Retrospective model-based inference guides model-free credit assignment

An extensive reinforcement learning literature shows that organisms assign credit efficiently, even under conditions of state uncertainty. However, little is known about credit-assignment when state uncertainty is subsequently resolved. Here, we address this problem within the framework of an interaction between model-free (MF) and model-based (MB) control systems. We present and support experimentally a theory of MB retrospective-inference. Within this framework, a MB system resolves uncertainty that prevailed when actions were taken thus guiding an MF credit-assignment. Using a task in which there was initial uncertainty about the lotteries that were chosen, we found that when participants’ momentary uncertainty about which lottery had generated an outcome was resolved by provision of subsequent information, participants preferentially assigned credit within a MF system to the lottery they retrospectively inferred was responsible for this outcome. These findings extend our knowledge about the range of MB functions and the scope of system interactions

Evidence of fatal skeletal injuries on Malapa Hominins 1 and 2

Malapa is one of the richest early hominin sites in Africa and the discovery site of the hominin species, Australopithecus sediba. The holotype and paratype (Malapa Hominin 1 and 2, or MH1 and MH2, respectively) skeletons are among the most complete in the early hominin record. Dating to approximately two million years BP, MH1 and MH2 are hypothesized to have fallen into a natural pit trap. All fractures evident on MH1 and MH2 skeletons were evaluated and separated based on wet and dry bone fracture morphology/characteristics. Most observed fractures are post-depositional, but those in the right upper limb of the adult hominin strongly indicate active resistance to an impact, while those in the juvenile hominin mandible are consistent with a blow to the face. The presence of skeletal trauma independently supports the falling hypothesis and supplies the first evidence for the manner of death of an australopith in the fossil record that is not attributed to predation or natural death

Global, regional, and national estimates of the impact of a maternal Klebsiella pneumoniae vaccine: A Bayesian modeling analysis.

BACKGROUND: Despite significant global progress in reducing neonatal mortality, bacterial sepsis remains a major cause of neonatal deaths. Klebsiella pneumoniae (K. pneumoniae) is the leading pathogen globally underlying cases of neonatal sepsis and is frequently resistant to antibiotic treatment regimens recommended by the World Health Organization (WHO), including first-line therapy with ampicillin and gentamicin, second-line therapy with amikacin and ceftazidime, and meropenem. Maternal vaccination to prevent neonatal infection could reduce the burden of K. pneumoniae neonatal sepsis in low- and middle-income countries (LMICs), but the potential impact of vaccination remains poorly quantified. We estimated the potential impact of such vaccination on cases and deaths of K. pneumoniae neonatal sepsis and project the global effects of routine immunization of pregnant women with the K. pneumoniae vaccine as antimicrobial resistance (AMR) increases. METHODS AND FINDINGS: We developed a Bayesian mixture-modeling framework to estimate the effects of a hypothetical K. pneumoniae maternal vaccine with 70% efficacy administered with coverage equivalent to that of the maternal tetanus vaccine on neonatal sepsis infections and mortality. To parameterize our model, we used data from 3 global studies of neonatal sepsis and/or mortality-with 2,330 neonates who died with sepsis surveilled from 2016 to 2020 undertaken in 18 mainly LMICs across all WHO regions (Ethiopia, Kenya, Mali, Mozambique, Nigeria, Rwanda, Sierra Leone, South Africa, Uganda, Brazil, Italy, Greece, Pakistan, Bangladesh, India, Thailand, China, and Vietnam). Within these studies, 26.95% of fatal neonatal sepsis cases were culture-positive for K. pneumoniae. We analyzed 9,070 K. pneumoniae genomes from human isolates gathered globally from 2001 to 2020 to quantify the temporal rate of acquisition of AMR genes in K. pneumoniae isolates to predict the future number of drug-resistant cases and deaths that could be averted by vaccination. Resistance rates to carbapenems are increasing most rapidly and 22.43% [95th percentile Bayesian credible interval (CrI): 5.24 to 41.42] of neonatal sepsis deaths are caused by meropenem-resistant K. pneumoniae. Globally, we estimate that maternal vaccination could avert 80,258 [CrI: 18,084 to 189,040] neonatal deaths and 399,015 [CrI: 334,523 to 485,442] neonatal sepsis cases yearly worldwide, accounting for more than 3.40% [CrI: 0.75 to 8.01] of all neonatal deaths. The largest relative benefits are in Africa (Sierra Leone, Mali, Niger) and South-East Asia (Bangladesh) where vaccination could avert over 6% of all neonatal deaths. Nevertheless, our modeling only considers country-level trends in K. pneumoniae neonatal sepsis deaths and is unable to consider within-country variability in bacterial prevalence that may impact the projected burden of sepsis. CONCLUSIONS: A K. pneumoniae maternal vaccine could have widespread, sustained global benefits as AMR in K. pneumoniae continues to increase

