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Abstract Age-related cataracts is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation, and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Our study identified 101 independent genome-wide significant loci, 57 of which are novel. We identified multiple genes and biological pathways associated with the cataracts, including four drug-gene interactions. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults.

Abstract Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

Background: More physical activity and less sitting time are associated with less severe depression, but the psychological mechanisms underlying these associations remain unclear. Repetitive negative thinking (RNT) and difficulties regulating emotions are key transdiagnostic risk factors for depression and are key targets in current psychotherapies. The current study tested RNT and emotion regulation difficulties as mediators of the associations of depression with (1) physical activity and (2) sitting time. Method: We analysed data from community-dwelling adults in middle to late adulthood (aged 46–68 at baseline; N = 1189) from The Busselton Healthy Ageing Study, assessed three times across 11 years. Serial mediation models were tested cross-sectionally, prospectively, and persistently (i.e., throughout the course of the study). Results: Results indicated support for cross-sectional serial mediation for physical activity and sitting time models, but not for longitudinal models. However, RNT individually mediated the persistent sitting time-depression model. Limitations: All data was self-reported. Mediators could only be assessed at the last time point within the larger study, constraining the temporal associations that could be tested. Further studies assessing mediators across time using different methods and time intervals are needed. Conclusions: Our findings provide some initial evidence for psychological pathways by which the benefits of greater physical activity and lower sitting time may be conferred. If supported longitudinally and in experimental designs, increased physical activity and reduced sitting time may be beneficial therapeutic targets for older adults at risk for depression and/or who experience difficulties with rumination and emotion regulation.

To fully leverage “smart” transportation infrastructure data-stream investments, the creation of applications that provide real-time meaningful and actionable corridor-performance metrics is needed. However, the presence of gaps in data streams can lead to significant application implementation challenges. To demonstrate and help address these challenges, a digital twin smart-corridor application case study is presented with two primary research objectives: (1) explore the characteristics of volume data gaps on the case study corridor, and (2) investigate the feasibility of prioritizing data streams for data imputation to drive the real-time application. For the first objective, a K-means clustering analysis is used to identify similarities and differences among data gap patterns. The clustering analysis successfully identifies eight different data loss patterns. Patterns vary in both continuity and density of data gap occurrences, as well as time-dependent losses in several clusters. For the second objective, a temporal-neighboring interpolation approach for volume data imputation is explored. When investigating the use of temporal-neighboring interpolation imputations on the digital twin application, performance is, in part, dependent on the combination of intersection approaches experiencing data loss, demand relative to capacity at individual locations, and the location of the loss along the corridor. The results indicate that these insights could be used to prioritize intersection approaches suitable for data imputation and to identify locations that require a more sensitive imputation methodology or improved maintenance and monitoring.

IntroductionEvidence of the benefits of arts engagement to community wellbeing has been mounting since the 1990s. However, large scale, quantitative, epidemiological studies of the “arts–healthy aging” relationship, or the types of arts older adults voluntarily choose to engage in as part of their everyday life, for enjoyment, entertainment or as a hobby (vs. therapy or interventions) are limited. The aims of this study were to describe older adult recreational arts engagement via the Busselton Healthy Ageing Study (BHAS) cohort, and to determine if there was an association between arts engagement, general health and mental wellbeing.MethodsOverall, 2,843 older adults (born 1946–1964) from the BHAS cohort (n = 5,107) who had completed a supplementary arts survey (n = 3,055, 60%) and had data on required variables were included in this study (93% of those eligible). The dependent variable was general health (SF12) and subjective mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale, WEMWBS). The independent variable was hours engaged in recreational arts in the last 12 months. A descriptive analysis followed by a linear regression analysis was conducted.ResultsThe prevalence of recreational arts engagement in the last 12 months was 85% (mean = 132 h/year). Older adults engaged in the arts in a number of ways including attending events (79%), actively participating/making art (40%), as an arts society/club/organization member (20%), by learning about the arts (13%) or by volunteering/working in the arts (non-professional, 11%). When general health was assessed via the SF12, the average physical component score (PCS) was 50.1 (SD 8.9) and the average mental component score (MCS) was 53.6 (SD 8.3). When mental wellbeing was assessed, the average WEMWBS score was 54.9 (SD = 8.6). After adjustment for 12 demographic and lifestyle covariates, it was found that older adults who engaged in any recreational arts in the last 12 months had significantly higher WEMWBS scores and higher SF12 physical component scores than those who did not engage in the arts (0 h/year).DiscussionEvidence of an arts-health relationship was found in this study. The suitability of the arts as a population based, healthy aging strategy to influence the mental wellbeing and general health of older adults should be investigated further.

