Card9 Broadly Regulates Host Immunity against Experimental Pulmonary Cryptococcus neoformans 52D Infection.

The ubiquitous soil-associated fungus Cryptococcus neoformans causes pneumonia that may progress to fatal meningitis. Recognition of fungal cell walls by C-type lectin receptors (CLRs) has been shown to trigger the host immune response. Caspase recruitment domain-containing protein 9 (Card9) is an intracellular adaptor that is downstream of several CLRs. Experimental studies have implicated Card9 in host resistance against C. neoformans; however, the mechanisms that are associated with susceptibility to progressive infection are not well defined. To further characterize the role of Card9 in cryptococcal infection, Card9em1Sq mutant mice that lack exon 2 of the Card9 gene on the Balb/c genetic background were created using CRISPR-Cas9 genome editing technology and intratracheally infected with C. neoformans 52D. Card9em1Sq mice had significantly higher lung and brain fungal burdens and shorter survival after C. neoformans 52D infection. Susceptibility of Card9em1Sq mice was associated with lower pulmonary cytokine and chemokine production, as well as reduced numbers of CD4+ lymphocytes, neutrophils, monocytes, and dendritic cells in the lungs. Histological analysis and intracellular cytokine staining of CD4+ T cells demonstrated a Th2 pattern of immunity in Card9em1Sq mice. These findings demonstrate that Card9 broadly regulates the host inflammatory and immune response to experimental pulmonary infection with a moderately virulent strain of C. neoformans.

Evaluating the impact of landscape configuration, patterns and composition on land surface temperature: an urban heat island study in the Megacity Lahore, Pakistan.

The urban heat island (UHI) phenomenon is negatively impacted by rapid urbanization, which significantly affects people's everyday lives, socioeconomic activities, and the urban thermal environment. This study focuses on the impact of composition, configuration, and landscape patterns on land surface temperature (LST) in Lahore, Pakistan. The study uses Landsat 5-TM and Landsat 8-OLI/TIRS data acquired over the years 2000, 2010 and 2020 to derive detailed information on land use, normalized difference vegetation index, LST, urban cooling islands (UCI), green cooling islands (GCI) and landscape metrics at the class and landscape level such as percentage of the landscape (PLAND), patch density (PD), class area (CA), largest patch index (LPI), number of patches (NP), aggregation index (AI), Landscape Shape Index (LSI), patch richness (PR), and mean patch shape index (SHAPE_MN). The study's results show that from the years 2000 to 2020, the built-up area increased by 17.57%, whereas vacant land, vegetation, and water bodies declined by 03.79%, 13.32% and 0.4% respectively. Furthermore, landscape metrics at the class level (PLAND, LSI, LPI, PD, AI, and NP) show that the landscape of Lahore is becoming increasingly heterogeneous and fragmented over time. The mean LST in the study area exhibited an increasing trend i.e. 18.87°C in 2000, 20.93°C in 2010, and 22.54°C in 2020. The significant contribution of green spaces is vital for reducing the effects of UHI and is highlighted by the fact that the mean LST of impervious surfaces is, on average, roughly 3°C higher than that of urban green spaces. The findings also demonstrate that there is a strong correlation between mean LST and both the amount of green space (which is negative) and impermeable surface (which is positive). The increasing trend of fragmentation and shape complexity highlighted a positive correlation with LST, while all area-related matrices including PLAND, CA and LPI displayed a negative correlation with LST. The mean LST was significantly correlated with the size, complexity of the shape, and aggregation of the patches of impervious surface and green space, although aggregation demonstrated the most constant and robust correlation. The results indicate that to create healthier and more comfortable environments in cities, the configuration and composition of urban impermeable surfaces and green spaces should be important considerations during the landscape planning and urban design processes.

Long-term survival and functional outcomes of critically ill patients with hematologic malignancies: a Canadian multicenter prospective study.

