The tuberculous pleural effusion.

Pleural tuberculosis (TB) is a common entity with similar epidemiological characteristics to pulmonary TB. It represents a spectrum of disease that can variably self-resolve or progress to TB empyema with severe sequelae such as chronic fibrothorax or empyema necessitans. Coexistence of and progression to pulmonary TB is high. Diagnosis is challenging, as pleural TB is paucibacillary in most cases, but every effort should be made to obtain microbiological diagnosis, especially where drug resistance is suspected. Much attention has been focussed on adjunctive investigations to support diagnosis, but clinicians must be aware that apparent diagnostic accuracy is affected both by the underlying TB prevalence in the population, and by the diagnostic standard against which the specified investigation is being evaluated. Pharmacological treatment of pleural TB is similar to that of pulmonary TB, but penetration of the pleural space may be suboptimal in complicated effusions. Evidence for routine drainage is limited, but evacuation of the pleural space is indicated in complicated disease. Educational aims: To demonstrate that pleural TB incorporates a wide spectrum of disease, ranging from self-resolving lymphocytic effusions to severe TB empyema with serious sequelae.To emphasise the high coexistence of pulmonary TB with pleural TB, and the importance of obtaining sputum for culture (induced if necessary) in all cases.To explore the significant diagnostic challenges posed by pleural TB, and consequently the frequent lack of information about drug sensitivity prior to initiating treatment.To highlight the influence of underlying TB prevalence in the population on the diagnostic accuracy of adjunctive investigations for the diagnosis of pleural TB.To discuss concerns around penetration of anti-TB medications into the pleural space and how this can influence decisions around treatment duration in practice.

Sarcoidosis following COVID infection: A case series.

Here we describe three cases of sarcoidosis which were diagnosed following COVID infection. Treating clinicians should consider post-COVID-19 sarcoidosis in their differential, as it represents a potentially treatable cause of persistent symptomatology.

Interprofessional communication in the hospital setting : a systematic review of the qualitative literature.

Communication plays a key role in the provision of safe patient care, and miscommunication in healthcare can lead to avoidable patient harm or mortality. Interprofessional communication (IPCom) can be challenging due to differences in training, education and roles between healthcare professions. The aim of this systematic review was to synthesize the qualitative evidence regarding healthcare providers' perceptions of interprofessional communication in the hospital setting. Four databases (PubMed, CINAHL, Web of Science, and Embase) were searched for studies that met the inclusion criteria. Eighteen studies were identified as suitable for inclusion in the review and were examined using thematic synthesis. Thematic synthesis led to the development of five descriptive themes: 1) 'Hierarchy", 2) "Interprofessional Ethos," 3) "Healthcare Environment," 4) "Personal Factors" and 5) "Methods of Communication," and two overarching analytical themes: "Barriers to Communication" and "Facilitators to Communication." Personal factors, such as strong interprofessional relationships, were found to be important facilitators to IPCom, while organizational factors, such as challenging and hierarchical working environments, were found to pose barriers to IPCom.

Beyond antibiotics: recent developments in the diagnosis and management of nontuberculous mycobacterial infection.

Nontuberculous mycobacteria (NTM) pulmonary disease represents a significant clinical challenge with suboptimal therapy and increasing prevalence globally. Although clinical practice guidelines seek to standardise the approach to diagnosis and treatment of NTM disease, a lack of robust evidence limits their utility and significant variability exists in clinical practice. Here we walk through some novel approaches in diagnosis and therapy that are under development to tackle a disease where traditional strategies are failing. Educational aims: To recognise the growing prevalence and importance of NTM pulmonary disease globally.To identify shortfalls in current diagnostic and therapeutic strategies, and highlight the challenges that must be addressed in future research and development efforts.To appreciate the role of novel therapeutic approaches such as immunomodulation of host defence, and to explore some examples of burgeoning therapies.

Pharmacist and patient experiences of primary care during the COVID-19 pandemic: An interview study.