The ongoing COVID-19 pandemic has had a devastating impact on cities around the world. In this paper, we analyse city fragility and resilience through the lens of the social compact framework. This framework enables an understanding of the interplay of agreements between citizens and city, state and national governments that exist within city systems. We examine three different case studies during the COVID-19 pandemic to understand instances of fragility in developed cities and how this fragility can affect a city's capability to respond to sudden disasters or emergencies. We identify the challenges and nuances that come with attempting to address urban fragility and improve city resilience, before finally presenting robustness as a way to conceptualise complex city systems and a means to thinking about more pro-active and adaptive policy.

Background: Persistent posttraumatic symptoms (PPS) may manifest after a mild-moderate traumatic brain injury (mmTBI) even when standard brain imaging appears normal. Transcranial direct current stimulation (tDCS) represents a promising treatment that may ameliorate pathophysiological processes contributing to PPS.Objective/Hypothesis: We hypothesized that in a mmTBI population, active tDCS combined with training would result in greater improvement in executive functions and post-TBI cognitive symptoms and increased resting state connectivity of the stimulated region, i.e., left dorsolateral prefrontal cortex (DLPFC) compared to control tDCS.Methods: Thirty-four subjects with mmTBI underwent baseline assessments of demographics, symptoms, and cognitive function as well as resting state functional magnetic resonance imaging (rsfMRI) in a subset of patients (n = 24). Primary outcome measures included NIH EXAMINER composite scores, and the Neurobehavioral Symptom Inventory (NSI). All participants received 10 daily sessions of 30 min of executive function training coupled with active or control tDCS (2 mA, anode F3, cathode right deltoid). Imaging and assessments were re-obtained after the final training session, and assessments were repeated after 1 month. Mixed-models linear regression and repeated measures analyses of variance were calculated for main effects and interactions.Results: Both active and control groups demonstrated improvements in executive function (EXAMINER composite: p < 0.001) and posttraumatic symptoms (NSI cognitive: p = 0.01) from baseline to 1 month. Active anodal tDCS was associated with greater improvements in working memory reaction time compared to control (p = 0.007). Reaction time improvement correlated significantly with the degree of connectivity change between the right DLPFC and the left anterior insula (p = 0.02).Conclusion: Anodal tDCS improved reaction time on an online working memory task in a mmTBI population, and decreased connectivity between executive network and salience network nodes. These findings generate important hypotheses for the mechanism of recovery from PPS after mild-moderate TBI.

This paper presents a perspective on the role immersive technologies can play in the future of urban transformation. Specifically, this paper looks to answer the following questions – How can Augmented Reality be implemented as an enabler of civic participation in the urban transformation process? What specific and novel affordances does Augmented Reality present in this context? And how do these affordances demonstrate a unique interaction paradigm between citizens and cities? We review the current literature on future cities, urban transformation, digital civic participation and augmented reality usage to determine the current state of digitally enhanced urban transformation processes. As a result, we identify an opportunity in which recent developments in Augmented Reality technologies afford entirely new ways of approaching civic participation.We suggest new Augmented Reality technologies can be considered as a novel way to engage citizens in decision making processes and as a result improve the resilience, adaptability and sustainability of future cities. Augmented Reality can allow citizens and other stakeholders to visualise and imagine possible urban transformations, to contribute to an ongoing discussion between citizens and with city councils, and to participate in a feedback loop in which ideas are refined, analysed, and iterated in a collaborative process. We finally discuss challenges, tensions, and open issues of a research agenda aimed at developing immersive technologies for participatory urban transformation.

