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T cells are activated by antigen and co-stimulatory receptor signaling and undergo robust proliferation and differentiation into effector cells with protective function. Such quantitatively and qualitatively amplified T cell responses are effective in controlling acute infection and are followed by contraction of the effector population and the formation of resting memory T cells for enhanced protection against previously experienced antigens. However, in the face of persistent antigen during chronic viral infection, in autoimmunity, or in the tumor microenvironment, T cells exhibit distinct responses relative to those in acute insult in several aspects, including reduced clonal expansion and impaired effector function associated with inhibitory receptor expression, a state known as exhaustion. Nevertheless, their responses to chronic infection and tumors are sustained through the establishment of hierarchical heterogeneity, which preserves the duration of the response by generating newly differentiated effector cells. In this review, we highlight recent findings on distinct dynamics of T cell responses under “exhausting” conditions and the roles of the transcription factors that support attenuated yet long-lasting T cell responses as well as the establishment of dysfunctional states.

At the 2023 Conference on Retroviruses and Opportunistic Infections (CROI), several investigators used tests of recent HIV infection to track which populations are currently most heavily impacted by HIV and to estimate HIV infection rates in those populations. Assisted partner notification for HIV was successfully applied for spouses of persons with HIV and sexual and injection partners of people who inject drugs; however, delays in linkage to care were seen for non-spousal partners in one study. Lack of awareness of HIV positive status remains an issue in various populations; several presentations focused on novel strategies for improving HIV testing uptake in these populations. Doxycycline administered as 200 mg post sexual exposure significantly reduced the risk of syphilis, chlamydia, and gonorrhea infection in men who have sex with men but did not prevent bacterial sexually transmitted infections in cisgender women; reasons for this discrepancy are currently being explored. Although oral HIV preexposure prophylaxis (PrEP) is increasingly being used in populations in greatest need of prevention tools, PrEP uptake and persistence remain low in a number of key populations, including people who inject drugs. Several innovative delivery models show early promise in addressing gaps along the PrEP continuum. The successful use of injectable cabotegravir PrEP in several populations was presented at this conference, although uptake remains low globally. The pipeline of novel long-acting and rapid-onset PrEP agents appears to be robust, including implants, vaginal rings, and topical inserts, with several presentations focusing on preclinical and early clinical trials.

Several innovative methods were presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI) targeting different aspects of the HIV care continuum to improve testing, linkage to care, and viral suppression. Some of these approaches were directed at more vulnerable groups, such as pregnant women, adolescents, and individuals who inject drugs. In contrast was the devastating impact of the COVID-19 pandemic, with negative outcomes on HIV viral load suppression and retention in care. Data were presented on hepatitis B virus (HBV) suppression showing that tenofovir alafenamide (TAF)/emtricitabine (FTC)/bictegravir (BIC) may be superior to tenofovir disoproxil fumarate/FTC plus dolutegravir in suppressing HBV in HIV/HBV-coinfected individuals. A pilot study examining a 4-week trial of direct-acting antiviral therapy to treat hepatitis C in recently infected individuals showed lower rates of sustained virologic response at 12 weeks than longer courses. Additional data were presented on the use of long-acting cabotegravir/rilpivirine, comparing this regimen with oral TAF/FTC/BIC and the use of long-acting cabotegravir/rilpivirine in those with viremia. Data were presented on a novel strategy of lenacapavir with 2 broadly neutralizing antibodies given every 6 months as maintenance antiretroviral therapy (ART). Data were presented on improving HIV care outcomes in adolescents, interventions to prevent mother-to-child transmission, and HIV reservoirs in children and adolescents. Data were also presented on interactions between ART and hormonal contraception, as well as ART-related weight gain and impact on pregnancy. A study examining BIC pharmacokinetics in pregnancy was presented, as well as retrospective data on outcomes of adolescents receiving TAF/FTC/BIC.

The 2023 Conference on Retroviruses and Opportunistic Infections (CROI) emphasized emerging infectious diseases such as COVID-19 and mpox. Despite emerging from countries in which it was endemic only 9 months before the conference, mpox was well covered, with more than 60 presentations addressing various topics. There was a focus on the rapid development and implementation of tests to reduce the time to diagnosis, as well as multiplex panels to increase the accuracy of differential diagnosis. Presenters also highlighted the ability to diagnose mpox from multiple compartments, such as with rectal and pharyngeal swabs, and provided crucial information on the duration of positivity that may impact isolation requirements. Clinical experiences were described, including risk factors for severe disease and syndemic management. High rates of concomitant sexually transmitted infection (STI) were reported. Finally, prevention was a key topic, with presenters pointing to the contributions of individual behavioral changes and vaccine efficacy to reducing new cases.

