and the presence of endolymphatic hydrops with constant flip angle but not with heavily-T2 variable flip angle sequences. Interreader agreement was always perfect with constant flip angle sequences while it was fair-to-moderate with heavily-T2 variable flip angle sequences.

CONCLUSIONS:

3D-FLAIR constant flip angle sequences provide a higher signal intensity ratio and are superior to heavily-T2 variable flip angle sequences in reliably evaluating the cochlear blood-labyrinth barrier impairment and the endolymphatic space.

SUMMARY:

Polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) are recently described CNS tumors. Classically, PLNTYs are epileptogenic and are a subtype of a heterogeneous group of low-grade neuroepithelial tumors that cause refractory epilepsy, such as angiocentric gliomas, oligodendrogliomas, gangliogliomas, and pleomorphic xanthoastrocytomas. Although they are a relatively new entity, a number of imaging and histologic characteristics of PLNTYs are already known. We present the imaging and pathologic findings of such a tumor as well as the surgical approach and clinical management.

The relationship between a landlord and his tenant is often fraught with tension. Just ask the average unhappy tenant and he will most likely tell you that his landlord’s sole ambition is to rip him off and make his life as difficult as possible. An unhappy landlord on the other hand, tends to view the situation somewhat differently and feels that no matter how much he does for his tenant, there are always problems, and always reasons to delay paying the rent.

Publisher Wired Productions and developer Camel 101 have delayed psychological horror game, Those Who Remain, from May 15 to May 28 for the PlayStation 4, Xbox One and Windows PC via Steam. 

View the official release date trailer below:

Here is an overview of the game:

As the lights go out, the embers of darkness are stoked in the sleepy town of Dormont.

Whispers of disappearances carry through the town as a burgeoning, uneasy and irrational fear begins to spread and darkness comes to be an unwelcome reflection to Those Who Remain.

Some mistakes should never happen, not when your life is complete – and yet they do. Edward had the good life, a beautiful wife and the perfect little girl, yet finds himself several whiskeys down and driving through the night of Dormont to end his secret affair – in a bid to fix his mistakes.

As Edward pulls into the Golden Oak Motel, he is unaware just how much this night will change his life…

Key Features:

The horrors and darkness that thrive in the corner of every eye are torn loose…

Those Who Remain places you in an up-close, psychological horror story set in the sleepy town of Dormont – a town in a spiralling split from the fabric of reality, warped by darkness and the deeds of the Citizens who reside.

Confront the uncomfortable horrors reflected by the darkness and survive the night of Dormont as Edward is confronted with a test of his sanity, morality and the shadows of evil that lurks below.

• Darkness Has Eyes -Navigate and survive the encroaching darkness and stay in the protection of the light by any means[br]
• Worlds Torn Asunder – Pave your way ahead by moving between Dormont and its dark otherworldly counterpart to further solve the mysteries held within the dark
• Conscience of Choice – Choose to help any surviving citizens of Dormont you encounter or leave them to the darkness. Innocence cannot always be assumed, and the township of Dormont hides a cursed trove of secrets
• Savor your Sanity – Keep your sanity in check as you delve deeper into the darkness of Dormont – expected rules of the real world have been torn apart
• Follow your Path – Your decisions and choices will determine the fate of Edward, through multiple different branching outcomes

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443413/those-who-remain-delayed-to-may-28-for-ps4-xbox-one-and-steam/

The ExoMars mission, a joint venture between the European and Russian space agencies, will be delayed for two years. It has already been plagued by issues and the coronavirus hasn't helped

With four legs but no back or front, ALPHRED 2 can run, jump, and punch through boards in any direction

Blue Frog Robotics CEO Rodolphe Hasselvander on the future of Buddy

Skimming system tripled previous best effort at oil collection.

FIFA 20 Team Of The Season So Far continues this week, hopefully with the release of the Bundesliga FUT Squad. Here some predictions on who might be included, plus when they'll be announced.

First Minister Nicola Sturgeon has said the Scottish Government is looking into expanding the current guidance about exercise during the lockdown.

Thanks to Marlon Brando, this practical garment turned into the epitome of rebel streetwear before becoming a style staple

Physically, I’m about as robust as Stick Man. I’m weak enough to have seriously considered that my five-year-old is now physically stronger than me. When I hear “core”, all I think of is Andrea and her Irish singing siblings. So the idea of wearing a very heavy jacket like this sturdy biker one, gives me pause for thought. It will, I realise, force a rethink of how I move, and how I walk.

But I’m being open-minded about the style, because the biker jacket has come a long way. It was created by Irving Schott in 1928, in conjunction with Harley-Davidson, with a specific function in mind (belt buckles placed in certain places to protect you from the wind while riding; zippers for easy access). Marlon Brando’s jacket in The Wild One was from this range. Brando helped move it to the mainstream, and since then it’s been loved by wrong ’uns, rebels, greasers and Ramones.

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Your house number could be the key to the safe relaxation of COVID-19-related restrictions if governments follow a new exit strategy, which proposes the use of an 'odds-and-evens' approach to allowing people to head back to work and enjoy other activities after weeks of lockdown.

This uncanny story of preppy drug dealers has a touch of Heathers and a bit of Bret Easton Ellis, and an intriguing take on what high school is really like

Tayarisha Poe, like her partial namesake, has a gift for the uncanny. She is the photographer and film-maker behind this feature debut, which began as an online multimedia project and was developed as a conventional movie through the Sundance screenwriters and directors labs. What has emerged is an intriguing, opaque, tonally elusive story that seems weirdly unfinished. It is set in a privileged high school – a world of ivy-covered stone buildings and shady quadrangles where rich kids are separated into malign and mutually hostile cliques. It has a touch of Donna Tartt and Bret Easton Ellis, a hint of Heathers and a bit of the elegant, disdainful satire of Dear White People.

Somehow, though, it is odder, more stylised and contrived, always holding out the possibility that it is set in the future, or in an alternative present on some other planet, or inside the head of one of its characters who is having a disturbing dream – the kind that ends just as it is about to give up its meaning. Right until the closing credits, I half-expected the face of each person on screen to flip upwards, revealing a Stepford-like set of dials.

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Disruptor Beam, the mobile gaming startup behind Star Trek Timelines, has a new name and a new business. It’s now calling itself Beamable, and it’s selling a set of tools to help game developers add commerce and social functionality to their titles. The company’s direction became clear earlier this year when it sold Timelines to […]

Hundreds of protesters gathered in front of a Georgia courthouse on Friday to decry the killing of an unarmed black man in February and the delay in charging two white men in a shooting captured on video that was released earlier this week.

A 5-year old boy has died in New York from a rare inflammatory syndrome believed to be linked to the novel coronavirus, highlighting a potential new risk for children in the pandemic, Governor Andrew Cuomo said on Friday.