Viral superinfection occurs when multiple viral particles subsequently infect the same host. In nature, several viral species are found to have evolved diverse mechanisms to prevent superinfection (superinfection exclusion) but how this strategic choice impacts the fate of mutations in the viral population remains unclear. Using stochastic simulations, we find that genetic drift is suppressed when superinfection occurs, thus facilitating the fixation of beneficial mutations and the removal of deleterious ones. Interestingly, we also find that the competitive (dis)advantage associated with variations in life history parameters is not necessarily captured by the viral growth rate for either infection strategy. Putting these together, we then show that a mutant with superinfection exclusion will easily overtake a superinfecting population even if the latter has a much higher growth rate. Our findings suggest that while superinfection exclusion can negatively impact the long-term adaptation of a viral population, in the short-term it is ultimately a winning strategy.

Remdesivir is under evaluation for treatment of COVID-19 in clinical trials. Here, the authors report results of remdesivir treatment in a patient with COVID-19 and the genetic antibody deficiency XLA. They show a temporally correlated clinical and virological response, suggesting that remdesivir can reduce SARS-CoV-2 replication in patients.

Abstract Background Periprosthetic fractures are increasingly encountered in hip arthroplasty. The Vancouver classification system is widely used. Little knowledge exists regarding the association of the Vancouver classification with either cemented or uncemented stems. The aim was to analyse a series of fractures and determine associations. Methods A series of consecutive patients over 8 years was identified including only post-operative fractures of primary hip arthroplasties. Baseline and radiographic characteristics were recorded including the type of stem fixation (cemented or uncemented) and Vancouver classification. Statistical analysis was performed to determine the association of the Vancouver classification between cemented and uncemented stems. Results A total of 172 patients were identified (84 cemented stems, 88 uncemented stems). There were 30 Vancouver A fractures (12 cemented vs.18 uncemented, p > 0.05), 125 Vancouver B fractures (63 cemented vs. 62 uncemented, p > 0.05) and 17 Vancouver C fractures (9 cemented vs. 8 uncemented, p > 0.05). The Vancouver B2 fracture occurred most frequently (N = 95; 44 cemented vs. 51 uncemented, p > 0.05) and consists of four distinct fracture patterns: the previously described comminuted ‘burst’, clamshell and spiral patterns and the newly observed ‘reverse’ clamshell. The burst and spiral fracture patterns are significantly associated with cemented stems, and the clamshell pattern is significantly associated with uncemented stems. Conclusions Vancouver A, B and C fractures occur equally in cemented and uncemented stems. Awareness of four distinct Vancouver B2 fracture patterns, including the newly observed reverse clamshell, will aid surgeons in predicting stem instability.

Actinomycosis is an indolent human infectious disease caused by gram-positive anaerobic filamentous bacteria Actinomyces. Despite its sluggish growth, clinical manifestations can be acute or chronic. Over the last five decades, a significant incidence decline in the western world is due to the discovery of effective antimicrobials and improved oral hygiene. Actinomycosis is now rarely encountered and often misdiagnosed as its manifestations mimic malignancy and other infectious diseases. Due to prior use of antimicrobials, laboratory diagnostic processes often fail to isolate the organism making it arduous to establish the diagnosis. Clinical classification is based on the geographical distribution of the disease as oro-cervicofacial, thoracic, abdominopelvic, neurologic, musculoskeletal, and disseminated. Disseminated and pulmonary actinomycosis in an immunocompetent individual is extremely rare. Here we present a 53-year-old healthy male presenting with acute disseminated actinomycosis with bilateral pulmonary nodules, right upper lobe pneumonia, and pelvic osteomyelitis from Actinomyces odontolyticus infection.