Studies of acute and post-acute COVID-19 were presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI). Early treatment with ensitrelvir, a novel protease inhibitor, hastened viral clearance and symptom resolution during coronavirus disease 2019 (COVID-19) and appeared to reduce the prevalence of long COVID symptoms. The development of novel agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including those with broader sarbecovirus activity such as anti-angiotensin-converting enzyme 2 monoclonal antibodies, is underway. A growing understanding of the pathophysiology of long COVID has provided several potential therapeutic targets for individuals experiencing this condition. Efforts to understand COVID-19 in people with HIV have led to novel insights into the biology and natural history of SARS-CoV-2 coinfection in this vulnerable subpopulation. These and other studies are summarized herein.

BACKGROUND: Respiratory infections are increasingly difficult to treat due to the emergence of multidrug-resistant bacteria. Rediscovery and implementation of inhaled bacteriophage (phage) therapy as a standalone or supplement to antibiotic therapy is becoming recognized as a promising solution to combating respiratory infections caused by these superbugs. To ensure maximum benefit of the treatment, phages must remain stable during formulation as a liquid or powder and delivery using a nebulizer or dry powder inhaler. METHODS: Pseudomonas-targeting PEV phages were used as model phages to assess the feasibility of aerosolizing biologically viable liquid formulations using commercial nebulizers in the presence and absence of inhaled antibiotics. The advantages of powder formulations were exploited by spray drying to produce inhalable powders containing PEV phages with and without the antibiotic ciprofloxacin. RESULTS: The produced phage PEV20 and PEV20–ciprofloxacin powders remained stable over long-term storage and exhibited significant bacterial killing activities in a mouse lung infection model. CONCLUSION: These studies demonstrated that inhaled phage (-antibiotic) therapy has the potential to tackle respiratory infections caused by superbugs.

Joint immobilization is frequently administered after fractures and ligament injuries and can cause joint contracture as a side effect. The structures responsible for immobilization-induced joint contracture can be roughly divided into muscular and articular. During remobilization, although myogenic contracture recovers spontaneously, arthrogenic contracture is irreversible or deteriorates further. Immediately after remobilization, an inflammatory response is observed, characterized by joint swelling, deposit formation in the joint space, edema, inflammatory cell infiltration, and the upregulation of genes encoding proinflammatory cytokines in the joint capsule. Subsequently, fibrosis in the joint capsule develops, in parallel with progressing arthrogenic contracture. The triggers of remobilization-induced joint inflammation are not fully understood, but two potential mechanisms are proposed: 1) micro-damage induced by mechanical stress in the joint capsule, and 2) nitric oxide (NO) production via NO synthase 2. Some interventions can modulate remobilization-induced inflammatory and subsequent fibrotic reactions. Anti-inflammatory treatments, such as steroidal anti-inflammatory drugs and low-level laser therapy, can attenuate joint capsule fibrosis and the progression of arthrogenic contracture in remobilized joints. Antiproliferative treatment using the cell-proliferation inhibitor mitomycin C can also attenuate joint capsule fibrosis by inhibiting fibroblast proliferation without suppressing inflammation. Conversely, aggressive exercise during the early remobilization phases is counterproductive, because it facilitates inflammatory and then fibrotic reactions in the joint. However, the adverse effects of aggressive exercise on remobilization-induced inflammation and fibrosis are offset by anti-inflammatory treatment. To prevent the progression of arthrogenic contracture during remobilization, therefore, care should be taken to control inflammatory and fibrotic reactions in the joints.

Neutrophils are the most abundant innate immune cell and are equipped with highly destructive molecular cargo. As such, these cells were long thought to be short-lived killer cells that unleash their full cytotoxic programs on pathogens following infection and on host bystander cells after sterile injury. However, this view of neutrophils is overly simplistic and as a result is outdated. Numerous studies now collectively highlight neutrophils as far more complex and having a host of homeostatic and tissue-reparative functions. In this review, we summarize these underappreciated roles across organs and injury models.

Funder: British Infection Association; Id: http://dx.doi.org/10.13039/501100004664, Funder: Evelyn Trust; Id: http://dx.doi.org/10.13039/501100004282, Funder: NIHR Imperial Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100013342, Summary: Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen‐eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole‐like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase‐derived antimicrobial agents and granule‐delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate.

Transgender and gender-diverse populations have unique medical and psychosocial needs. It is important that clinicians address these needs with a gender-affirming approach in all aspects of health care for these populations. Given the significant burden of HIV experienced by transgender people, such approaches in providing HIV care and prevention are essential both to engage this population in care and to work toward ending the HIV epidemic. This review presents a framework for practitioners caring for transgender and gender-diverse individuals to deliver affirming, respectful health care in HIV treatment and prevention settings.

The golden age of antibiotics, which lasted from the 1930s until 2005, brought a brisk clip of antibiotic discovery and fueled optimism about the victory of modern medicine over bacterial infections. Since then, however, with a stalled antibiotic discovery effort and widespread antibiotic use, antimicrobial resistance has emerged as a major global health threat. Bacteriophages, or phages (literally viruses that infect certain bacteria), have coevolved with bacteria for almost 4 billion years and are the most abundant organisms on the earth. Substantial progress is being made such that selection, engineering, and synthetic production of phages may make it possible for these lethal enemies of bacteria to be harnessed as potent allies in our battle against antimicrobial resistance.

