Alginate-based artificial antigen presenting cells expand functional CD8+ T cells with memory characteristics for adoptive cell therapy.

The development of artificial Antigen Presenting Cells (aAPCs) has led to improvements in adoptive T cell therapy (ACT), an immunotherapy, for cancer treatment. aAPCs help to streamline the consistent production and expansion of T cells, thus reducing the time and costs associated with ACT. However, several issues still exist with ACT, such as insufficient T cell potency, which diminishes the translational potential for ACT. While aAPCs have been used primarily to increase production efficiency of T cells for ACT, the intrinsic properties of a biomaterial-based aAPC may affect T cell phenotype and function. In CD8+ T cells, reactive oxygen species (ROS) and oxidative stress accumulation can activate Forkhead box protein O1 (FOXO1) to transcribe antioxidants which reduce ROS and improve memory formation. Alginate, a biocompatible and antioxidant rich biomaterial, is promising for incorporation into an aAPC formulation to modulate T cell phenotype. To investigate its utility, a novel alginate-based aAPC platform was developed that preferentially expanded CD8+ T cells with memory related features. Alginate-based aAPCs allowed for greater control of CD8+ T cell qualities, including, significantly improved in vivo persistence and augmented in vivo anti-tumor T cell responses.

Adverse selection and consumer inertia: empirical evidence from the Dutch health insurance market.

This paper examines to what extent consumer inertia can reduce adverse selection in health insurance markets. To this end, we investigate consumer choice of deductible in the Dutch health insurance market over the period 2013-2018, using panel data based on a large random sample (266 k) of all insured individuals in the Netherlands. The Dutch health insurance market offers a unique setting for studying adverse selection, because during annual open enrollment periods all adults are free to choose an extra deductible up to 500 euro per year. By focusing on deductible choices of those who do not switch health plans, we are able to examine the 'pure' adverse selection effect (i.e., not distorted by other health plan attributes). We estimate a dynamic logit model to examine individuals' deductible choice. We find evidence of adverse selection, as people with higher previous health care cost are substantially less likely to take up or keep a 500-euro deductible. We also find that adverse selection is counteracted by a high level of consumer inertia, as the average partial effect on deductible choice of the previous selected deductible level is much larger than the average partial effect of a change in health care costs.

You can bring plankton to fecal indicator organisms, but you cannot make the plankton graze: particle contribution to E. coli and MS2 inactivation in surface waters.

Organisms that are associated with feces ("fecal indicator organisms") are monitored to assess the potential for fecal contamination of surface water bodies in the United States. However, the effect of the complex mixtures of chemicals and the natural microbial community within surface water ("particles") on fecal indicator organism persistence is not well characterized. We aimed to better understand how particles, including biological (e.g., potential grazers) and inert (e.g., minerals) types, affect the fecal indicator organisms Escherichia coli K-12 ("E. coli") and bacteriophage MS2 in surface waters. A gradient of particles captured by a 0.2-µm-pore-size filter ("large particles") was generated, and the additional particles and dissolved constituents that passed through the filter were deemed "small particles." We measured the ratio of MS2 and E. coli that survived over a 24-h incubation period for each condition (0%-1,000% large-particle concentration in raw water) and completed a linear regression that included large- and small-particle coefficients. Particles were characterized by quantifying plankton, total bacterial cells, and total solids. E. coli and MS2 persistence was not significantly affected by large particles, but small particles had an effect in most waters. Small particles in higher-salinity waters had the largest, negative effect on E. coli and MS2 survival ratios: Significant small-particle coefficients ranged from -1.7 to -5.5 day-1 in the marine waters and -0.89 to -3.2 day-1 in the fresh and estuarine waters. This work will inform remediation efforts for impaired surface water bodies.IMPORTANCEMany surface water bodies in the United States have organisms associated with fecal contamination that exceed regulatory standards and prevent safe recreation. The process to remediate impaired water bodies is complicated because these fecal indicator organisms are affected by the local environmental conditions. For example, the effect of particles in surface water on fecal indicator concentrations are difficult to quantify in a way that is comparable between studies and water bodies. We applied a method that overcomes this limitation to assess the effects of large particles, including natural plankton that could consume the seeded fecal indicator organisms. Even in environmental water samples with diverse communities of plankton present, no effect of large particles on fecal indicator concentrations was observed. These findings have implications for the interpretation and design of future studies, including that particle characterization of surface water may be necessary to assess the fate of fecal indicators.