Introduction We aimed to determine normal thresholds for positive bronchodilator responses for oscillometry in an Australian general population sample aged ≥40 years, to guide clinical interpretation. We also examined relationships between bronchodilator responses and respiratory symptoms, asthma diagnosis, smoking and baseline lung function. Methods Subjects recruited from Sydney, Melbourne and Busselton, Australia, underwent measurements of spirometry, resistance (Rrs6) and reactance (Xrs6) at 6 Hz, before and after inhalation of salbutamol 200 μg. Respiratory symptoms and/or medication use, asthma diagnosis, and smoking were recorded. Threshold bronchodilator responses were defined as the fifth percentile of decrease in Rrs6 and 95th percentile increase in Xrs6 in a healthy subgroup. Results Of 1318 participants, 1145 (570 female) were analysed. The lower threshold for ΔRrs6 was −1.38 cmH2O·s·L−1 (−30.0% or −1.42 Z-scores) and upper threshold for ΔXrs6 was 0.57 cmH2O·s·L−1 (1.36 Z-scores). Respiratory symptoms and/or medication use, asthma diagnosis, and smoking all predicted bronchodilator response, as did baseline oscillometry and spirometry. When categorised into clinically relevant groups according to those predictors, ΔXrs6 was more sensitive than spirometry in smokers without current asthma or chronic obstructive pulmonary disease (COPD), ∼20% having a positive response. Using absolute or Z-score change provided similar prevalences of responsiveness, except in COPD, in which responsiveness measured by absolute change was twice that for Z-score. Discussion This study describes normative thresholds for bronchodilator responses in oscillometry parameters, including intra-breath parameters, as determined by absolute, relative and Z-score changes. Positive bronchodilator response by oscillometry correlated with clinical factors and baseline function, which may inform the clinical interpretation of oscillometry.

Background: Normal airway microbial communities play a central role in respiratory health but are poorly characterized. Cigarette smoking is the dominant global environmental influence on lung function, and asthma has become the most prevalent chronic respiratory disease worldwide. Both conditions have major microbial components that are incompletely defined. Methods: We investigated airway bacterial communities in a general population sample of 529 Australian adults. Posterior oropharyngeal swabs were analyzed by sequencing of the 16S rRNA gene. The microbiota were characterized according to their prevalence, abundance and network memberships. Findings: The microbiota were similar across the general population, and were strongly organized into co-abundance networks. Smoking was associated with diversity loss, negative effects on abundant taxa, profound alterations to network structure and expansion of Streptococcus spp. By contrast, the asthmatic microbiota were selectively affected by an increase in Neisseria spp. and by reduced numbers of low abundance but prevalent organisms. Interpretation: Our study shows that the healthy airway microbiota in this population were contained within a highly structured ecosystem, suggesting balanced relationships between the microbiome and human host factors. The marked abnormalities in smokers may contribute to chronic obstructive pulmonary disease (COPD) and lung cancer. The narrow spectrum of abnormalities in asthmatics encourages investigation of damaging and protective effects of specific bacteria. Funding: The study was funded by the Asmarley Trust and a Wellcome Joint Senior Investigator Award to WOCC and MFM (WT096964MA and WT097117MA). The Busselton Healthy Ageing Study is supported by the Government of Western Australia (Office of Science, Department of Health) the City of Busselton, and private donations.

Introduction: Emergency medical services (EMS) dispatchers have made efforts to determine whether patients are high risk for coronavirus disease 2019 (COVID-19) so that appropriate personal protective equipment (PPE) can be donned. A screening tool is valuable as the healthcare community balances protection of medical personnel and conservation of PPE. There is little existing literature on the efficacy of prehospital COVID-19 screening tools. The objective of this study was to determine the positive and negative predictive value of an emergency infectious disease surveillance tool for detecting COVID-19 patients and the impact of positive screening on PPE usage. Methods: This study was a retrospective chart review of prehospital care reports and hospital electronic health records. We abstracted records for all 911 calls to an urban EMS from March 1–July 31, 2020 that had a documented positive screen for COVID-19 and/or had a positive COVID-19 test. The dispatch screen solicited information regarding travel, sick contacts, and high-risk symptoms. We reviewed charts to determine dispatch-screening results, the outcome of patients’ COVID-19 testing, and documentation of crew fidelity to PPE guidelines. Results: The sample size was 263. The rate of positive COVID-19 tests for all-comers in the state of Massachusetts was 2.0%. The dispatch screen had a sensitivity of 74.9% (confidence interval [CI], 69.21–80.03) and a specificity of 67.7% (CI, 66.91–68.50). The positive predictive value was 4.5% (CI, 4.17–4.80), and the negative predictive value was 99.3% (CI, 99.09–99.40). The most common symptom that triggered a positive screen was shortness of breath (51.5% of calls). The most common high-risk population identified was skilled nursing facility patients (19.5%), but most positive tests did not belong to a high-risk population (58.1%). The EMS personnel were documented as wearing full PPE for the patient in 55.7% of encounters, not wearing PPE in 8.0% of encounters, and not documented in 27.9% of encounters. Conclusion: This dispatch-screening questionnaire has a high negative predictive value but moderate sensitivity and therefore should be used with some caution to guide EMS crews in their PPE usage. Clinical judgment is still essential and may supersede screening status.