Hepatitis B virus (HBV) infection is common among people with HIV owing to shared modes of viral transmission. Compared with individuals with HBV infection alone, people with HIV/HBV coinfection experience an accelerated progression of liver disease, including increased risks for hepatocellular carcinoma, liver-related mortality, and all-cause mortality. Therefore, HBV screening and appropriate treatment are crucial for people with HIV. This article reviews the epidemiology, natural history, and management of HIV/HBV coinfection, as well as recommendations for prevention of HBV infection among people with HIV.

Project Co-ordinators: Dr. Jose Alfonso Gómez Calero (Instituto de Agricultura Sostenible (IAS-CISC), Dr. Weifeng Xu (Fujian Agriculture and Forest University, FAFU)., [Background] Soil salinity, in both natural and managed environments, is highly heterogeneous, and understanding how plants respond to this spatiotemporal heterogeneity is increasingly important for sustainable agriculture in the era of global climate change. While the vast majority of research on crop response to salinity utilizes homogeneous saline conditions, a much smaller, but important, effort has been made in the past decade to understand plant molecular and physiological responses to heterogeneous salinity mainly by using split-root studies. These studies have begun to unravel how plants compensate for water/nutrient deprivation and limit salt stress by optimizing root-foraging in the most favourable parts of the soil., [Scope] This paper provides an overview of the patterns of salinity heterogeneity in rain-fed and irrigated systems. We then discuss results from split-root studies and the recent progress in understanding the physiological and molecular mechanisms regulating plant responses to heterogeneous root-zone salinity and nutrient conditions. We focus on mechanisms by which plants (salt/nutrient sensing, root-shoot signalling and water uptake) could optimize the use of less-saline patches within the root-zone, thereby enhancing growth under heterogeneous soil salinity conditions. Finally, we place these findings in the context of defining future research priorities, possible irrigation management and crop breeding opportunities to improve productivity from salt-affected lands., E.B.L., T.C., I.C.D., P.B. and N.B. thank the University of Western Australia for funding the workshop. I.C.D. thanks the European Union (Project 773903 – SHui) for supporting ongoing work on split-root plants. N.B. was a recipient of the Marie Curie Fellowship funded by the European Union (grant 700001).

Recently, there has been an increasing interest on the sustainability advantage of 3D concrete printing (3DCP), where the original cement-based mixtures used for printing could be replaced or incorporated with environmental-friendly materials. The development in digital modeling and design tools also creates a new realm of form-finding architecture for 3DCP, which is based on topological optimization of volumetric mass and physical performance. This review provides a perspective of using different green cementitious materials, applications of structural optimization, and modularization methods for realizing sustainable construction with additive manufacturing. The fresh and hardened mechanical properties of various sustainable materials for extrusion-based 3D printing are presented, followed by discussions on different topology optimization techniques. The current state of global research and industrial applications in 3DCP, along with the development of sustainable construction materials, is also summarized. Finally, research and practical gaps identified in this review lead to several recommendations on material developments, digital design tool's prospects for 3DCP to achieve the sustainability goal.

Highlights • Older people are more susceptible to poor health outcomes after infection. • Ageing is associated with reduced antibody titres in response to vaccination, limiting vaccine efficacy. • A key contributing factor to the poor humoral immunity in ageing is the reduced size and function of the germinal centre response. • The diminished germinal centre response in ageing can be attributed to changes in many of the cellular players involved in the response., Vaccines are a highly effective intervention for conferring protection against infections and reducing the associated morbidity and mortality in vaccinated individuals. However, ageing is often associated with a functional decline in the immune system that results in poor antibody production in older individuals after vaccination. A key contributing factor of this age-related decline in vaccine efficacy is the reduced size and function of the germinal centre (GC) response. GCs are specialised microstructures where B cells undergo affinity maturation and diversification of their antibody genes, before differentiating into long-lived antibody-secreting plasma cells and memory B cells. The GC response requires the coordinated interaction of many different cell types, including B cells, T follicular helper (Tfh) cells, T follicular regulatory (Tfr) cells and stromal cell subsets like follicular dendritic cells (FDCs). This review discusses how ageing affects different components of the GC reaction that contribute to its limited output and ultimately impaired antibody responses in older individuals after vaccination. An understanding of the mechanisms underpinning the age-related decline in the GC response is crucial in informing strategies to improve vaccine efficacy and extend the healthy lifespan amongst older people.