PURPOSE: Patients with hematologic malignancy (HM) commonly develop critical illness. Their long-term survival and functional outcomes have not been well described. METHODS: We conducted a prospective, observational study of HM patients admitted to seven Canadian intensive care units (ICUs) (2018-2020). We followed survivors at 7 days, 6 months and 12 months following ICU discharge. The primary outcome was 12-month survival. We evaluated functional outcomes at 6 and 12 months using the functional independent measure (FIM) and short form (SF)-36 as well as variables associated with 12-month survival. RESULTS: We enrolled 414 patients including 35% women. The median age was 61 (interquartile range, IQR: 52-69), median Sequential Organ Failure Assessment (SOFA) score was 9 (IQR: 6-12), and 22% had moderate-severe frailty (clinical frailty scale [CFS] ≥ 6). 51% had acute leukemia, 38% lymphoma/multiple myeloma, and 40% had received a hematopoietic stem cell transplant (HCT). The most common reasons for ICU admission were acute respiratory failure (50%) and sepsis (40%). Overall, 203 (49%) were alive 7 days post-ICU discharge (ICU survivors). Twelve-month survival of the entire cohort was 21% (43% across ICU survivors). The proportion of survivors with moderate-severe frailty was 42% (at 7 days), 14% (6 months), and 8% (12 months). Median FIM at 7 days was 80 (IQR: 50-109). Physical function, pain, social function, mental health, and emotional well-being were below age- and sex-matched population scores at 6 and 12 months. Frailty, allogeneic HCT, kidney injury, and cardiac complications during ICU were associated with lower 12- month survival. CONCLUSIONS: 49% of all HM patients were alive at 7 days post-ICU discharge, and 21% at 12 months. Survival varied based upon hematologic diagnosis and frailty status. Survivors had important functional disability and impairment in emotional, physical, and general well-being.

Ecological monitoring of urban thermal field variance index and determining the surface urban heat island effects in Lahore, Pakistan.

Lahore is the second major metropolitan city in Pakistan in terms of urban population and built-up area, making the city a more ideal place to form the surface urban heat island (SUHI) effects. In the last two decades, the considerable land-use conversion from a natural surface (vegetation) and permeable (waterbody) surface into an impervious (built-up area) surface has lead to an increase in land surface temperature (LST) in Lahore. The human thermal comfort (HTC) of the residents is also impacted by the higher LST. The present study uses multi-temporal Landsat (5&8) satellite imageries to examine the ecological and thermal conditions of Lahore between 2000 and 2020. The ecological and thermal conditions of Lahore are assessed by calculating the urban heat islands and UTFVI (urban thermal field variance index), based on LST data which quantitatively assessed the UHI effect and the quality of human life. The outcomes establish that the urban built-up area has increased by 18%, while urban vegetation, vacant land, and waterbody decreased by 13%, 4%, and 0.04%, respectively. In the last 20 years, the mean LST of the study region has risen by about 3.67 °C. The UHI intensity map shows intensification and a rise in surface temperature variation from 4.5 °C (2000) to 5.9 °C (2020). Furthermore, the finding shows that the ecological and thermal conditions are worse in construction sites, transition zones, and urban areas in comparison to nearby rural areas. The lower UTFVI was observed in dense vegetation cover areas while a hot spot of higher UTFVI was predominantly observed in the areas of transition zones and built-up area expansion. Those areas with higher hot spots are more vulnerable to the urban heat island effect. The main conclusions of this study are essential for educating city officials and urban planners in developing a sustainable urban land development plan to reduce urban heat island effects by investing in open green spaces for urban areas of cities.

Exploring the effect of COVID-19 pandemic lockdowns on urban cooling: A tale of three cities.