Not all types of depressed patients who persist with their antidepressant treatment improve in side effect complaints: A comparison of treatment completers and dropouts in the STAR*D trial.

INTRODUCTION: There is a "traditional belief" that antidepressant side effect complaints improve with medication persistence; however, support for this theory has remained inconclusive. We aimed to examine if side effect complaints improved over time by modeling the relationship between side effect complaints and time at dropout for patients receiving citalopram during the first level of acute treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHODS: We categorized the 2833 patients into five patterns by week of dropout. We used pattern-mixture modeling to model change in side effect complaints (frequency, intensity, and burden) over the 12-week course of treatment, while accounting for attrition and depressive severity. Using post-hoc linear contrasts, we compared the attrition patterns with the completers' pattern for severity of side effect complaints at each respective last visit prior to dropout as well as averaged side effect complaints across the duration of treatment. We also reported frequencies and tolerability of side effects for nine organ/function systems over the course of treatment. RESULTS: Patients who dropped out early exhibited worsening side effect burden and patients who dropped out later showed improvements in side effect frequency and intensity. Treatment completers improved in all side effect complaints over the course of treatment. Early attrition patterns had more severe side effect complaints for both tests of post-hoc linear contrasts than later attrition patterns and completers. CONCLUSIONS: Side effect complaints from antidepressant treatment improve over time, but only for some types of patients. As a precaution for early dropout, clinicians should monitor patients who exhibit worsening and more severe side effect complaints-especially in the first 6 weeks of antidepressant treatment. In addition, clinicians may want to consider changing the type of treatment early on for these patients, rather than encouraging them to persist with their current medication.

Maintaining exercise in fitness centre settings: insights from the physical activity maintenance theory.

PURPOSE: This study examines factors that influence long-term fitness centre participation, applying the Physical Activity Maintenance Theory to assess psychological and contextual influences on exercise adherence. METHODS: Semi-structured interviews were conducted with 17 regular fitness centre attendees in Taubaté, São Paulo, Brazil. Data were analysed using Bardin's Content Analysis, exploring the participants' experiences and the factors contributing to their sustained activity. RESULTS: Autonomous motivation, such as enjoyment and satisfaction from workouts, along with self-efficacy, emerged as crucial for continued fitness centre attendance. The environment, including ambiance, social support, and facility quality, significantly impacted exercise persistence. However, challenges like time constraints, weather conditions, and personal issues occasionally hindered engagement. The study also highlights the role of personalized fitness programmes in supporting long-term adherence, suggesting that tailoring these programmes to individual goals could further enhance commitment. CONCLUSIONS: The findings underscore the importance of fitness centres creating environments that align with individual needs and preferences. Customized programmes that cater to both personal and communal needs could bolster long-term adherence. Future research should explore the impact of personalized, community-integrated fitness approaches on sustaining active lifestyles, emphasizing the importance of accommodating individual preferences in maintaining regular exercise habits.

Relevance of charged and polar amino acids for functionality of membrane toxin TisB.