The coronavirus disease 2019 (COVID-19) pandemic causes an overwhelming number of hospitalization and deaths with a significant socioeconomic impact. The vast majority of studies indicate that asthma and allergic diseases do not represent a risk factor for COVID-19 susceptibility nor cause a more severe course of disease. This raises the opportunity to investigate the underlying mechanisms of the interaction between an allergic background and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The majority of patients with asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies and drug allergies exhibit an over-expression of type 2 immune and inflammatory pathways with the contribution of epithelial cells, innate lymphoid cells, dendritic cells, T cells, eosinophils, mast cells, basophils, and the type 2 cytokines interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31. The potential impact of type 2 inflammation-related allergic diseases on susceptibility to COVID-19 and severity of its course have been reported. In this review, the prevalence of asthma and other common allergic diseases in COVID-19 patients is addressed. Moreover, the impact of allergic and non-allergic asthma with different severity and control status, currently available asthma treatments such as inhaled and oral corticosteroids, short- and long-acting β2 agonists, leukotriene receptor antagonists and biologicals on the outcome of COVID-19 patients is reviewed. In addition, possible protective mechanisms of asthma and type 2 inflammation on COVID-19 infection, such as the expression of SARS-CoV-2 entry receptors, antiviral activity of eosinophils and cross-reactive T-cell epitopes, are discussed. Potential interactions of other allergic diseases with COVID-19 are postulated, including recommendations for their management.

Introduction Male factor infertility concerns 7–10% of men and among these 40–60% remain unexplained. Sources of data This review is based on recent published literature regarding the genetic causes of male infertility. Areas of agreement Screening for karyotype abnormalities, biallelic pathogenic variants in the CFTR gene and Y-chromosomal microdeletions have been routine in andrology practice for >20 years, explaining ~10% of infertility cases. Rare specific conditions, such as congenital hypogonadotropic hypogonadism, disorders of sex development and defects of sperm morphology and motility, are caused by pathogenic variants in recurrently affected genes, which facilitate high diagnostic yield (40–60%) of targeted gene panel-based testing. Areas of controversy Progress in mapping monogenic causes of quantitative spermatogenic failure, the major form of male infertility, has been slower. No ‘recurrently’ mutated key gene has been identified and worldwide, a few hundred patients in total have been assigned a possible monogenic cause. Growing points Given the high genetic heterogeneity, an optimal approach to screen for heterogenous genetic causes of spermatogenic failure is sequencing exomes or in perspective, genomes. Clinical guidelines developed by multidisciplinary experts are needed for smooth integration of expanded molecular diagnostics in the routine management of infertile men. Areas timely for developing research Di−/oligogenic causes, structural and common variants implicated in multifactorial inheritance may explain the ‘hidden’ genetic factors. It is also critical to understand how the recently identified diverse genetic factors of infertility link to general male health concerns across lifespan and how the clinical assessment could benefit from this knowledge.

Emerging trends in technological innovations, data analysis and practical applications have facilitated the measurement of cycling power output in the field, leading to improvements in training prescription, performance testing and race analysis. This review aimed to critically reflect on power profiling strategies in association with the power-duration relationship in cycling, to provide an updated view for applied researchers and practitioners. The authors elaborate on measuring power output followed by an outline of the methodological approaches to power profiling. Moreover, the deriving a power-duration relationship section presents existing concepts of power-duration models alongside exercise intensity domains. Combining laboratory and field testing discusses how traditional laboratory and field testing can be combined to inform and individualize the power profiling approach. Deriving the parameters of power-duration modelling suggests how these measures can be obtained from laboratory and field testing, including criteria for ensuring a high ecological validity (e.g. rider specialization, race demands). It is recommended that field testing should always be conducted in accordance with pre-established guidelines from the existing literature (e.g. set number of prediction trials, inter-trial recovery, road gradient and data analysis). It is also recommended to avoid single effort prediction trials, such as functional threshold power. Power-duration parameter estimates can be derived from the 2 parameter linear or non-linear critical power model: P(t) = W′/t + CP (W′—work capacity above CP; t—time). Structured field testing should be included to obtain an accurate fingerprint of a cyclist’s power profile.

Interpositional gap arthroplasty has established itself as the the standard surgical treatment of Temporomandibular joint (TMJ) ankylosis. The autogenous tissue has replaced the alloplastic and other xenografts materials owing to its bioavailability, easy uptake, and no additional cost. Commonly used autogenous tissue has been temporalis muscle and fascia, fascia lata, skin graft, auricular and costal cartilage, the masseter and/or medial pterygoid muscle. With the turn of the century, TMJ surgeons started using autogenous fat from the lower abdomen and today it has taken over as the most favored autogenous filler material in TMJ ankylosis surgery or total joint replacement (TMJ-TJR). The use of buccal fat pad (BFP) has increased in the last decade due to its local availability and pedicled nature. This paper will discuss various autogenous tissues used in interposition and bring forth the journey of the autogenous fat as the preferred interpositional material now and rest the case in its favor.