COVID-19 pandemic has had a major impact on our society, environment and public health, in both positive and negative ways. The main aim of this study is to monitor the effect of COVID-19 pandemic lockdowns on urban cooling. To do so, satellite images of Landsat 8 for Milan and Rome in Italy, and Wuhan in China were used to look at pre-lockdown and during the lockdown. First, the surface biophysical characteristics for the pre-lockdown and within-lockdown dates of COVID-19 were calculated. Then, the land surface temperature (LST) retrieved from Landsat thermal data was normalized based on cold pixels LST and statistical parameters of normalized LST (NLST) were calculated. Thereafter, the correlation coefficient (r) between the NLST and index-based built-up index (IBI) was estimated. Finally, the surface urban heat island intensity (SUHII) of different cities on the lockdown and pre-lockdown periods was compared with each other. The mean NLST of built-up lands in Milan (from 7.71 °C to 2.32 °C), Rome (from 5.05 °C to 3.54 °C) and Wuhan (from 3.57 °C to 1.77 °C) decreased during the lockdown dates compared to pre-lockdown dates. The r (absolute value) between NLST and IBI for Milan, Rome and Wuhan decreased from 0.43, 0.41 and 0.16 in the pre-lockdown dates to 0.25, 0.24, and 0.12 during lockdown dates respectively, which shows a large decrease for all cities. Analysis of SUHI for these cities showed that SUHII during the lockdown dates compared to pre-lockdown dates decreased by 0.89 °C, 1.78 °C, and 1.07 °C respectively. The results indicated a high and substantial impact of anthropogenic activities and anthropogenic heat flux (AHF) on the SUHI due to the substantial reduction of huge anthropogenic pressure in cities. Our conclusions draw attention to the contribution of COVID-19 lockdowns (reducing the anthropogenic activities) to creating cooler cities.

An analysis of machine learning risk factors and risk parity portfolio optimization.

Many academics and experts focus on portfolio optimization and risk budgeting as a topic of study. Streamlining a portfolio using machine learning methods and elements is examined, as well as a strategy for portfolio expansion that relies on the decay of a portfolio's risk into risk factor commitments. There is a more vulnerable relationship between commonly used trademarked portfolios and neural organizations based on variables than famous dimensionality decrease strategies, as we have found. Machine learning methods also generate covariance and portfolio weight structures that are more difficult to assess. The least change portfolios outperform simpler benchmarks in minimizing risk. During periods of high instability, risk-adjusted returns are present, and these effects are amplified for investors with greater sensitivity to chance changes in returns R.

Low-dose trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (LOW-TMP): protocol for a phase III randomised, placebo-controlled, dose-comparison trial.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%-60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality. METHODS AND ANALYSIS: A phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI. ETHICS AND DISSEMINATION: This study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04851015.

Quantifying the human disturbance intensity of ecosystems and its natural and socioeconomic driving factors in urban agglomeration in South China.

The impact of human activities on terrestrial ecosystems is becoming more intense than ever in history. Human disturbance analyses play important roles in appropriately managing the human-environment relationship. In this study, a human disturbance index (HDI) that uses land use and land cover data from 1980, 2000, 2010, and 2018 is proposed to assess the human disturbance of ecosystems in the Guangdong-Hong Kong-Macao Greater Bay Area. The HDI is first calculated by classifying the human disturbance intensity into seven levels and 13 categories from weak to strong in ecosystems. Then the driving factors of the HDI spatial pattern change are explored using a geographically weighted regression (GWR) model. The results showed that the spatial pattern of the HDI was high in the middle and low in the surrounding areas. The intensity of human disturbance increased, and the medium and high disturbance areas expanded during 1980-2018, especially in Guangzhou, Foshan, Shenzhen, and Dongguan. Human disturbance displayed an obvious spatial heterogeneity. The GWR model had a better explanation effect of the analysis of the HDI change drivers. The driving effect of the socioeconomic conditions was significantly stronger than that of the natural environmental. This study assists in understanding the distribution and change characteristics of the ecological environment in areas with strong human activities and provides a reference for related studies.

The IL-1 Receptor Is Required to Maintain Neutrophil Viability and Function During Aspergillus fumigatus Airway Infection.

Aspergillus fumigatus airway infections are associated with increased rates of hospitalizations and declining lung function in patients with chronic lung disease. While the pathogenesis of invasive A. fumigatus infections is well studied, little is known about the development and progression of airway infections. Previous studies have demonstrated a critical role for the IL-1 cytokines, IL-1α and IL-1ß in enhancing pulmonary neutrophil recruitment during invasive aspergillosis. Here we use a mouse model of A. fumigatus airway infection to study the role of these IL-1 cytokines in immunocompetent mice. In the absence of IL-1 receptor signaling, mice exhibited reduced numbers of viable pulmonary neutrophils and increased levels of neutrophil apoptosis during fungal airway infection. Impaired neutrophil viability in these mice was associated with reduced pulmonary and systemic levels of G-CSF, and treatment with G-CSF restored both neutrophil viability and resistance to A. fumigatus airway infection. Taken together, these data demonstrate that IL-1 dependent G-CSF production plays a key role for host resistance to A. fumigatus airway infection through suppressing neutrophil apoptosis at the site of infection.