Bacterial dormancy is marked by reduced cellular activity and the suspension of growth. It represents a valuable strategy to survive stressful conditions, as exemplified by the long-term tolerance towards antibiotics that is attributable to a fraction of dormant cells, so-called persisters. Here, we investigate the membrane toxin TisB (29 amino acids) from the chromosomal toxin-antitoxin system tisB/istR-1 in Escherichia coli. TisB depolarizes the inner membrane in response to DNA damage, which eventually promotes a stress-tolerant state of dormancy within a small fraction of the population. Using a plasmid-based system for moderate tisB expression and single amino acid substitutions, we dissect the importance of charged and polar amino acids. We observe that the central amino acids lysine 12 and glutamine 19 are of major importance for TisB functionality, which is further validated for lysine 12 in the native context upon treatment with the DNA-damaging antibiotic ciprofloxacin. Finally, we apply a library-based approach to test additional TisB variants in higher throughput, revealing that at least one positive charge at the C-terminus (either lysine 26 or 29) is mandatory for TisB-mediated dormancy. Our study provides insights into the molecular basis for TisB functionality and extends our understanding of bacterial membrane toxins.

Mechanistic concepts involved in biofilm associated processes of Campylobacter jejuni: persistence and inhibition in poultry environments.

Campylobacter species, predominantly Campylobacter jejuni, remains a significant zoonotic pathogen worldwide, with the poultry sector being the primary vector for human transmission. In recent years. there has been a notable rise in the incidence of human campylobacteriosis, necessitating a deeper understanding of the pathogen's survival mechanisms and transmission dynamics. Biofilm presence significantly contributes to C. jejuni persistence in poultry and subsequent food product contamination, and this review describes the intricate processes involved in biofilm formation. The ability of Campylobacter to form biofilms on various surfaces, including stainless steel, plastic, and glass, is a critical survival strategy. Campylobacter biofilms, with their remarkable resilience, protect the pathogen from environmental stresses such as desiccation, pH extremes, biocides and sanitizing agents. This review explores the molecular and genetic mechanisms of C. jejuni biofilm formation, highlighting regulatory genes involved in motility, chemotaxis, and stress responses. Flagellar proteins, particularly flaA, flaB, flaG, and adhesins like cadF and flpA, are identified as the main molecular components in biofilm development. The role of mixed-species biofilms, where C. jejuni integrates into existing biofilms of other bacteria to enhance pathogen resilience, is also discussed. This review also considers alternative interventions to control C. jejuni in poultry production, in the context of increasing antibiotic resistance. It explores the effectiveness of prebiotics, probiotics, synbiotics, bacteriocins, bacteriophages, vaccines, and organic acids, with a focus on their mechanisms of action in reducing bacterial colonization and biofilm formation. Studies show that mixtures of organic acids and compounds like Carvacrol and Eugenol significantly downregulate genes linked with motility and adhesion, thereby disrupting biofilm integrity. It discusses the impact of environmental factors, such as temperature and oxygen levels on biofilm formation, providing insights into how industrial conditions can be manipulated to reduce contamination. This paper stresses the need for a multifaceted approach to control Campylobacter in poultry, integrating molecular and genetic insights with practical interventions. By advancing our understanding of biofilm dynamics and gene regulation, we aim to inform the development of more effective strategies to enhance food safety and protect public health.

Immunogenicity and immune persistence of Zagreb 2-1-1 regimen of rabies vaccine in Chinese healthy individuals: A randomized, parallel-controlled of homologous vaccine with different immune procedure study.