The interleukin-17 (IL-17) family consists of six family members (IL-17A–IL-17F) and all the corresponding receptors have been identified recently. This family is mainly involved in the host defense mechanisms against bacteria, fungi and helminth infection by inducing cytokines and chemokines, recruiting neutrophils, inducing anti-microbial proteins and modifying T-helper cell differentiation. IL-17A and some other family cytokines are also involved in the development of psoriasis, psoriatic arthritis and ankylosing spondylitis by inducing inflammatory cytokines and chemokines, and antibodies against IL-17A as well as the receptor IL-17RA are being successfully used for the treatment of these diseases. Involvement in the development of inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and tumors has also been suggested in animal disease models. In this review, we will briefly review the mechanisms by which IL-17 cytokines are involved in the development of these diseases and discuss possible treatment of inflammatory diseases by targeting IL-17 family members., Graphical Abstract Graphical Abstract

Chemosensory processes are integral to the physiology of most organisms. This function is typically performed by specialized cells that are able to detect input signals and to convert them to an output dedicated to a particular group of target cells. Tuft cells are cholinergic chemosensory epithelial cells capable of producing immunologically relevant effector molecules. They are scattered throughout endoderm-derived hollow organs and function as sensors of luminal stimuli, which has been best studied in mucosal barrier epithelia. Given their epithelial origin and broad distribution, and based on their interplay with immune pathways, tuft cells can be considered a prototypical example of how complex multicellular organisms engage innate immune mechanisms to modulate and optimize organ physiology. In this review, I provide a concise overview of tuft cells and discuss how these cells influence organ adaptation to dynamic luminal conditions.

Autoimmune neurological disorders are commonly treated with immunosuppressive therapy. In patients with refractory conditions, standard immunosuppression is often insufficient for complete recovery or to prevent relapses. These patients rely on other treatments to manage their disease. While treatment of refractory cases differs between diseases, intravenous immunoglobulin, plasma exchange (PLEX), and immune-modulating treatments are commonly used. In this review, we focus on five autoimmune neurological disorders that were the themes of the 2018 Midlands Neurological Society meeting on PLEX in refractory neurology: Autoimmune Encephalitis (AE), Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum disorders (NMOSD), Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and Myasthenia Gravis (MG). The diagnosis of inflammatory neuropathies is often challenging, and while PLEX can be very effective in refractory autoimmune diseases, its ineffectiveness can be confounded by misdiagnosis. One example is POEMS syndrome (characterized by Polyneuropathy Organomegaly, Endocrinopathy, Myeloma protein, Skin changes), which is often wrongly diagnosed as CIDP; and while CIDP responds well to PLEX, POEMS does not. Accurate diagnosis is therefore essential. Success rates can also differ within ‘one’ disease: e.g. response rates to PLEX are considerably higher in refractory relapsing remitting MS compared to primary or secondary progressive MS. When sufficient efforts are made to correctly pinpoint the diagnosis along with the type and subtype of refractory autoimmune disease, PLEX and other immunotherapies can play a valuable role in the patient management. Graphical abstract

At the 2022 Conference on Retroviruses and Opportunistic Infections, several speakers discussed disparities in HIV and COVID-19 infections and outcomes. Although the lifetime risk of HIV infection in the United States is higher overall in males than females, Black females have higher risk than White males. In 12 countries in sub-Saharan Africa, women aged 15 to 34 years accounted for more than half of all infections. Because knowledge of HIV serostatus is important for treatment and for prevention, several novel strategies were evaluated in the distribution of HIV self-test kits to undertested populations in the United States and sub-Saharan Africa. Data were presented on new products in the pre-exposure prophylaxis (PrEP) pipeline, including long-acting injectable cabotegravir, islatravir, vaginal rings, and in-situ forming implants. Challenges remain in the rollout of oral PrEP, and a number of innovative strategies to address barriers were discussed. Models suggest that the greatest impact of novel PrEP agents would be to increase the pool of persons using PrEP, rather than through improved efficacy. COVID-19 caused substantial declines in HIV and sexually transmitted infection prevention and treatment services, which have started to rebound, but are not yet at prepandemic levels in several settings.

Comorbid conditions have a major impact on the health, quality of life, and survival of people with HIV, particularly as this population ages. The 2022 Conference on Retroviruses and Opportunistic Infections (CROI) featured excellent science related to specific comorbidities, such as cardiovascular disease, type 2 diabetes, cancer, and frailty. The role of systemic inflammation in the pathogenesis of cardiovascular disease was an important theme, with strong evidence regarding the impact of microbial translocation. Other studies examined functional impairment, frailty, and potential important contributors, such as concomitant medications and sleep disturbances. The ANCHOR (Anal Cancer/High-grade Squamous Intraepithelial Lesions Outcomes Research) study provided crucial evidence that treatment of high-risk anal lesions reduces the incidence of anal cancer, which has important implications in the prevention of this devastating comorbidity. In addition, numerous presentations demonstrated the importance of comorbid conditions in COVID-19 outcomes in people with HIV and described persistent symptoms after acute SARS-CoV-2 infection has resolved. This review focuses on the abstracts presented at CROI 2022 in these areas, highlighting those with the most clinical impact.

Tuberculosis (TB) remains the leading cause of death among people with HIV, and annual risk of progression from latent TB infection to active disease in this population is 10%. Diagnostic tests for latent and active TB remain suboptimal for people with HIV who have a CD4+ count below 200 cells/μL, and there is an urgent need for assays that predict progression from latent to active disease, monitor treatment response, and test for cure after latent and active TB treatment. Traditional treatment duration for latent infection and active TB disease has been onerous for patients; however, shorter-course regimens are increasingly available across the spectrum of TB, including for drug-resistant TB. Simultaneous treatment of HIV and TB is complicated by drug-drug interactions, although trials are ongoing to better understand the magnitude of these interactions and guide clinicians in how to use short-course regimens, particularly for people with HIV.