Beware of covert enemies: Candida orthopsilosis malignant otitis externa with base of the skull osteomyelitis, a case report and review of literature.

BACKGROUND: Malignant otitis externa (MOE) is a serious infection of the external auditory canal that is frequently associated with skull base osteomyelitis (SBO) as well as secondary neurological sequelae. Patients with poorly controlled diabetes mellitus or immunosuppression are at increased risk of developing such critical infection for multiple local and systemic factors. While most cases are secondary to bacterial infections particularlyPseudomonas aeruginosa, fungal infections are also occasionally encountered, often associated with delayed diagnosis and high morbidity and mortality. CASE REPORT: We report a case of a 63 years old man with uncontrolled diabetes mellitus who presented with symptoms and signs of MOE, supported by radiological assessments. The patient was treated presumptively with a prolonged course of antibiotics without clinical improvement, coupled with progression of radiological findings and significant disease extension. Reassessment with biopsies and tissue cultures from external auditory meatus, tempo-mandibular bone, as well as base of the skull grew Candida orthopsilosis. The patient received induction treatment with high dose liposomal amphotericin followed by fluconazole to control disease progression and complications. CONCLUSION: Candida MOE with secondary skull base osteomyelitis is rare and difficult to diagnose with no clear guidance on assessment and management. Clinicians should be aware of the unusual presentations where microbiological and histopathological evaluations are essential for proper management.

Adherence to antiretroviral therapy among HIV positive men who inject drugs in Pakistan.

BACKGROUND: People who inject drugs (PWID) living with HIV have poorer adherence to HIV antiretroviral therapy (ART) and elevated mortality compared to other populations. Little is known about factors associated with adherence among PWID in low-and middle-income countries, including in countries where opioid agonist therapy (OAT) is unavailable. We aimed to estimate ART adherence among men who inject drugs (MWID) living with HIV in Pakistan and identify factors independently associated with adherence. METHODS: Nai Zindagi Trust (NZT) provides a range of HIV prevention, testing and treatment services to PWID in Pakistan. This study utilized data from HIV positive MWID who received ART refill/s from public sector ART Centres via NZT's Social Mobilizer Adherence Support Unit between September 2016 and December 2018. Multivariable logistic regression modelled factors independently associated with ART adherence. RESULTS: Among 5,482 HIV positive MWID registered with NZT who had attended the AAU and were supplied with ART refills between September 2016 and December 2018., 55% were adherent to ART. Independent predictors of adherence were being married (AOR 1.38, 95% CI:1.23-1.55, p<0.001) and >5 years of education compared to those with no education (AOR 1.19, 95% CI:1.05-1.35, p = 0.005). MWID living on the street at night had lower adjusted odds of ART adherence (AOR 0.75, 95% CI:0.62-0.91, p = 0.003). CONCLUSIONS: Findings indicate that MWID living with HIV continue to face barriers to ART adherence in Pakistan. Despite considerable evidence supporting the impact of OAT in increasing ART adherence among PWID, OAT remains illegal and inaccessible in Pakistan. Evidence-based interventions, including OAT, are needed to increase adherence and improve clinical outcomes, health equity and survival among PWID living with HIV in Pakistan.

HIV incidence and associated risk factors in female spouses of men who inject drugs in Pakistan.