This study was a randomized, parallel-controlled of homologous vaccines with different immune procedure research to evaluate the immunogenicity and immune persistence of Zagreb 2-1-1 regimen of rabies vaccine in Chinese healthy individuals. 240 subjects aged ≤ 20、21-50、≥51 y were randomly divided into 2 groups (1:1), Zagreb 2-1-1 regimen receivers as experimental group and Essen 5 regimen receivers as controlled group. Researchers collected venous blood of each subject before vaccine injection and on the day 7, 14, 42, 180, 365 after first dose. The immunogenicity and immune persistence was assessed by neutralizing antibody. The positive rate of neutralizing antibody in experimental group was 14.53% on the 7th day, and raised to 100% on the 14th day. It showed no significant difference between experimental and controlled group (P>0.05). Either in experimental or controlled group, GMC of neutralizing antibody was up to the peak on the 14th day, and it showed no significant difference between two groups (P>0.05). On the 42nd day, the antibody positive rate remained 100% with both Zagreb 2-1-1 and Essen 5 regimens, and the GMC of antibodies also remained high level. Then, on the 180th and 365th day with both regimens, the GMC of antibodies dropped dramatically, although it remained above the protective level of 0.5 IU/ml, the positive rates dropped to 84.40% and 84.11% (on the 180th day), and 61.29% and 58.62% (on the 365th day). Rabies vaccine injected by Zagreb 2-1-1 regimen can produce neutralizing antibody fastly and perdurably.Registration: ClinicalTrials.gov #NCT01821911and NCT01827917.

The Persistence of Traditional Healing for Mental Illness Among the Korekore People in Rushinga District, Zimbabwe.

Despite concerted attempts by colonial governments to stamp out traditional healing practices, the Korekore-speaking Shona people have continued to seek healing for mental illness from traditional healers in present-day Zimbabwe. In this article, I discuss the health-seeking trajectories of Korekore people when confronted with mental illness, particularly when and why they seek out traditional healing, and the role that traditional healers play in the quest for therapy.

Real world evidence on the effectiveness and safety of tofacitinib in ulcerative colitis in Lebanon.

OBJECTIVE: To evaluate the effectiveness and safety of tofacitinib in patients with ulcerative colitis (UC) in clinical practice in Lebanon. DESIGN: This was a retrospective cross-sectional study. The data were collected from hospital records. Patients with moderate to severe UC treated with tofacitinib between 2018 and 2021 were included. Patients' demographics, disease-specific characteristics, clinical assessment at three time points (8, 26, and 52 weeks), endoscopic evaluation at 24 weeks, and adverse events were collected. RESULTS: A total of 60 UC patients with a mean duration of disease of 7.9 ± 4.7 years were enrolled. 61.7% of patients had extensive disease, and 58.3% had received ≥ 1 biologic prior to tofacitinib. Clinical remission was reported in 25, 34, and 31 patients (41.7%, 56.7%, and 56.4%) at 8, 26, and 52 weeks respectively. Endoscopic remission (endoscopic Mayo score 0 or 1) was observed in 58.3% of patients at 52 weeks. About one-third of patients (31.7%) stopped tofacitinib at one year, primarily for lack of efficacy or loss of response, with no significant difference between biologics-naïve and experienced patients (24% vs. 37.1% respectively). No serious adverse events or deaths were reported. Adverse events were reported in 3 patients (5.0%) - one C. difficile infection, one case of reversible lymphopenia, and one case of facial acne. No serious adverse events or deaths were noted. On multivariate analysis, biologic-naïve status and reduction or normalization of CRP were associated with clinical remission (OR = 10.87, 95% CI = 1.57, 100, and OR = 78.47, 95% CI = 2.09, 2940.32 respectively), while reduction or normalization of CRP was associated with endoscopic remission at 1 year (OR = 19.03, 95% CI = 1.64, 221.09). CONCLUSION: Tofacitinib was effective in the treatment of moderately severe ulcerative colitis in this real-world cohort in Lebanon. Further, the predictors associated with clinical and endoscopic remissions were found to be biologic-naïve status and reduction in CRP. Observed AEs were consistent with the known safety profile. One of the major limitations of this study is the smaller sample size and the retrospective nature of the study.

Transfer and persistence of intruder DNA within an office after reuse by owner.

