Motivated by models of cancer formation in which cells need to acquire $k$ mutations to become cancerous, we consider a spatial population model in which the population is represented by the $d$-dimensional torus of side length $L$. Initially, no sites have mutations, but sites with $i-1$ mutations acquire an $i$th mutation at rate $\mu_i$ per unit area. Mutations spread to neighboring sites at rate $\alpha$, so that $t$ time units after a mutation, the region of individuals that have acquired the mutation will be a ball of radius $\alpha t$. We calculate, for some ranges of the parameter values, the asymptotic distribution of the time required for some individual to acquire $k$ mutations. Our results, which build on previous work of Durrett, Foo, and Leder, are essentially complete when $k = 2$ and when $\mu_i = \mu$ for all $i$.

Research suggests that the perception of attractiveness is multimodal, however, it is unclear how visual and auditory cues interact. Voice pitch seems important, as men judge high-pitched female voices to be more attractive, possibly due to their association with youthfulness, fertility, and femininity. We investigated whether an increase in voice pitch in female voices would lead to increased ratings of attractiveness, femininity, and health, and decreased age ratings. In a within-subject design we found higher-pitched female voices were rated more attractive, more feminine, and younger, but not healthier compared to non-manipulated voices. However, when manipulated and control voices were presented simultaneously with synchronized face videos, voice manipulations did not affect the ratings of the faces. These results support the multiple-message hypothesis that voices and faces signal different aspects of an individual’s overall quality. Further experiments will have to examine the effect of face attractiveness manipulations on voice ratings.

Attractiveness research is typically conducted using static photographs of human faces, often cropped or otherwise edited. We present a database of videos of faces, while talking with synchronized audio that will facilitate more ecologically valid, multimodal research into face and voice attractiveness. Our database contains videos, synchronized voice recordings, and photographs of 20 male and 20 female German speakers under different emotional conditions (neutral, sad, happy, angry, flirty). Recordings were simultaneously made from three different angles (frontal, profile, 3/4 view) in front of a green screen. We report the results of a comprehensive validation of this database to make it usable for multisensory empirical aesthetics research, but also for face or emotion research. An online study was conducted to collect ratings on several dimensions including general attractiveness, allowing us to uncover the effects of predictors for facial attractiveness in a natural setting.

It has long been debated whether aesthetics is something uniquely human. Our ongoing project aims to empirically address comparative aesthetics in a collaboration between psychologists and biologists. Defining aesthetic responses as approach behaviour associated with sensory pleasure and corresponding physiological states, we are exploring whether humans and non-human animals share similar mechanisms in their evaluation of sexually attractive stimuli. Specifically, we compare humans and ring doves (Streptopelia risoria), a species whose courtship behaviour and physiology have been extensively investigated in behavioural and neuroendocrinology research. Both species form pair bonds, communicate using visual and auditory signals, and can be tested in laboratory conditions with conspecifics or using video and auditory stimuli. Truly comparative work involves using as similar an experimental approach as possible for both human and animal participants. Here we report our comparative methods and experimental paradigms, and some recent results.

Background

While the development of targeted molecular therapy to inhibit vascular endothelial growth factor (VEGF) has revolutionized the treatment and visual prognosis of highly prevalent retinal diseases such as diabetic retinopathy and age-related macular degeneration, each intravitreal injection of these agents carries a small risk of endophthalmitis which can be visually devastating. In the absence of specific guidelines, current management of post-injection endophthalmitis is typically extrapolated from data regarding endophthalmitis occurring after cataract surgery despite potential differences in pathogenic organisms and clinical course. Here, we assess the contribution of intravitreal injections of anti-VEGF agents to all cases of endophthalmitis at our tertiary care referral center and characterize the clinical outcomes and microbial pathogens associated with post-injection endophthalmitis in order to inform management of this serious iatrogenic condition.

Results

During the 7-year study period analyzed, 199 cases of endophthalmitis were identified using billing records. Of these, the most common etiology was post-surgical, accounting for 62 cases (31.2 %), with bleb-associated, endogenous, and corneal ulcer-related infections representing the next most frequent causes, comprising 15.6 % (31/199), 13.1 % (26/199), and 13.6 % (27/199) of all cases, respectively. Intravitreal injections of anti-VEGF agents represented 8.5 % of endophthalmitis (17/199 cases). Intraocular cultures yielded positive results in 75 % of post-injection cases, with the majority associated with coagulase-negative Staphylococcus. Consistent with prior literature, a case of Strep viridans displayed more rapid onset and progression. We also report the first association of Enterobacter cloacae and Lactococcus garvieae with post-injection endophthalmitis. While all but one patient were treated with initial vitreous tap and intravitreal injection of antibiotics, both patients with these rare organisms exhibited persistent vitritis requiring subsequent vitrectomy. Long-term outcomes of post-injection endophthalmitis indicated visual recovery to baseline levels, even with resumption of anti-VEGF agents following resolution of the acute infection.

Conclusions

Acute endophthalmitis following intravitreal injections of anti-VEGF agents is an uncommon but potentially devastating complication which may be managed effectively with vitreous tap and injection of intravitreal antibiotics. However, persistent vitritis requiring subsequent vitrectomy should raise suspicion for unusual pathogens.