Sperm design and variation in the New World blackbirds (Icteridae)

Post-copulatory sexual selection (PCSS) is thought to be one of the evolutionary forces responsible for the rapid and divergent evolution of sperm design. However, whereas in some taxa particular sperm traits are positively associated with PCSS, in other taxa, these relationships are negative, and the causes of these different patterns across taxa are poorly understood. In a comparative study using New World blackbirds (Icteridae), we tested whether sperm design was influenced by the level of PCSS and found significant positive associations with the level of PCSS for all sperm components but head length. Additionally, whereas the absolute length of sperm components increased, their variation declined with the intensity of PCSS, indicating stabilizing selection around an optimal sperm design. Given the diversity of, and strong selection on, sperm design, it seems likely that sperm phenotype may influence sperm velocity within species. However, in contrast to other recent studies of passerine birds, but consistent with several other studies, we found no significant link between sperm design and velocity, using four different species that vary both in sperm design and PCSS. Potential reasons for this discrepancy between studies are discussed

Segment-specific association between cervical pillar hyperplasia (CPH) and degenerative joint disease (DJD)

BACKGROUND: Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown etiology and clinical significance. Global assessment of pillar hyperplasia of the cervical spine as a unit has not shown a relationship with degenerative joint disease, but a more sensible explanation of the architectural influence of CPH on cervical spine biomechanics may be segment-specific. OBJECTIVE: The objective of this study was to determine the level of association between degenerative joint disease (DJD) and cervical pillar hyperplasia (CPH) in an age- and gender-matched sample on a [cervical spine] by-level basis. RESEARCH METHODS: Two-hundred and forty radiographs were collected from subjects ranging in age between 40 and 69 years. The two primary outcome measures used in the study were the segmental presence/absence of cervical pillar hyperplasia from C3 to C6, and segment-specific presence/absence of degenerative joint disease from C1 to C7. Contingency Coefficients, at the 5% level of significance, at each level, were used to determine the strength of the association between CPH and DJD. Odds Ratios (OR) with their 95% Confidence Intervals (95% CI) were also calculated at each level to assess the strength of the association. RESULTS: Our study suggests that an approximately two-to-one odds, or a weak-to-moderate correlation, exists at C4 and C5 CPH and adjacent level degenerative disc disease (DDD); with the strongest (overall) associations demonstrated between C4 CPH and C4–5 DDD and between C5 CPH and C5–6 DDD. Age-stratified results demonstrated a similar pattern of association, even reaching the initially hypothesized OR ≥ 5.0 (95% CI > 1.0) or "moderately-strong correlation of C ≥ .4 (p ≤ .05)" in some age categories, including the 40–44, 50–59, and 60–64 years of age subgroups; these ORs were as follows: OR = 5.5 (95% CI 1.39–21.59); OR = 6.7 (95% CI 1.65–27.34); and OR = 5.3 (95% CI 1.35–21.14), respectively. CONCLUSION: Our results suggest that CPH has around two-to-one odds, that is, only a weak-to-moderate association with the presence of DJD (DDD component) at specific cervical spine levels; therefore, CPH may be but one of several factors that contributes (to a clinically important degree) to the development of DJD at specific levels in the cervical spine