The heightened sensitivity of DNA typing techniques, paired with the extensive use of trace DNA in forensic investigations, has resulted in an increased need to understand how and when DNA is deposited on surfaces of interest. This study focussed on the transfer, persistence, and prevalence of trace DNA in a single occupation of an office space by an intruder, when all contacts made during occupation and for the two hours prior and post occupation were known. The extent to which DNA could be recovered from contacted/not contacted surfaces was investigated. This study investigates the impacts of these movements and use of an office space when the duration of occupancy, surface contact histories and shedder status of participants are known. Contacts were documented and surfaces in the office space were targeted for sampling. Categories were set for target sampling that included different types of contact. Direct and indirect DNA transfer was detected in 55 % and 6 % of samples, respectively. Contactless DNA transfer was detected in 0.5 % of samples. The owner was observed as the sole/major/majority contributor in 77 % of the samples and as minor contributor in 10 % of samples. The intruder was observed as the sole/major/majority contributor in 14 % of samples and as the minor contributor in 16 %. An increased number of contacts increased the relative DNA contribution of the individual making the contact, however, not all observed direct contacts resulted in detectable DNA transfer. The outcome of this study will aid in better sample targeting strategies and contribute to the pool of data assisting in the development of activity level assessments.

Phosphorylation of VapB antitoxins affects intermolecular interactions to regulate VapC toxin activity in Mycobacterium tuberculosis.

Toxin-antitoxin modules are present in many bacterial pathogens. The VapBC family is particularly abundant in members of the Mycobacterium tuberculosis complex, with 50 modules present in the M. tuberculosis genome. In type IIA modules, the VapB antitoxin protein binds to and inhibits the activity of the co-expressed cognate VapC toxin protein. VapB proteins may also bind to promoter region sequences and repress the expression of the vapB-vapC operon. Though VapB-VapC interactions can control the amount of free VapC toxin in the bacterial cell, the mechanisms that affect this interaction are poorly understood. Based on our recent finding of Ser/Thr phosphorylation of VapB proteins in M. tuberculosis, we substituted phosphomimetic or phosphoablative amino acids at the phosphorylation sites of two VapB proteins. We found that phosphomimetic substitution of VapB27 and VapB46 resulted in decreased interaction with their respective cognate VapC proteins, whereas phosphoablative substitution did not alter binding. Similarly, we determined that phosphomimetic substitution interfered with VapB binding to promoter region DNA sequences. Both decreased VapB-VapC interaction and decreased VapB repression of vapB-vapC operon transcription would result in increased free VapC in the M. tuberculosis cell. In growth inhibition experiments, M. tuberculosis strains expressing vapB46-vapC46 constructs containing a phosphoablative vapB mutation resulted in lower toxicity compared to a strain expressing native vapB46, whereas similar or greater toxicity was observed in the strain expressing the phosphomimetic vapB mutation. These results identify a novel mechanism by which VapC toxicity activity can be regulated by VapB phosphorylation.IMPORTANCEIntracellular bacterial toxins are present in many bacterial pathogens and have been linked to bacterial survival in response to stresses encountered during infection. The activity of many toxins is regulated by a co-expressed antitoxin protein that binds to and sequesters the toxin protein. The mechanisms by which an antitoxin may respond to stresses to alter toxin activity are poorly understood. Here, we show that antitoxin interactions with its cognate toxin and with promoter DNA required for antitoxin and toxin expression can be altered by Ser/Thr phosphorylation of the antitoxin and, thus, affect toxin activity. This reversible modification may play an important role in regulating toxin activity within the bacterial cell in response to signals generated during infection.

Evaluation of rimegepant utilization patterns and patient characteristics among new users: a United States administrative claims-based study.