The Conference on Retroviruses and Opportunistic Infections (CROI) 2022, which was held as a virtual conference, continues to serve as the preeminent forum that features research advances in HIV-1 and its associated coinfections. The conference has extended its area of coverage to include research advances in SARS- CoV-2. As pointed out in the presentation from Hatziioannou in the New Investigators workshop, there has been an explosion in research activity on SARS-CoV-2 that has eclipsed that for HIV-1. In the past 12 months, there were approximately 6600 publications on HIV-1 and approximately 64,000 on SARS-CoV-2. Although these numbers include review articles, they reveal the tremendous response by researchers to the existential threats posed by lentiviruses and coronaviruses. This poses challenges for any conference committee tasked with selecting abstracts for presentation from the large number submitted for consideration. CROI organizers have consistently been able to assemble a program that, through invited presentations, abstract-driven talks, posters, interactive sessions, workshops, and symposia, showcases the most recent research advances.

Adolescents with HIV are growing into adulthood and are at risk for comorbidities. Comorbidities in adolescents often go unrecognized, increasing morbidity and mortality, and contributing to poorer outcomes for youth with HIV. Youth with perinatally and nonperinatally acquired HIV are at risk of developing HIV-associated and non-HIV comorbidities, including cardiovascular diseases, diabetes, mental health disorders, renal diseases, and bone disorders. Youth with HIV are also at risk for altered fat distribution and weight gain associated with certain classes of antiretroviral therapy. Sexually transmitted infections from inconsistent condom use pose a sexual health challenge for youth with HIV. Prompt interventions through comprehensive history taking, physical exams, regular screening, and prevention and treatment of clinically evident comorbid conditions are needed to prevent progression and complications.

The 2022 Conference on Retroviruses and Opportunistic Infections provided a rich source of new data and comprehensive reviews on antiviral therapy. For COVID-19, intramuscular sotrovimab was noninferior to intravenous sotrovimab, serostatus did not predict the efficacy of sotrovimab, and molnupiravir appeared safe and modestly effective in decreasing hospitalization rates. Trials from low- and middle-income countries provided data to support transitioning those on first-line therapy with or without virologic suppression and those virologically suppressed on second-line therapy to dolutegravir-based regimens. Additional data supported the use of lenacapavir as a long-acting antiretroviral drug. Data across the United States demonstrate the negative impact of the COVID-19 pandemic on the HIV care continuum, although enhanced outreach efforts and decentralization of antiretroviral therapy delivery were associated with improvements in care engagement outcomes. Researchers described potential mechanisms for the emergence of integrase strand transfer inhibitor resistance. Studies on proviral genotyping high-lighted the limitations of its use in predicting clinically significant resistance. Several studies looked at the epidemiology and treatment of hepatitis C and B and the status of current hepatitis C virus elimination efforts. Data presented on HIV, COVID-19, and maternal and pediatric health included 2-year virologic outcome data of very early antiretroviral therapy in potentially reducing the latent HIV reservoir in infants with HIV. Data presented on COVID-19 and HIV therapeutics in children included SARS-CoV-2-neutralizing monoclonal antibodies in children younger than 12 years of age, remdesivir in hospitalized infants and children, and long-acting therapies for HIV treatment in children.

The 2022 outbreak of monkeypox virus infection has expanded far beyond regions in which the disease was previously endemic. Monkeypox has a wide range of manifestations, some of which are unique to this outbreak. Novel clinical presentations, testing limitations, and a lack of available treatments have contributed to delays in recognition, diagnosis, and treatment of monkeypox. As health care workers and governments fight this rare viral infection, which may become a routine diagnosis, early recognition of potential signs and symptoms along with appropriate testing is essential to prevent continuing spread and potential endemicity.

The 2022 Conference on Retroviruses and Opportunistic Infections featured new and important findings about the neurologic complications of HIV-1, COVID-19, and other infections. Long-term analyses identified that cognitive decline over time, phenotypic aging, and stroke are associated with various comorbidities in people with HIV. Neuroimaging studies showed greater neuroinflammation, white matter damage, demyelination, and overall brain aging in people with chronic HIV infection. Childhood trauma and exposure to environmental pollutants contribute to these neuroimaging findings. Studies of blood and cerebrospinal fluid biomarkers showed that systemic inflammation, neurodegeneration, endothelial activation, oxidative stress, and iron dysregulation are associated with worse cognition in people with HIV. Some animal studies focused on myeloid cells of the central nervous system, but other animal and human studies showed that lymphoid cells also contribute to HIV neuropathogenesis. The deleterious central nervous system effects of polypharmacy and anticholinergic drugs in people with HIV were demonstrated. In contrast, a large randomized controlled trial showed that integrase strand transfer inhibitor therapy was not associated with neurotoxicity. Studies of cryptococcal meningitis demonstrated the cost-effectiveness of single high-dose liposomal amphotericin and the prognostic value of the cryptococcal antigen lateral flow assay. People hospitalized with COVID-19 had more anxiety over time after discharge. The SARS-CoV-2 nucleocapsid antigen is present in cerebrospinal fluid in the absence of viral RNA. Systemic inflammation, astrocyte activation, and tryptophan metabolism pathways are associated with post-COVID-19 neurologic syndromes. Whether these processes are independent or intertwined during HIV-1 and COVID-19 infections requires further study.

The infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and resultant coronavirus diseases-19 (COVID-19) disproportionally affects minorities, especially African Americans (AA) compared to the Caucasian population. The AA population is disproportionally affected by COVID-19, in part, because they have high prevalence of underlying conditions such as obesity, diabetes, and hypertension, which are known to exacerbate not only kidney diseases, but also COVID-19. Further, a decreased adherence to COVID-19 guidelines among tobacco smokers could result in increased infection, inflammation, reduced immune response, and lungs damage, leading to more severe form of COVID-19. As a result of high prevalence of underlying conditions that cause kidney diseases in the AA population coupled with tobacco smoking make the AA population vulnerable to severe form of both COVID-19 and kidney diseases. In this review, we describe how tobacco smoking interact with SARS-CoV-2 and exacerbates SARS-CoV-2-induced kidney diseases including renal failure, especially in the AA population. We also explore the role of extracellular vesicles (EVs) in COVID-19 patients who smoke tobacco. EVs, which play important role in tobacco-mediated pathogenesis in infectious diseases, have also shown to be important in COVID-19 pathogenesis and organ injuries including kidney. Further, we explore the potential role of EVs in biomarker discovery and therapeutics, which may help to develop early diagnosis and treatment of tobacco-induced renal injury in COVID-19 patients, respectively. Graphical Abstract

Group 2 innate lymphoid cells (ILC2s), discovered in 2010, have been recognized as immune cells with unique functions and their involvement in various diseases has been clarified. Before 2010, the antigen-specific response was a primary focus of immunology research, and immune responses were considered almost equivalent to biological responses to foreign antigens. However, with the emergence of ILC2s, the importance of ‘antigen-independent responses’ was confirmed, and this concept has permeated basic and clinical research as well as drug development. When ILC2s were discovered, their function in the acute phase of diseases garnered attention because of their rapid and potent type 2 immune response. However, several studies have revealed that the main role of ILC2s is more closely related to the chronicity of diseases, such as allergy and fibrosis, than to the induction of diseases. In this review, we discuss how ILC2 research has affected the concept of ‘Taishitsu’, a Japanese term describing the overall nature of an individual as determined by the interaction of genetic and acquired predisposition.

Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin diseases in the world. It is characterized by recurrent eczematous lesions and intense itch, and many cytokines are involved in the pathogenesis of AD. Among them, much attention has been paid to interleukin 31 (IL-31) as an AD-associated itch mediator. IL-31 is mainly produced by CD4+ helper T cells and transmits the signals via a heterodimeric receptor composed of IL-31 receptor A (IL-31RA) and oncostatin M receptor (OSMR), both of which are expressed in dorsal root ganglion (DRG) neurons. However, the molecular mechanisms of how IL-31 is produced in helper T cells upon stimulation and transmits the itch sensation to the brain were largely unknown. Recently, by using original mouse models of AD, we have identified endothelial PAS domain 1 (EPAS1) and neurokinin B (NKB) as key molecules critical for IL-31 production and IL-31-mediated itch transmission, respectively. These molecules could be novel drug targets for AD-associated itch. This review highlights our recent findings, which show the functional significance of these molecules in the IL-31-induced itch sensation, referring to their application to drug development.

Duchenne muscular dystrophy is a highly progressive muscle wasting disorder due to primary abnormalities in one of the largest genes in the human genome, the DMD gene, which encodes various tissue-specific isoforms of the protein dystrophin. Although dystrophinopathies are classified as primary neuromuscular disorders, the body-wide abnormalities that are associated with this disorder and the occurrence of organ crosstalk suggest that a multi-systems pathophysiological view should be taken for a better overall understanding of the complex aetiology of X-linked muscular dystrophy. This article reviews the molecular and cellular effects of deficiency in dystrophin isoforms in relation to voluntary striated muscles, the cardio-respiratory system, the kidney, the liver, the gastrointestinal tract, the nervous system and the immune system. Based on the establishment of comprehensive biomarker signatures of X-linked muscular dystrophy using large-scale screening of both patient specimens and genetic animal models, this article also discusses the potential usefulness of novel disease markers for more inclusive approaches to differential diagnosis, prognosis and therapy monitoring that also take into account multi-systems aspects of dystrophinopathy. Current therapeutic approaches to combat muscular dystrophy are summarised.