Cutaneous non-tuberculous mycobacterial (NTM) infections are an emerging infectious disease and require a protracted course of combination antibiotics. Antimicrobial choice is limited by resistance and toxicity. Tedizolid is a new oxazolidinone antibiotic with in vitro activity against some NTM, but its use in the management of extrapulmonary NTM has not been described. We report on the utility of prolonged tedizolid use (8 months), after linezolid intolerance, in combination therapy in a case of difficult Mycobacterium chelonae cutaneous infection. Although tedizolid contributed to clinical remission, it may have also contributed to a multifocal peripheral neuropathy. Its efficacy may also have been limited by continued immunosuppression, with evidence to suggest disease relapse or treatment failure after completion of combination therapy. Tedizolid can be considered, with caution, in combination therapy for difficult cases of cutaneous NTM infection.

Abstract Objectives An emerging field of research is examining the association of infectious and environmental pathogens with type 2 diabetes mellitus (T2DM). An understudied pathogen of interest is the protozoan parasite Toxoplasma gondii (T. gondii). The objective of this study was to investigate the possible correlation between T. gondii infection and T2DM. We conducted a systematic review and meta-analysis on the currently available T. gondii seroprevalence data from case-control studies looking at subjects with T2DM in comparison to healthy controls to estimate the risk of T2DM. Methods Ten electronic databases were searched using specific Medical Subject Headings terms without language or date restrictions. Fixed and random effects models were used to determine odds ratios with statistical significance being set at 5.0%. Results Ten publications reporting T. gondii seroprevalence from 4072 subjects met the eligibility criteria. Seven of these studies reported a significant association between T. gondii infection and T2DM (p < 0.05). The overall weighted prevalence of T. gondii infection in subjects with T2DM was 47.8% (range 6.4–65.1%) in comparison to 25.9% (range 3.2–59.0%) of healthy controls (p < 0.001). The common odds ratio, calculated using a random effects model, was 2.32 (95% CI 1.66–3.24, p < 0.001). Conclusions T. gondii infection should continue to be regarded as a possible contributing factor in T2DM disease development. Further studies that include inflammatory biomarker analysis are warranted to determine the specific role of this parasite in the pathogenesis of T2DM.

Abstract Background The primary aim was to compare the outcomes of locked plating of closed distal femur periprosthetic and non-periprosthetic fractures by testing the hypothesis that outcomes would be worse in the periprosthetic group. The secondary aim of this study was to identify risk factors for non-union. Methods A single-center study over an 8-year period utilizing a retrospective cohort design was performed. Sixty-eight patients with periprosthetic fractures and 57 patients with non-periprosthetic fractures met inclusion criteria for the study. There was a significant difference between groups in mean age (80.1 years periprosthetic vs. 70.9 years non-periprosthetic (p