OBJECTIVE: To assess tablet utilization patterns and describe pre-treatment characteristics among new users of rimegepant. BACKGROUND: Rimegepant is the only oral calcitonin gene-related peptide antagonist approved in the United States for both the acute and preventive treatment of migraine. METHODS: We conducted a retrospective cohort study of people with migraine who initiated treatment with rimegepant using two US commercial claims databases (MarketScan and Optum). Patients (≥18 years old) with migraine who newly initiated rimegepant were included. Patients were stratified into two groups representing acute (quantity = 8) and prevention (quantity = 15 or 16) use cohorts. Baseline characteristics and medication use history were assessed on index and during the 365-day pre-index period. Rimegepant utilization periods were calculated based on days supplied and varying approaches to define use periods. Tablet quantity per 30 days was reported separately for both acute and prevention cohorts. RESULTS: In MarketScan, a total of 14,037 rimegepant users were identified; 11,195 (79.8%) in the acute group and 1,880 (13.4%) in the prevention group. Rimegepant utilization for acute use was 4.9 ± 2.1 tablets per 30 days and for preventive use was 13.1 ± 7.7 tablets per 30 days. There was high baseline prevalence of triptan contraindications, warnings, and high cardiovascular risk, with a combined 46.2% meeting one or more of these criteria. Acute medication overuse was also common (25.1%) prior to rimegepant initiation. Results were consistent in the Optum database. CONCLUSION: Our analysis provides the first real-world data available on tablet utilization and characteristics of new users of rimegepant.

There is little information available on the characteristics of people with migraine who start to use rimegepant, which is the only medicine approved for both the prevention of migraine attacks and the acute treatment of migraine attacks after they have started. Information on new users of rimegepant at least 18 years of age was obtained from two commercial databases of US healthcare claims (MarketScan and Optum). The researchers used this information to evaluate people's age, sex, pre-existing illnesses, and prior use of migraine medications at the time they started using rimegepant, and they also used several different methods to estimate how often people used rimegepant after treatment was started. The MarketScan database contained information on 14,037 people with migraine who started using rimegepant, with this group having an average age of 43 years and being comprised mostly of females (88%). Prior to starting rimegepant, almost half (46%) of the people were considered to have high cardiovascular risk and 25% considered at risk of overusing acute migraine medications. Most of the 14,037 people (80%) who started rimegepant used it to treat migraine attacks after they started and this group used approximately 5 tablets every month. The smaller number of people who used rimegepant to prevent migraine attacks used approximately 13 tablets every month. The information obtained from the Optum database was similar to that obtained from the MarketScan database. The researchers' analysis is the first to describe the characteristics of people with migraine who start to use rimegepant outside the setting of a controlled clinical trial. Their results show that new users of rimegepant represent a complex population with a significant profile of pre-existing illness and a diverse treatment history.

Uptake and Persistence of Safer Conception Strategies Among South African Women Planning for Pregnancy.

Safer conception strategies can minimize HIV acquisition during periconception periods among women living in HIV-endemic areas. We examined uptake and predictors of persistent use of the same safer conception strategy among a cohort of HIV-uninfected South African women ages 18-35 years planning for pregnancy with a partner living with HIV or of unknown HIV-serostatus. The safer conception strategies we evaluated included oral PrEP, condomless sex limited to peak fertility, and waiting for a better time to have a child (until, for example, the risks of HIV acquisition are reduced and/or the individual is prepared to care for a child); persistence was defined as using the same safer conception strategy from the first visit through 9 months follow-up. Modified Poisson regression models were used to examine predictors of persistent use of the same strategy. The average age of 227 women in our cohort was 24.6 (range: 18.0, 35.7) years. In this cohort, 121 (74.2%) women reported persisting in the same strategy through 9 months. Employment and HIV knowledge were associated with the persistent use of any strategy. Our results highlight the need to provide safer conception services to women exposed to HIV during periconception periods. Findings also offer some insights into factors that might influence persistent use. Further research is needed to better understand how to involve male partners and how their involvement might influence women's consistent use of safer conception strategies during periconception periods.

Antibiotic heteroresistance and persistence: an additional aid in hospital acquired infections by Enterococcus spp.?