INTRODUCTION: Female sexual partners of men who inject drugs (MWID) living with HIV are at risk of HIV transmission. HIV prevalence estimates among non-drug using female sex partners of MWID are scarce, with no studies documenting HIV incidence. We investigated HIV prevalence and incidence among female spouses of MWID registered at Nai Zindagi Trust (NZT), Pakistan, between 2012 and 2019. METHODS: NZT registration and service provision data for female spouses who participated in HIV testing and counselling calculated HIV prevalence and incidence using the person years (PY) method. Cox proportional hazards models identified factors associated with incident infection. RESULTS: Overall HIV prevalence among female spouses of MWID was 8.5%. Among 3478 HIV-negative female spouses, 109 incident infections were observed, yielding an incidence rate of 1.5/100PY (95% CI 1.2-1.8). Independent predictors of incident infection were registration in Punjab province (AHR 1.73 95% CI 1.13-2.68, p = 0.012) and 1-5 years of education (AHR 1.89 95% CI 1.22-2.93, p = 0.004). Knowledge of HIV at registration was protective against infection (AHR 0.51, 95% CI 0.26-0.99, p = 0.047), along with a MWID spouse who had initiated antiretroviral therapy (ART) (AHR 0.25, 95% CI 0.16-0.38, p < 0.001), while incident infection was inversely associated with number of children (≥ 5 children AHR 0.44 95% CI 0.22-0.88, p = 0.022). CONCLUSIONS: Additional efforts are needed to reduce HIV transmission among female spouses of MWID, including targeted provision of HIV education and access to HIV screening. Interventions that target MWID are also required, including evidence-based drug treatment and access to ART, including support to maximize adherence. Finally, consideration should be given to making HIV pre-exposure prophylaxis available to female spouses at high risk of HIV transmission, particularly young women and those whose husbands are not receiving, or have difficulty adhering to, ART.

Fine-grained assessment of greenspace satisfaction at regional scale using content analysis of social media and machine learning.

Assessing perceptions of green spaces is of considerable interest to developers aiming for sustainable urbanization. However, there are numerous challenges facing the development of a rapid, effective, and fine-grained method to assess large-scale greenspace perception. Survey-based studies of perception yielded detailed assessments of green spaces but lacked regional comparisons. The few big-data-based studies of greenspace perception lacked fine-grained explorations. Therefore, we used content analysis to interpret perception in two ways: perceived frequency and perceived satisfaction, including overall park satisfaction and satisfaction with individual landscape features. We analyzed social media posts about urban parks in Beijing, China. A structured lexicon was developed to capture detailed landscape features, and machine learning was employed to assess satisfaction levels. Both of these techniques performed well in interpreting greenspace satisfaction from volunteered textual comments. A detailed study of 50 parks demonstrated that overall park satisfaction was positive. Additionally, individual landscape features were more influential than frequency of landscape features in affecting satisfaction. Our framework confirmed the potential of online comments as complementary to traditional surveys in assessing greenspace perception, while enhancing our understanding of this perception on a regional scale. Practically, this study can facilitate sustainable policy-making regarding urban green spaces, specifically through offering a structured landscape-feature lexicon, rapid regional comparison of various parks, and an emphasis on quality rather than quantity of landscape features.

Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians.

OBJECTIVES: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. DESIGN: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. SETTING: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. CONCLUSIONS: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.

Radiology in Neurolaryngology.

The role of imaging in assessment of neurolaryngology will predominantly involve the assessment of pathology along that of laryngeal nerve pathways. The anatomical pathways of the vagus and laryngeal nerves are well described in standard anatomical textbooks and will not be detailed here. Whilst there are 3 principle laryngeal nerves/branches, the recurrent laryngeal nerve will clearly constitute the mainstay of imaging input. This chapter will elaborate on the pathology encountered at the various levels and the imaging characteristics of these disorders. Prior to this, there will be a summary of normal laryngeal imaging appearances to familiarise with the characteristics of radiological anatomy.

The acute response of the nucleus pulposus of the cervical intervertebral disc to three supine postures in an asymptomatic population.