The long circulating half-life and inherently bivalent architecture of IgGs provide an ideal vehicle for presenting otherwise short-lived G-protein-coupled receptor agonists in a format that enables avidity-driven enhancement of potency. Here, we describe the site-specific conjugation of a dual agonist peptide (an oxyntomodulin variant engineered for potency and in vivo stability) to the complementarity-determining regions (CDRs) of an immunologically silent IgG4. A cysteine-containing heavy chain CDR3 variant was identified that provided clean conjugation to a bromoacetylated peptide without interference from any of the endogenous mAb cysteine residues. The resulting mAb-peptide homodimer has high potency at both target receptors (glucagon receptor, GCGR, and glucagon-like peptide 1 receptor, GLP-1R) driven by an increase in receptor avidity provided by the spatially defined presentation of the peptides. Interestingly, the avidity effects are different at the two target receptors. A single dose of the long-acting peptide conjugate robustly inhibited food intake and decreased body weight in insulin resistant diet-induced obese mice, in addition to ameliorating glucose intolerance. Inhibition of food intake and decrease in body weight was also seen in overweight cynomolgus monkeys. The weight loss resulting from dosing with the bivalently conjugated dual agonist was significantly greater than for the monomeric analog, clearly demonstrating translation of the measured in vitro avidity to in vivo pharmacology.

An emerging field of research is starting to examine the association of infectious pathogens with type 2 diabetes mellitus (T2DM). An understudied parasite of interest is Toxoplasma gondii. Globally, very few studies have been conducted to investigate this association. Additionally, very little data exists on the prevalence of T. gondii in the general Australian population. Our group sought to determine the prevalence, association, and risk factors between T. gondii infection and T2DM from a representative Australian human population. Through a cross-sectional, age- and gender-matched case-control study, 150 subjects with T2DM together with 150 control subjects from the Busselton Health Study cohort were investigated. Sera samples were tested for the presence of anti-T. gondii IgG and IgM antibodies using enzyme-linked immunosorbent assays. Survey-derived data were also analyzed to evaluate associated risk factors. The IgG seroprevalence was found to be 62% and 66% for the T2DM and control groups, respectively (OR:0.84; p=0.471). IgM antibodies were detected in 5% of the T2DM patients and in 10% of the controls (OR=0.51; p=0.135). There were no significant differences between male and female IgG seroprevalence rates for both groups (OR:0.88, 0.80; p=0.723). The IgG seropositivity rate increased significantly in T2DM patients aged 45-84 years in comparison to those aged 18-44 years (p

Greater understanding of factors influencing the maturation of antibody responses against pneumococcal polysaccharides (PcPs) may improve pneumococcal vaccination strategies. Although PcPs are type 2 T cell-independent antigens thought not to induce follicular immune responses, we have previously shown that IgG2 antibody responses against antigens in the 23-valent unconjugated PcP vaccine (PPV23) are associated with expansion of ICOS+ circulating T follicular helper (cTFH) cells in HIV seronegative subjects but not HIV patients. As IL-7Rα signaling in CD4+ T cells may affect TFH cell function and is adversely affected by HIV-1 infection, we have examined the relationship of IL-7Rα expression on ICOS+ cTFH cells with PcP-specific IgG2 antibody responses. PPV23 vaccination was undertaken in HIV patients receiving antiretroviral therapy (n = 25) and HIV seronegative subjects (n = 20). IL-7Rα expression on ICOS+ and ICOS− cTFH cells was assessed at day(D) 0, 7, and 28. Fold increase between D0 and D28 in serum IgG1 and IgG2 antibodies to PcP serotypes 4, 6B, 9V, and 14 and the frequency of IgG1+ and IgG2+ antibody secreting cells (ASCs) at D7 were also assessed. Decline in IL-7Rα expression on ICOS+ cTFH cells between D0 and D7 occurred in 75% of HIV seronegative subjects and 60% of HIV patients (Group A), with changes in IL-7Rα expression being more pronounced in HIV patients. Group A patients exhibited abnormally high IL-7Rα expression pre-vaccination, an association of serum IgG2, but not IgG1, antibody responses with a decline of IL-7Rα expression on ICOS+ cTFH cells between D0 and D7, and an association of higher IgG2+ ASCs with lower IL-7Rα expression on ICOS+ cTFH cells at D7. As decline of IL-7Rα expression on CD4+ T cells is an indicator of IL-7Rα signaling, our findings suggest that utilization of IL-7 by cTFH cells affects production of IgG2 antibodies to PPV23 antigens in some HIV patients.