Enterococcus, particularly E. faecium and E. faecalis, are responsible for many hospital-acquired infections. With their intrinsic antibiotic resistance and ability to form biofilms, enterococcal infections are already challenging to manage. However, when heterogenous populations are present, such as those exhibiting heteroresistance and persistence, the complexity of these infections increases exponentially not only due to their treatment but also due to their difficult diagnosis. In this study, we provide a summary of the current understanding of both heteroresistance and persistence in terms of mechanisms, diagnosis and treatment and subsequently review recent literature pertaining to these susceptibility types specifically in enterococci.

Some bacteria are common causes of illness among hospital patients. Some of these infections are very difficult to treat, as the bacteria can respond differently to antibiotics. This review looks at how a type of bacteria called Enterococcus can respond differently to antibiotics, and how we can diagnose or kill them more easily.

Salvage hysterectomy for persistent residual cervical cancer: assessment of prognostic factors.

In this multicenter retrospective cohort study of 99 patients who underwent salvage hysterectomy for residual disease in the uterine cervix following the completion of definitive radiotherapy for cervical cancer across 25 Japan Clinical Oncology Group-affiliated centers from 2005-2014, (i) time duration from the completion of definitive radiotherapy to the diagnosis of residual disease in the uterine cervix, (ii) salvage hysterectomy surgical margin status, and (iii) extent of residual disease, were independently associated with progression-free survival (PFS). Specifically, (i) time duration to identify residual disease of >62 days was associated with decreased PFS compared to ≤62 days (4-year rates 21.8% vs. 55.0%, adjusted-hazard ratio [aHR]=2.69, 95% confidence interval [CI]=1.55-4.67); (ii) presence of tumor in the surgical margin of hysterectomy specimen was associated with 4 times increased risk of disease progression compared to tumor-free surgical margin (4-year PFS rates 0% vs. 45.3%, aHR=4.27, 95% CI=2.20-8.29); and (iii) hazards of disease progression was 4.5-fold increased when the residual disease extended beyond the uterine cervix compared to residual disease within the uterine cervix only (4-year PFS rates 11.1% vs. 50.6%, aHR=4.54, 95% CI=2.60-7.95). In the absence of these 3 prognostic factors, 4-year PFS rate reached nearly 80% (78.6%, SAL-HYS criteria). In sum, these data suggested that early detection of persistent, residual disease following definitive radiotherapy for cervical cancer may be the key to improve survival if salvage hysterectomy is considered as a tailored treatment option. Ideal surgical candidate would be uterine cervix-contained disease and assurance of adequate tumor-free surgical margin.

Potential role of alveolar macrophages in HIV persistence and lung disease.

While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancies, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH support a higher burden of multimorbidity, including pulmonary diseases of both an infectious and non-infection nature, which may be a consequence of the formation of HIV reservoirs. Their gut, lymph nodes, brain, testes and lungs constitute important anatomic sites for the reservoirs. While CD4+ T cells, and particularly memory CD4+ T cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor HIV infection. AM are the most abundant cells in bronchoalveolar (BAL) fluid in healthy conditions, and act as sentinels in the alveolar space by patrolling and clearing debris, microbes and surfactant recycling. Long-lived tissue-resident AM of embryonic origin have the capacity of self-renewal without replenishment from peripheral monocytes. As in other tissues, close cell-cell contacts in lungs also provide a milieu conducive for cell-to-cell spread of HIV infection and establishment of reservoirs. As lungs are in constant exposure to antigens from the external environment, this situation contributes to pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent-an environment facilitating HIV persistence. Factors such as tobacco and e-cigarette smoking, lung microbiome dysbiosis and respiratory coinfections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. Herein, the potential role of AM in HIV persistence is discussed. Furthermore, their contribution towards pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART, is explored. Finally, strategies to eliminate HIV-infected AM are discussed.

[Potential role of alveolar macrophages in HIV persistence and lung disease]. / Rôle potentiel des macrophages alvéolaires dans la persistance du VIH et les maladies pulmonaires.