Introduction: A number of significant changes designed to reduce the spread of COVID-19 were introduced in primary care during the COVID-19 pandemic. In Ireland, these included fundamental legislative and practice changes such as permitting electronic transfer of prescriptions, extending duration of prescription validity, and encouraging virtual consultations. Although such interventions served an important role in preventing the spread of infection, their impact on practice and patient care is not yet clear. The aim of this study was to investigate patient and healthcare professional (pharmacist and general practitioner) experiences to understand the impact of COVID-19 on primary care and medication safety during the first two years of the COVID-19 pandemic in Ireland. Methods: A qualitative study using semi-structured interviews was undertaken between October 2021 and January 2022. Participants included twelve patients, ten community pharmacists, and one general practitioner. Interviews were transcribed verbatim and analysed using thematic analysis. Only patient and pharmacist interviews were included. Findings: Themes from the interviews included: 1) Access to care, 2) Technological changes, 3) Experiences of care, and 4) Patient safety. Particular challenges identified included the difficulty faced by patients when accessing care, impacts on experiences of patient care, and extensive changes to pharmacy practice during the pandemic. Conclusions: This study found that COVID-19 countermeasures considerably impacted patient and pharmacist experiences of primary care in terms of care and medication safety. While many changes were welcomed, others such as virtual consultations were received more cautiously likely due to the rapid and unplanned nature of their introduction. Further research is needed to identify how to optimise these changes to improve pharmacist and patient experience, and to understand the impact on patient safety.

Changes to primary care delivery during the COVID-19 pandemic and perceived impact on medication safety: A survey study.

Introduction: The COVID-19 pandemic has had a profound impact on the delivery of primary care around the world. In Ireland, the use of technologies such as virtual consultations and the electronic transfer of prescriptions became widespread in order to deliver care to patients while minimising infection risk. The impact of these changes on medication safety is not yet known. Objectives: The aims of this survey study were to investigate 1) the changes that have occurred in Irish primary care since the start of the COVID-19 pandemic and 2) the impact of these changes on medication safety. Methods: Anonymous, online surveys were distributed to general practitioners (GPs) and pharmacists from August-September 2021. Surveys contained quantitative (multiple-choice, Likert scale) and qualitative (free-text) questions concerning workflow changes, medication safety incidents and near misses, and GP/pharmacist perspectives on medication safety and COVID-19. Reported medication safety incidents and near misses were categorised according to the WHO Conceptual Framework for the International Classification for Patient Safety. Results: In total, there were 251 responses to the survey, comprising of 211 pharmacists and 40 GPs. The most significant workflow changes during the pandemic were the widespread use of a secure clinical email service (Healthmail) that facilitates electronic prescription transfer and communication (75.3% of respondents) and the increased use of telephone consultations (49%). Overall, Healthmail was widely perceived to have had a positive impact on medication safety. Most GPs did not perceive a change in the frequency of medication safety incidents during the pandemic, while most pharmacists reported a slight increase in incidents. Survey participants highlighted pressure, patient expectations, and patient monitoring as significant challenges encountered during the pandemic. Conclusions: During the pandemic, a number of significant changes occurred in primary care in Ireland, particularly involving communication of healthcare information, with varying impacts on workflow and medication safety. Future research should focus on the optimisation of electronic prescribing and telemedicine services in Ireland, patient perspectives on the changes in primary care, and interventions to improve medication safety in primary care.

Thirst for change in a challenging environment: healthcare providers' perceptions of safety culture in a large Irish teaching hospital.

BACKGROUND: The Irish healthcare system is currently recognised as being understaffed and under-resourced due to historic underfunding and the aftermath of the 2008 global financial crisis. This descriptive study investigated healthcare providers' perceptions of the safety culture in a large Irish teaching hospital. AIM: The aim of this study was to investigate healthcare workers' perceptions of the safety culture in a large Irish teaching hospital in a climate of national under-resourcing of healthcare. METHODS: Seventeen semi-structured interviews were carried out with patient-attending staff between February and June 2019. Interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: Two predominant themes emerged from the interviews: (1) challenging environment and (2) thirst for change. Study participants described the poor working conditions in the hospital, but also recognised the importance of teamwork and communication in maintaining patient safety and had a strong appetite for change regarding the safety culture in the hospital. CONCLUSION: This study highlights the complex relationship between working conditions and safety culture. Hospital staff were committed to providing the best possible care for their patients but struggled to provide safe care in a challenging work environment. A clear appetite for change was identified amongst HCPs regarding patient safety culture in Irish healthcare.

General practitioners' views of pharmacist services in general practice: a qualitative evidence synthesis.