Intra-anal imiquimod cream against human papillomavirus infection in men who have sex with men living with hiv: A single-arm, open-label pilot study

Men who have sex with men (MSM) living with HIV have a high prevalence and incidence of anal high-risk human papillomavirus (hrHPV) and anal cancer. We conducted an open-label, single-arm pilot study to examine the tolerability of imiquimod cream among MSM aged ≥18 years, living with HIV, who tested positive for anal hrHPV at Melbourne Sexual Health Centre between April 2018 and June 2020. We instructed men to apply 6.25 mg imiquimod intra-anally and peri-anally 3 doses per week for 16 weeks (period 1) and then one dose per week for a further 48 weeks (period 2). Twenty-seven MSM enrolled in period 1 and 24 (86%) applied at least 50% of doses. All men reported adverse events (AEs), including 39.5% grade 1, 39.5% grade 2, and 21% grade 3 AEs on at least one occasion. Eighteen MSM (67%) temporarily stopped using imiquimod during period 1, most commonly due to local AEs (n = 11) such as irritation and itching. Eighteen MSM continued in period 2 and all applied at least 50% of doses with no treatment-limiting AEs reported. Imiquimod 3 doses per week caused local AEs in most men and was not well tolerated. In contrast, once-a-week application was well tolerated over 48-weeks with no treatment-limiting AEs

A mediation approach to understanding socio-economic inequalities in maternal health-seeking behaviours in Egypt.

BACKGROUND: The levels and origins of socio-economic inequalities in health-seeking behaviours in Egypt are poorly understood. This paper assesses the levels of health-seeking behaviours related to maternal care (antenatal care [ANC] and facility delivery) and their accumulation during pregnancy and childbirth. Secondly, it explores the mechanisms underlying the association between socio-economic position (SEP) and maternal health-seeking behaviours. Thirdly, it examines the effectiveness of targeting of free public ANC and delivery care. METHODS: Data from the 2008 Demographic and Health Survey were used to capture two latent constructs of SEP: individual socio-cultural capital and household-level economic capital. These variables were entered into an adjusted mediation model, predicting twelve dimensions of maternal health-seeking; including any ANC, private ANC, first ANC visit in first trimester, regular ANC (four or more visits during pregnancy), facility delivery, and private delivery. ANC and delivery care costs were examined separately by provider type (public or private). RESULTS: While 74.2% of women with a birth in the 5-year recall period obtained any ANC and 72.4% delivered in a facility, only 48.8% obtained the complete maternal care package (timely and regular facility-based ANC as well as facility delivery) for their most recent live birth. Both socio-cultural capital and economic capital were independently positively associated with receiving any ANC and delivering in a facility. The strongest direct effect of socio-cultural capital was seen in models predicting private provider use of both ANC and delivery. Despite substantial proportions of women using public providers reporting receipt of free care (ANC: 38%, delivery: 24%), this free-of-charge public care was not effectively targeted to women with lowest economic resources. CONCLUSIONS: Socio-cultural capital is the primary mechanism leading to inequalities in maternal health-seeking in Egypt. Future studies should therefore examine the objective and perceived quality of care from different types of providers. Improvements in the targeting of free public care could help reduce the existing SEP-based inequalities in maternal care coverage in the short term

An ERP Assessment of Hemispheric Projections in Foveal and Extrafoveal Word Recognition