While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancies, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH support a higher burden of multimorbidity, including pulmonary diseases of both an infectious and non-infection nature, which may be a consequence of the formation of HIV reservoirs. Their gut, lymph nodes, brain, testes and lungs constitute important anatomic sites for the reservoirs. While CD4+ T-cells, and particularly memory CD4+ T-cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor HIV infection. AM are the most abundant cells in bronchoalveolar (BAL) fluid in healthy conditions, and act as sentinels in the alveolar space by patrolling and clearing debris, microbes and surfactant recycling. Long-lived tissue-resident AM of embryonic origin have the capacity of self-renewal without replenishment from peripheral monocytes. As in other tissues, close cell-cell contacts in lungs also provide a milieu conducive for cell-to-cell spread of HIV infection and establishment of reservoirs. As lungs are in constant exposure to antigens from the external environment, this situation contributes to pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent-an environment facilitating HIV persistence. Factors such as tobacco and e-cigarette smoking, lung microbiome dysbiosis and respiratory co-infections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. Herein, the potential role of AM in HIV persistence is discussed. Furthermore, their contribution towards pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART, is explored. Finally, strategies to eliminate HIV-infected AM are discussed.

Age truncation due to disease shrinks metapopulation viability for amphibians.

Metapopulations often exist in a fragile balance between local extinctions and (re)colonisations, in which case emerging threats that alter species vital rates may drastically increase metapopulation extinction risk. We combined empirical data with metapopulation simulations to examine how demographic shifts associated with amphibian chytrid fungus (Batrachochytrium dendrobatidis, Bd) have altered metapopulation viability for threatened amphibians in Australia. Comparing the ages of museum specimens collected before Bd emerged in Australia with individuals from geographically matched remnant populations revealed significant truncation of age structures post-Bd, with a halving of annual adult survival probabilities. Spatially realistic metapopulation modelling demonstrated that reduced adult survival led to major reductions in the parameter space over which persistence was possible for the focal species, with contractions to landscapes with higher landscape connectivity, lower environmental stochasticity and considerably higher recruitment rates. Metapopulation persistence post-Bd required greater landscape connectivity than pre-Bd. This arises from a landscape-level analogue of compensatory recruitment at the population level, in which higher (re)colonisation rates can offset more frequent local extinctions, enabling persistence of amphibians susceptible to Bd. Interactions between recruitment rate, environmental stochasticity and landscape connectivity were also more important for metapopulation persistence post-Bd. Higher recruitment was required to mitigate the impacts of environmental stochasticity, and higher landscape connectivity was required to mitigate the impacts of environmental stochasticity and poor recruitment. Increased reliance on these interdependencies shrunk the parameter space over which metapopulations could persist post-Bd. Our study demonstrates that emerging threats that alter species vital rates can drastically reduce the capacity of certain environments to support metapopulations. For our focal species, reductions in adult survival rates due to Bd produced major reductions in the conditions under which persistence was possible, providing a mechanistic insight into the processes underpinning observed range and niche contractions of amphibians impacted by this pathogen. More broadly, our study illustrates how environmentally mediated host resilience can enable persistence following the emergence of novel pathogens. This pathway to persistence is worthy of greater attention on both conceptual and applied grounds.

Resistance to change as a function of response speed.

This study examined the effects of different response-speed requirements on resistance to change. Undergraduates were exposed to a simulated scenario aiming to destroy pollution sources by clicking on moving targets. During baseline, a multiple variable interval (VI) 15 s VI 15 s was in effect. Points (100) served as reinforcers. In the Low-Speed Component, the response button moved across the computer screen at a speed of 30 % of the screen length per second. In the High-Speed Component, the response button moved across the computer screen at a speed of 60 % of the screen length per second. A VI 10 s of point loss (-95) disrupted responding during the test. Behavioral resistance was calculated as proportional changes from baseline response rates to test response rates. When the point-loss disrupted responding, greater resistance was observed in the Low-Speed Component, corroborating previous studies with other dimensions of physical requirements.