BACKGROUND: Pharmacist services in general practice are expanding worldwide, with evidence to show pharmacists' presence in general practice has financial, workload, and clinical benefits. Yet, little is known globally about general practitioners' (GPs') views on their presence in general practice. OBJECTIVE: To synthesize the qualitative research evidence on GPs' views of pharmacist services in general practice. METHODS: Qualitative evidence synthesis; 8 electronic databases were searched from inception to April 2021 for qualitative studies that reported the views of GPs regarding pharmacist services in general practice. Data from included studies were analyzed using thematic synthesis. The Confidence in the Evidence from Reviews of Qualitative research (CERQual) approach was used to assess the confidence in individual review findings. RESULTS: Nineteen studies were included, which captured the views of 159 GPs from 8 different countries. Four analytical themes describing the factors that should be considered in the development or optimization of pharmacist services in general practice, based on the views of GPs, were developed from the coded data and descriptive themes: (i) optimal environment for a pharmacist, (ii) the ideal pharmacist characteristics, (iii) complex stakeholder relationships, and (iv) benefits of an effective pharmacist. CONCLUSION: Based on the synthesis of GPs' views, we have created a conceptual model of factors that should be considered by policymakers, GPs, pharmacists, and other relevant stakeholders when developing or optimizing pharmacist services in general practice going forward.

This review presents the evidence, for the first time, on general practitioners' (GPs') views of pharmacist services in the general practice setting worldwide. Pharmacist services in general practice have the potential to yield several benefits for the practice, patient, and GPs themselves. However, to include pharmacist services in the practice is a complex process; this review gives an insight into GPs' thoughts on the matter, what works­and if so, why­and what does not work. This review will therefore prove useful to GPs, pharmacists, practice managers, policymakers, and academics wishing to establish or improve pharmacist services in the general practice environment.

Medication safety incidents associated with the remote delivery of primary care: a rapid review.

OBJECTIVES: The COVID-19 pandemic triggered rapid, fundamental changes, notably increased remote delivery of primary care. While the impact of these changes on medication safety is not yet fully understood, research conducted before the pandemic may provide evidence for possible consequences. To examine the published literature on medication safety incidents associated with the remote delivery of primary care, with a focus on telemedicine and electronic prescribing. METHODS: A rapid review was conducted according to the Cochrane Rapid Reviews Methods Group guidance. An electronic search was carried out on Embase and Medline (via PubMed) using key search terms 'medication error', 'electronic prescribing', 'telemedicine' and 'primary care'. Identified studies were synthesised narratively; reported medication safety incidents were categorised according to the WHO Conceptual Framework for the International Classification for Patient Safety. KEY FINDINGS: Fifteen studies were deemed eligible for inclusion. All 15 studies reported medication incidents associated with electronic prescribing; no studies were identified that reported medication safety incidents associated with telemedicine. The most commonly reported medication safety incidents were 'wrong label/instruction' and 'wrong dose/strength/frequency'. The frequency of medication safety incidents ranged from 0.89 to 81.98 incidents per 100 electronic prescriptions analysed. SUMMARY: This review of medication safety incidents associated with the remote delivery of primary care identified common incident types associated with electronic prescriptions. There was a wide variation in reported frequencies of medication safety incidents associated with electronic prescriptions. Further research is required to determine the impact of the COVID-19 pandemic on medication safety in primary care, particularly the increased use of telemedicine.

Optimizing Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older Adults (OPERAM): cluster randomised controlled trial.

OBJECTIVE: To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital. DESIGN: Cluster randomised controlled trial. SETTING: 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors. PARTICIPANTS: 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term). INTERVENTION: Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person's prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing. MAIN OUTCOME MEASURE: Primary outcome was first drug related hospital admission within 12 months. RESULTS: 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug related hospital admission was 0.91 (0.69 to 1.19). The hazard ratio for first fall was 0.96 (0.79 to 1.15; 237 v 263 first falls) and for death was 0.90 (0.71 to 1.13; 172 v 203 deaths). CONCLUSIONS: Inappropriate prescribing was common in older adults with multimorbidity and polypharmacy admitted to hospital and was reduced through an intervention to optimise pharmacotherapy, but without effect on drug related hospital admissions. Additional efforts are needed to identify pharmacotherapy optimisation interventions that reduce inappropriate prescribing and improve patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02986425.

Obesity, COVID-19 and innate immunometabolism.

As COVID-19 continues to spread worldwide, severe disease and mortality have been observed in obese patients. We discuss how obesity and obesity-associated factors such as 'meta-flammation', dietary fat intake and paradoxical suppression of the innate immune response within the pulmonary compartment may be crucial determinants in the host response to a novel viral pathogen. Modulation of immune cell bioenergetics and metabolic potential plays a central role in the innate immune response to infection, and as we strive to combat this new global health threat, immunometabolism of the innate immune system warrants attention.

Imaging of genetically-mediated pancreatitis.