The existence and function of unilateral hemispheric projections within foveal vision may substantially affect foveal word recognition. The purpose of this research was to reveal these projections and determine their functionality.Single words (and pseudowords) were presented to the left or right of fixation, entirely within either foveal or extrafoveal vision. To maximize the likelihood of unilateral projections for foveal displays, stimuli in foveal vision were presented away from the midline. The processing of stimuli in each location was assessed by combining behavioural measures (reaction times, accuracy) with on-line monitoring of hemispheric activity using event-related potentials recorded over each hemisphere, and carefully-controlled presentation procedures using an eye-tracker linked to a fixation-contingent display.Event-related potentials 100–150 ms and 150–200 ms after stimulus onset indicated that stimuli in extrafoveal and foveal locations were projected unilaterally to the hemisphere contralateral to the presentation hemifield with no concurrent projection to the ipsilateral hemisphere. These effects were similar for words and pseudowords, suggesting this early division occurred before word recognition. Indeed, event-related potentials revealed differences between words and pseudowords 300–350 ms after stimulus onset, for foveal and extrafoveal locations, indicating that word recognition had now occurred. However, these later event-related potentials also revealed that the hemispheric division observed previously was no longer present for foveal locations but remained for extrafoveal locations. These findings closely matched the behavioural finding that foveal locations produced similar performance each side of fixation but extrafoveal locations produced left-right asymmetries.These findings indicate that an initial division in unilateral hemispheric projections occurs in foveal vision away from the midline but is not apparent, or functional, when foveal word recognition actually occurs. In contrast, the division in unilateral hemispheric projections that occurs in extrafoveal locations is still apparent, and is functional, when extrafoveal word recognition takes place

Inter-examiner reliability of the diagnosis of cervical pillar hyperplasia (CPH) and the correlation between CPH and spinal degenerative joint disease (DJD)

BACKGROUND: Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown aetiology. Its clinical importance is poorly understood at the present time; therefore, the objective of this study was to determine (1) the inter-examiner reliability of detecting CPH and (2) if there is a clinically important correlation (r > 0.4) between the number of cervical spine levels showing signs of degenerative joint disease (DJD) and CPH. METHODS: The sample consisted of 320 radiographs of human male and female subjects who ranged from 40 to 79 years of age. The inter-examiner reliability of assessing the presence/absence of pillar hyperplasia was evaluated on 50 neutral lateral radiographs by two examiners using line drawings and it was quantified using the kappa coefficient of concordance. To determine the presence/absence of hyperplastic pillars as well as the presence/absence of DJD at each intervertebral disc and zygapophysial joint, 320 AP open mouth, AP lower cervical and neutral lateral radiographs were then examined. The unpaired t-test at the 5% level of significance was performed to test for a statistically significant difference between the number of levels affected by DJD in patients with and without hyperplasia. The Spearman's rho at the 5% level of significance was performed to quantify the correlation between DJD and age. RESULTS: The inter-examiner reliability of detecting cervical pillar hyperplasia was moderate with a kappa coefficient of 0.51. The unpaired t-test indicated that there was no statistically significant difference (p > 0.05) between the presence/absence of cervical pillar hyperplasia and the number of levels affected by DJD in an age-matched population, regardless of whether all elements were considered together, or the discs and facets were analyzed separately. A Spearman correlation rank of 0.67 (p < 0.05) suggested a moderately strong correlation between the number of elements (i.e. discs/facets) affected, and the age of the individual. CONCLUSION: Cervical pillar hyperplasia is a reasonable concept that requires further research. Its evaluation is easy to learn and acceptably reliable. Previous research has suggested that CPH may affect the cervical lordosis, and therefore, alter biomechanics which may result in premature DJD. This current study, however, indicates that, globally, CPH does not appear to be related to the development of DJD

The use of microbubbles to target drug delivery

Ultrasound-mediated microbubbles destruction has been proposed as an innovative method for noninvasive delivering of drugs and genes to different tissues. Microbubbles are used to carry a drug or gene until a specific area of interest is reached, and then ultrasound is used to burst the microbubbles, causing site-specific delivery of the bioactive materials. Furthermore, the ability of albumin-coated microbubbles to adhere to vascular regions with glycocalix damage or endothelial dysfunction is another possible mechanism to deliver drugs even in the absence of ultrasound. This review focuses on the characteristics of microbubbles that give them therapeutic properties and some important aspects of ultrasound parameters that are known to influence microbubble-mediated drug delivery. In addition, current studies involving this novel therapeutical application of microbubbles will be discussed