BACKGROUND: The dynamic disc model refers to the ability of a spinal disc's position to be manipulated by body postures and movements. Research on lumbar discs has indicated movement of the anterior and posterior disc that correlates with posture of the spine. The aim of this study was to assess whether, despite its structural differences, the cervical disc responds to flexed and extended postures in a similar fashion to the lumbar disc. METHOD: A repeated measures study. Twenty five asymptomatic participants (age: 33.7 ±â€¯9.1 years) volunteered. Scans were performed in supine using an Esaote 0.2T magnetic resonance imaging scanner. Participants lay with their cervical spine initially placed in neutral, followed by flexion and finally extension. The position of the posterior disc nucleus pulposus at C5-6 and C6-7 was measured against a vertical line connecting the posterior vertebral bodies above and below each disc. RESULTS: Changes in cervical spine position were associated with significant changes in posterior disc nucleus pulposus position at both C5-6 and C6-7 (p < 0.01 for both). Post hoc testing showed a significant difference in posterior disc nucleus pulposus position at C5-6 between flexion and extension (p = 0.02). There was similarly a significant change at C6-7 between neutral and flexion (p = 0.001), and between flexion and extension (p = 0.02). CONCLUSIONS: These results indicate that the cervical posterior nucleus pulposus is affected by spinal loading, consistent with the concept of the dynamic disc model.

Gram-Negative Pneumonia Augments Non-Small Cell Lung Cancer Metastasis through Host Toll-like Receptor 4 Activation.

INTRODUCTION: Surgery is essential for cure of early-stage non-small cell lung cancer (NSCLC). Rates of postoperative bacterial pneumonias, however, remain high, and clinical data suggests that post-operative infectious complications confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory response to infection by recognizing evolutionarily conserved bacterial structures at the surface of numerous pulmonary cell types; yet, little is known about how host TLR activation influences NSCLC metastasis. TLR4 recognizes gram-negative bacterium lipopolysaccharide activating the innate immune system. METHODS: C57BL/6 and TLR4 knockout murine airways were inoculated with Escherichia coli or lipopolysaccharide. Hepatic metastasis assays and intravital microscopy were performed. Bronchoepithelial conditioned media was generated through coincubation of bronchoepithelial cells with TLR4 activating Escherichia coli or lipopolysaccharide. Subsequently, H59 NSCLC were stimulated with conditioned media and subject to various adhesion assays. RESULTS: We demonstrate that gram-negative Escherichia coli pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through TLR4 activation. Additionally, infected C57BL/6 mice demonstrate increased H59 NSCLC in vivo hepatic sinusoidal adhesion compared with negative controls, a response that is significantly diminished in TLR4 knockout mice. Similarly, intratracheal injection of purified TLR4 activating lipopolysaccharide increases in vivo adhesion of H59 cells to murine hepatic sinusoids. Furthermore, H59 cells incubated with bronchoepithelial conditioned medium show increased cell adhesion to in vitro extracellular matrix proteins and in vivo hepatic sinusoids through a mechanism dependent on bronchoepithelial TLR4 activation and interleukin-6 secretion. CONCLUSION: TLR4 is a viable therapeutic target for NSCLC metastasis augmented by gram-negative pneumonia.

Diabetic muscle infarction: often misdiagnosed and mismanaged.

A patient with type 2 diabetes, retinopathy, neuropathy, and nephropathy presented with severe right distal thigh pain, which awoke him from sleep. He was diagnosed with musculoskeletal pain and discharged home. Two days later, the severity of pain increased in his right thigh and, subsequently, he developed pain in the proximal lateral aspect of his left thigh, for which he returned to hospital. He had elevated creatine kinase and myoglobin levels. An ultrasound of the right thigh identified a loss of definition of the normal muscular striations and subcutaneous edema. On MRI, the axial STIR image demonstrated extensive T2 hyperintensity in the right vastus medialis and left vastus lateralis, consistent with the diagnosis of diabetic muscle infarction (DMI). This presentation emphasizes the need for a thorough patient history and physical examination, and the importance of directed imaging for the prompt diagnosis of DMI.

The alarmins IL-1 and IL-33 differentially regulate the functional specialisation of Foxp3+ regulatory T cells during mucosal inflammation.

CD4+Foxp3+ regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREG cells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREG cell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREG cells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREG cells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREG cells. In the absence of ST2, TREG cells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+ TREG over pro-inflammatory TREG cells in a Cryptococcus neoformans infection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREG cells, ultimately dictating the dynamics of adaptive immunity to pathogens.