OBJECTIVES: To review the imaging of patients with Genetically-Mediated Pancreatitis (GMP), identify common imaging findings in this cohort and assess phenotypical characteristics of specific genotypes. MATERIALS AND METHODS: Retrospective review of the databases of the Irish National Surgical Centre for Pancreatic Cancer (NSCPC) and Cystic Fibrosis (CF) from November 2010 to January 2018. Retrospective imaging and chart review for the patients with positive genetics for GMP. RESULTS: The NSCPC database contained 699 patients; the CF database included 352 patients. Of these 1051, 14 were identified as having GMP (age range: 20-65, M:F ratio of 1:1). 14 of 1051 patients from the database had positive genetics for GMP. 10 had imaging to support a diagnosis of hereditary pancreatitis or familial recurrent pancreatitis (1.3%) and 4 had imaging to support a diagnosis of CF-related pancreatitis. Imaging findings were considered in 3 categories, determined by genotype - PRSS1 hereditary pancreatitis, SPINK 1 autosomal recessive pancreatitis and those for CFTR - cystic fibrosis related pancreatitis. Imaging findings in PRSS1 hereditary pancreatitis patients included: pancreatic atrophy, calcification and main pancreatic duct (MPD) dilatation, referred to as the PRSS1 imaging triad. Patients with the SPINK1 gene mutation had less severe imaging manifestations (pancreatic atrophy 33%, MPD dilatation 33%, pancreatic calcification 33%). CFTR patients with imaging findings had pancreatic atrophy (100%). CONCLUSION: GMP should be suspected when the features of 'chronic pancreatitis' are seen in young adults with no history of excess alcohol intake. Genetic testing, endocrinology review and long-term imaging follow-up for pancreatic carcinoma are indicated.

Safety culture in a major accredited Irish university teaching hospital: a mixed methods study using the safety attitudes questionnaire.

BACKGROUND: The measurement of safety culture, the way in which members of an organisation think about and prioritise safety, in a hospital can provide valuable insight and inform quality improvement strategies. AIMS: The aim of this study is to describe the safety culture of a university teaching hospital in the Republic of Ireland. METHODS: This is a mixed methods survey study using the Safety Attitudes Questionnaire (SAQ). The SAQ was distributed to all staff in the study hospital. Staff attitudes towards six domains of patient safety culture were assessed over 32 Likert-scaled items. Thematic analysis was performed on qualitative data. RESULTS: A total of 768 staff members completed and returned a copy of the SAQ. The hospital scored above the international benchmark in five out of six domains, indicating a positive safety culture, but scored below the international benchmark in the domain 'Working Conditions'. This positive safety culture was not mirrored in the qualitative data, from which five themes emerged; three major-Staffing Issues, Patient-Focused Care and Hospital Environment-and two minor-Safe Reporting Culture and Training and Education. CONCLUSIONS: In this study, a mixed methods approach was successfully used to investigate the safety culture in a large Irish hospital. Although the SAQ results indicated a positive safety culture, the qualitative data revealed a number of issues that the hospital staff felt impacted negatively on patient safety. The results of this study will inform future work on the design of an intervention to improve patient safety in the hospital.

Mycobacterium tuberculosis Limits Host Glycolysis and IL-1ß by Restriction of PFK-M via MicroRNA-21.

Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1ß (IL-1ß). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function.

Cigarette Smoking Impairs the Bioenergetic Immune Response to Mycobacterium tuberculosis Infection.

Smoking is a major risk factor driving the tuberculosis epidemic, and smokers' alveolar macrophages (AM) demonstrate significant immune defects after infection. Recently, macrophage glycolytic reprogramming has emerged as crucial in the early host immune response to Mycobacterium tuberculosis (Mtb) infection. In the present study, we sought to compare baseline metabolic characteristics and the glycolytic response to infection of human AM from smokers and nonsmokers. AM were obtained at bronchoscopy, and extracellular flux analyses were performed to determine baseline metabolic characteristics compared with human monocyte-derived macrophages (MDM). Metabolic characterization of AM from smokers and nonsmokers was performed similarly. After infection with Mtb, differences in glycolytic response were measured by extracellular flux analyses and gene expression analyses and correlated with production of glycolysis-driven IL-1ß and prostaglandin E2. Similar experiments were performed in cigarette smoke extract-treated MDM as an alternative model. At baseline, human AM from nonsmokers have a significantly lower extracellular acidification rate/oxygen consumption rate ratio than MDM (P < 0.05), but they retain substantial glycolytic reserve. Compared with nonsmokers' AM, smokers' AM demonstrate reduced metabolic activity, reduced glycolytic reserve (P = 0.051), and reduced spare respiratory capacity (P < 0.01). After infection with Mtb, smokers' AM have significantly reduced glycolytic response, as measured by extracellular flux analyses (P < 0.05) and glycolytic gene expression analyses. Cigarette smoke extract-treated MDM similarly demonstrate reduced metabolic activity and reserves, as well as impaired glycolytic response to infection. Human AM demonstrate metabolic plasticity that allows glycolytic reprogramming to occur after Mtb infection. In smokers, this metabolic reserve is significantly attenuated, with consequent impairment of the glycolytic response to infection.