The field of neuroaesthetics has gained in popularity in recent years but also attracted criticism from the perspectives both of the humanities and the sciences. In an effort to consolidate research in the field, we characterize neuroaesthetics as the cognitive neuroscience of aesthetic experience, drawing on long traditions of research in empirical aesthetics on the one hand and cognitive neuroscience on the other. We clarify the aims and scope of the field, identifying relations among neuroscientific investigations of aesthetics, beauty, and art. The approach we advocate takes as its object of study a wide spectrum of aesthetic experiences, resulting from interactions of individuals, sensory stimuli, and context. Drawing on its parent fields, a cognitive neuroscience of aesthetics would investigate the complex cognitive processes and functional networks of brain regions involved in those experiences without placing a value on them. Thus, the cognitive neuroscientific approach may develop in a way that is mutually complementary to approaches in the humanities.

The epidemiology of H5N1 and H7N9 avian viruses of humans infected in China differs despite both viruses being avian reassortants that have inherited six internal genes from a common ancestor, H9N2. The median age of infected populations is substantially younger for H5N1 virus (26 years) compared with H7N9 virus (63 years). Population susceptibility to infection with seasonal influenza is understood to be influenced by cross-reactive CD8+ T cells directed towards immunogenic peptides derived from internal viral proteins which may provide some level of protection against further influenza infection. Prior exposure to seasonal influenza peptides may influence the age-related infection patterns observed for H5N1 and H7N9 viruses. A comparison of relatedness of immunogenic peptides between historical human strains and the two avian emerged viruses was undertaken for a possible explanation in the differences in age incidence observed. There appeared to be some relationship between past exposure to related peptides and the lower number of H5N1 virus cases in older populations, however the relationship between prior exposure and older populations among H7N9 virus patients was less clear.

In the randomized, placebo-controlled, double-blind phase 3 ACTIVE study (NCT01343004), 18 months of abaloparatide 80 μg daily (subcutaneous injection) in postmenopausal women at risk of osteoporotic fracture significantly reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and significantly increased bone mineral density (BMD) versus placebo regardless of baseline risk factors. Women from the abaloparatide and placebo groups who completed ACTIVE were eligible for ACTIVExtend (NCT01657162), in which all enrollees received sequential, open-label monotherapy with alendronate 70 mg once weekly for up to 24 months. This prespecified analysis evaluated whether fracture risk reductions and bone mineral density (BMD) gains associated with abaloparatide during ACTIVE persisted through the full 43-month ACTIVE-ACTIVExtend study period in nine prespecified baseline risk subgroups. Baseline risk subgroups included BMD T-score at the lumbar spine, total hip, and femoral neck (≤ - 2.5 versus > - 2.5 and ≤ -3.0 versus > - 3.0), history of nonvertebral fracture (yes/no), prevalent vertebral fracture (yes/no), and age (<65 versus 65 to <75 versus ≥75 years). Forest plots display treatment effect. Treatment-by-subgroup interactions were tested using the Breslow-Day test, Cox proportional hazards model, and ANCOVA model. After the combined ACTIVE-ACTIVExtend study period, reductions in relative risk for new vertebral, nonvertebral, clinical, and major osteoporotic fractures were greater among patients in the abaloparatide/alendronate group than among those in the placebo/alendronate group across all nine baseline risk subgroups. BMD gains at the lumbar spine, total hip, and femoral neck were greater in the abaloparatide/alendronate group versus the placebo/alendronate group. No clinically meaningful interaction between treatment assignment and any baseline risk variable was observed. The sequence of abaloparatide for 18 months followed by alendronate for up to 24 months appears to be an effective treatment option for a wide range of postmenopausal women at risk for osteoporotic fractures. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent, temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT (O⁶-methylguanine-DNA methyltransferase) has been associated with sensitivity to TMZ, whereas increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors; however, the evolutionary processes that drive this shift and more generally the emergence and growth of TMZ-resistant tumor subpopulations are still poorly understood. Here, we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM-surgery, chemotherapy, and radiation. We first found that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for patients with GBM with high and low levels of MGMT methylation at diagnosis.

Context

Recent observational studies have suggested that the use of selective serotonin reuptake inhibitors is associated with an increased fracture risk and an accelerated bone loss, although conflicting results have been reported. Furthermore, because many of these studies have been performed in depressed women, confounding by indication may influence these findings.

Objective

The objective of the study was to determine whether selective serotonin reuptake inhibitors affect bone metabolism Design: This was a randomized controlled trial.

Setting

The study was conducted in four US clinical sites.

Participants

Healthy peri- and postmenopausal women participated in the study.

Intervention

The intervention was escitalopram (10-20 mg/d) for the treatment of vasomotor symptoms.

Main outcome measures

Serum carboxyterminal collagen crosslinks (CTX) and serum amino-terminal propeptide of type I collagen (P1NP) were measured.

Results

One hundred forty-one peri- or postmenopausal nondepressed women (mean age 53.7 y, SD 4.1) had baseline and 8-week follow-up samples available for analysis and were included in the study (69 escitalopram, 72 placebo). The groups were balanced across a broad range of baseline characteristics, including age, race, body mass index, smoking status, and mood symptoms. The between-group differences in the change in CTX and P1NP from baseline to week 8 were compared by a repeated-measures linear regression model adjusted for race, clinical center, and baseline measurement. Treatment with escitalopram reduced serum P1NP by 1.02 ng/mL on average [95% confidence interval (CI) -5.17, 3.12] compared with a reduction of 1.88 ng/mL (95% CI -4.82, 1.06) in the placebo group (P = .65). Similarly, serum CTX decreased 0.02 ng/mL on average (95% CI -0.05, 0.01) in the escitalopram group compared with 0.00 ng/mL (95% CI -0.02, 0.02) in the placebo group (P = .24). The results were similar when the analysis was restricted to those women whose adherence to study medication was 70% or greater.

Conclusions

Although the study was limited to 8 weeks, these results suggest that escitalopram does not significantly alter bone metabolism in the short term.