Reaction-diffusion waves have long been used to describe the growth and spread of populations undergoing a spatial range expansion. Such waves are generally classed as either pulled, where the dynamics are driven by the very tip of the front and stochastic fluctuations are high, or pushed, where cooperation in growth or dispersal results in a bulk-driven wave in which fluctuations are suppressed. These concepts have been well studied experimentally in populations where the cooperation leads to a density-dependent growth rate. By contrast, relatively little is known about experimental populations that exhibit density-dependent dispersal. Using bacteriophage T7 as a test organism, we present novel experimental measurements that demonstrate that the diffusion of phage T7, in a lawn of host E. coli, is hindered by steric interactions with host bacteria cells. The coupling between host density, phage dispersal, and cell lysis caused by viral infection results in an effective density-dependent diffusion coefficient akin to cooperative behavior. Using a system of reaction-diffusion equations, we show that this effect can result in a transition from a pulled to pushed expansion. Moreover, we find that a second, independent density-dependent effect on phage dispersal spontaneously emerges as a result of the viral incubation period, during which, phage is trapped inside the host unable to disperse. Additional stochastic agent-based simulations reveal that lysis time dramatically affects the rate of diversity loss in viral expansions. Taken together, our results indicate both that bacteriophage can be used as a controllable laboratory population to investigate the impact of density-dependent dispersal on evolution, and that the genetic diversity and adaptability of expanding viral populations could be much greater than is currently assumed.

Often referred to as ‘The Great Mimicker’, syphilis infections have been on the rise since 2000 including cases of primary and secondary syphilis where 19,999 were reported in the USA in 2014. ​​The increase in cases has led the USPSTF to recommend screening for syphilis infection in persons who are at increased risk of infection. ​​Changes in screening and re-emergence of the disease necessitates review of the multitude of circumstances a patient can present for care. Immunocompetent patients begin to show classic symptoms within 10–90 days following infection with the spirochete. In the immunocompromised patient, the presenting symptoms are often atypical and more complex. With the rise in HIV infections, syphilitic infections have become increasingly common worldwide and several atypical presentations have been observed. ​​The following case is an atypical presentation of syphilis involving both central and peripheral nervous system findings in a patient without significant medical history.

Type 2 diabetes mellitus (T2DM) continues to be a major challenge for public health authorities worldwide. While potential causes such as obesity, physical inactivity, and dietary patterns have been proposed to explain the growing epidemic, there may also be unidentified environmental determinants. An emerging field of research is starting to examine the association of infectious and environmental pathogens with diabetes. In particular, the potential of these pathogens to cause low-grade inflammation that facilitates the risk and development of T2DM. An understudied pathogen of potential interest is the protozoan parasite Toxoplasma gondii (T. gondii). There is limited clinical evidence supporting the association between chronic T. gondii infection and the development of many disorders, including T2DM, in both animals and humans. This review (1) addresses the existing knowledge of the role of T. gondii in the inflammation process leading to T2DM, (2) examines the current studies describing the relationship between T. gondii and T2DM, and (3) makes recommendations for future studies to determine the role of T. gondii in the pathogenesis of T2DM. We believe that T. gondii may be an important target for T2DM intervention, and propose a new field of study, “toxoplasmic type 2 diabetes.”

We show that the interaction potential between sterically stabilized, nearly hard-sphere [poly(methyl methacrylate)–poly(lauryl methacrylate) (PMMA-PLMA)] colloids at a water-oil interface has a negligible unscreened-dipole contribution, suggesting that models previously developed for charged particles at liquid interfaces are not necessarily applicable to sterically stabilized particles. Interparticle potentials, U(r), are extracted from radial distribution functions [g(r), measured by fluorescence microscopy] via Ornstein-Zernike inversion and via a reverse Monte Carlo scheme. The results are then validated by particle tracking in a blinking optical trap. Using a Bayesian model comparison, we find that our PMMA-PLMA data is better described by a screened monopole only rather than a functional form having a screened monopole plus an unscreened dipole term. We postulate that the long range repulsion we observe arises mainly through interactions between neutral holes on a charged interface, i.e., the charge of the liquid interface cannot, in general, be ignored. In agreement with this interpretation, we find that the interaction can be tuned by varying salt concentration in the aqueous phase. Inspired by recent theoretical work on point charges at dielectric interfaces, which we explain is relevant here, we show that a screened 1/r^{2} term can also be used to fit our data. Finally, we present measurements for poly(methyl methacrylate)–poly(12-hydroxystearic acid) (PMMA-PHSA) particles at a water-oil interface. These suggest that, for PMMA-PHSA particles, there is an additional contribution to the interaction potential. This is in line with our optical-tweezer measurements for PMMA-PHSA colloids in bulk oil, which indicate that they are slightly charged.