Epigenetic induction of CD1d expression primes lung cancer cells for killing by invariant natural killer T cells.

Immunotherapies that target CD1d-restricted invariant NKT (iNKT) cells can prevent tumor growth in murine models but trials in humans have shown limited clinical efficacy. Here, we show that iNKT cells are depleted from blood and bronchial lavage samples from patients with non-small cell lung cancer (NSCLC) suggesting a role for these cells in immunity against NSCLC. We interrogated the Lung Cancer Explorer and Kaplan-Meier Plotter databases of NSCLC patients and found that pulmonary CD1d expression is reduced in patients with NSCLC and that low expression of CD1d mRNA is significantly associated with poor patient survival. We hypothesized that CD1d expression in NSCLC is epigenetically regulated and can be modulated using epigenetic targeting therapies. Treatment of the CD1d-negative NSCLC cell lines, A549 and SK-MES-1, with DNA methyltransferase inhibitors and histone deacetylase inhibitors resulted in a dose-dependent induction of CD1d mRNA and protein expression. Chromatin immunoprecipitation analysis indicated that this induction of CD1d expression directly involved chromatin remodelling. Induction of CD1d expression by A549 and SK-MES-1 cells using therapeutic low doses of DNA methyltransferase inhibitors and histone deacetylase inhibitors made them targets for iNKT cell-mediated cytolytic degranulation. Thus, epigenetic manipulation of CD1d expression may augment the efficacy of iNKT cell-based immunotherapies for NSCLC.

Metabolic reprogramming & inflammation: Fuelling the host response to pathogens.

Successful immune responses to pathogens rely on efficient host innate processes to contain and limit bacterial growth, induce inflammatory response and promote antigen presentation for the development of adaptive immunity. This energy intensive process is regulated through multiple mechanisms including receptor-mediated signaling, control of phago-lysomal fusion events and promotion of bactericidal activities. Inherent macrophage activities therefore are dynamic and are modulated by signals and changes in the environment during infection. So too does the way these cells obtain their energy to adapt to altered homeostasis. It has emerged recently that the pathways employed by immune cells to derive energy from available or preferred nutrients underline the dynamic changes associated with immune activation. In particular, key breakpoints have been identified in the metabolism of glucose and lipids which direct not just how cells derive energy in the form of ATP, but also cellular phenotype and activation status. Much of this comes about through altered flux and accumulation of intermediate metabolites. How these changes in metabolism directly impact on the key processes required for anti-microbial immunity however, is less obvious. Here, we examine the 2 key nutrient utilization pathways employed by innate cells to fuel central energy metabolism and examine how these are altered in response to activation during infection, emphasising how certain metabolic switches or 'reprogramming' impacts anti-microbial processes. By examining carbohydrate and lipid pathways and how the flux of key intermediates intersects with innate immune signaling and the induction of bactericidal activities, we hope to illustrate the importance of these metabolic switches for protective immunity and provide a potential mechanism for how altered metabolic conditions in humans such as diabetes and hyperlipidemia alter the host response to infection.

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery.

Centuries since it was first described, tuberculosis (TB) remains a significant global public health issue. Despite ongoing holistic measures implemented by health authorities and a number of new oral treatments reaching the market, there is still a need for an advanced, efficient TB treatment. An adjunctive, host-directed therapy designed to enhance endogenous pathways and hence compliment current regimens could be the answer. The integration of drug repurposing, including synthetic and naturally occurring compounds, with a targeted drug delivery platform is an attractive development option. In order for a new anti-tubercular treatment to be produced in a timely manner, a multidisciplinary approach should be taken from the outset including stakeholders from academia, the pharmaceutical industry, and regulatory bodies keeping the patient as the key focus. Pre-clinical considerations for the development of a targeted host-directed therapy are discussed here.

A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling.

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.