Dysfunction of T follicular-helper (TFH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS+ and ICOS- circulating memory TFH (cmTFH) cells (CD4+CD45RA-CD27+CXCR5+PD-1+) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM+ and IgG+ memory B cells at D0. In HIV seronegative subjects, production of IgG1+ and IgG2+ ASCs was consistently associated with the frequency of ICOS+ cmTFH cells but not ICOS- cmTFH cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS+ cmTFH cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 antibodies at D28 also correlated with ICOS+ cmTFH cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS+ cmTFH cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that TFH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients.

CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160–500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.

Mismatch negativity (MMN) is a scalp-recorded electrical potential that occurs in humans in response to an auditory stimulus that defies previously established patterns of regularity. MMN amplitude is reduced in people with schizophrenia. In this study, we aimed to develop a robust and replicable rat model of MMN, as a platform for a more thorough understanding of the neurobiology underlying MMN. One of the major concerns for animal models of MMN is whether the rodent brain is capable of producing a human-like MMN, which is not a consequence of neural adaptation to repetitive stimuli. We therefore tested several methods that have been used to control for adaptation and differential exogenous responses to stimuli within the oddball paradigm. Epidural electroencephalographic electrodes were surgically implanted over different cortical locations in adult rats. Encephalographic data were recorded using wireless telemetry while the freely-moving rats were presented with auditory oddball stimuli to assess mismatch responses. Three control sequences were utilized: the flip-flop control was used to control for differential responses to the physical characteristics of standards and deviants; the many standards control was used to control for differential adaptation, as was the cascade control. Both adaptation and adaptation-independent deviance detection were observed for high frequency (pitch), but not low frequency deviants. In addition, the many standards control method was found to be the optimal method for observing both adaptation effects and adaptation-independent mismatch responses in rats. Inconclusive results arose from the cascade control design as it is not yet clear whether rats can encode the complex pattern present in the control sequence. These data contribute to a growing body of evidence supporting the hypothesis that rat brain is indeed capable of exhibiting human-like MMN, and that the rat model is a viable platform for the further investigation of the MMN and its associated neurobiology.

Mice affected by a spontaneous mutation which arose within our colony exhibited a neuromuscular phenotype involving tremor and characteristic stretching of the rear limbs. The mutant, named stretcher, was used to breed a backcross cohort for genetic mapping studies. The gene responsible for the mutant phenotype was mapped to a small region on mouse chromosome 15, with a LOD score above 20. Candidate genes within the region included the Ndrg1 gene. Examination of this gene in the mutant mouse strain revealed that exons 10 to 14 had been deleted. Mutations in the human orthologue are known to result in Charcot-Marie-Tooth disease type 4D (CMT4D) a severe early-onset disorder involving Schwann cell dysfunction and extensive demyelination. The stretcher mutant mouse is more severely affected than mice in which the Ndrg1 gene had been knocked out by homologous recombination. Our results demonstrate that the Ndrg1str mutation provides a new model for CMT4D, and demonstrate that exons 10 to 14 of Ndrg1 encode amino acids crucial to the appropriate function of Ndrg1 in the central nervous system.

The Dynamic Data Driven Application Systems (DDDAS) concept is examined in the context of monitoring and managing surface transportation systems in day-to-day and emergency scenarios. An approach to predicting future system states termed ad hoc distributed simulations is described. This approach uses on-line distributed simulation models that can incorporate real-time data and utilizes rollback operations to update state predictions as new information becomes available. This paper focuses on examining the reliability of ad hoc distributed simulations in mobile computing environments, and specifically, assessing the accuracy of future state predictions in the face of unreliable communications.