Purpose To explore sex-based differences in energy substrate utilization during moderate-intensity aerobic exercise; to identify the underpinning candidate physiological mechanisms. Methods Three databases were searched from inception to August 2020. Pertinent studies quantifying the utilization of substrates during moderate aerobic exercise in healthy men and reproductive-age women were considered. Studies conducted on sedentary/recreationally active and athletic populations were included and analyzed separately. Results Thirty-five studies entered the meta-analysis (21 in sedentary/recreationally active, 14 in athletic populations). Compared to women, the respiratory exchange ratio was significantly higher both in sedentary (mean difference, MD: + 0.03; p p p = 0.006) and athletic men (SMD: 1.24; p p = 0.0002), while no sex-based differences in fat oxidation were observed in athletes (SMD: 0.06; p = 0.77). Paucity of data prevented robust meta-analyses for protein sources. Sex hormones and different adrenergic activation were the most cited mechanisms to discuss sex-based differences. Conclusions Meta-analyses confirmed that men display greater reliance on carbohydrates while women rely more on lipids to sustain moderate aerobic exercise. The latter finding was not confirmed in athletes, a novel aspect of the present study. Mechanistically driven research is needed to further dissect the physiological underpinnings of sex differences in substrate utilization during aerobic exercise, especially for proteins, which are still less investigated than other substrates.

BackgroundDue to fear and/or behaviour management problems, some children are unable to cooperate for dental treatment using local anaesthesia and psychological support alone. Sedation is required for these patients in order for dentists to be able to deliver high quality, pain-free dental care.The aim of this guideline is to evaluate the efficacy and relative efficacy of conscious sedation agents and dosages for behaviour management in paediatric dentistry and to provide guidance as to which sedative agents should be used.MethodsThese guidelines were developed using a multi-step approach adapted from that outlined by the National Institute for Clinical Excellence (NICE (2020) Developing NICE Guidelines: the manual.https://www.nice.org.uk/process/pmg20/chapter/introduction#main-stages-of-guideline-development. Accessed 7 Oct 2020). Evidence for this guideline was provided from a pre-existing Cochrane review (Ashley et al. Cochrane Database Syst Rev 12:CD003877, 2018) supplemented by an updated search and data extraction up to May 2020.ResultsStudies were from 18 different countries and had recruited 4131 participants overall with an average of 70 participants per study. Ages ranged from 0 to 16 years with an average age of 5.6 years across all included studies. A wide variety of drugs or combinations of drugs (n = 38) were used and delivered orally, intranasally, intravenously, rectally, intramuscularly, submucosally, transmucosally or by inhalation sedation. Twenty-four different outcome measures for behaviour were used. The wide range of drug combinations and outcome measures used greatly complicated description and analysis of the data.ConclusionOral midazolam is recommended for conscious dental sedation. Midazolam delivered via other methods or nitrous oxide/oxygen sedation could be considered, but the evidence for both was very low.

Summary: The definition of consciousness has been the subject of great interest for many scientists and philosophers. To better understand how evoked potentials may be identified as biomarkers of consciousness and recovery, the different theoretical models sustaining neural correlates of consciousness are reviewed. A multimodal approach can help to better predict clinical outcome in patients presenting with disorders of consciousness. Evoked potentials are inexpensive and easy-to-implement bedside examination techniques. Evoked potentials are an integral part of prognostic evaluation, particularly in cases of cognitive motor dissociation. Prognostic criteria are well established in postanoxic disorders of consciousness, especially postcardiac arrest but are less well determined in other etiologies. In the early examination, bilateral absence of N20 in disorder of consciousness patients is strongly associated with unfavorable outcome (i.e., death or unresponsive wakefulness syndrome) especially in postanoxic etiologies. This predictive value is lower in other etiologies and probably also in children. Both N20 and mismatch negativity are proven outcome predictors for acute coma. Many studies have shown that mismatch negativity and P3a are characterized by a high prognostic value for awakening, but some patients presenting unresponsive wakefulness syndrome also process a P3a. The presence of long-latency event-related potential components in response to stimuli is indicative of a better recovery. All neurophysiological data must be integrated within a multimodal approach combining repeated clinical evaluation, neuroimaging, functional imaging, biology, and neurophysiology combining passive and active paradigms.

The oral and nasal cavities are covered by the mucosal epithelium that starts at the beginning of the aero-digestive tract. These mucosal surfaces are continuously exposed to environmental antigens including pathogens and allergens and are thus equipped with a mucosal immune system that mediates initial recognition of pathogenicity and initiates pathogen-specific immune responses. At the dawn of our scientific effort to explore the mucosal immune system, dental science was one of the major driving forces as it provided insights into the importance of mucosal immunity and its application for the control of oral infectious diseases. The development of mucosal vaccines for the prevention of dental caries was thus part of a novel approach that contributed to building the scientific foundations of the mucosal immune system. Since then, mucosal immunology and vaccines have gone on a scientific journey to become one of the major entities within the discipline of immunology. Here, we introduce our past and current efforts and future directions for the development of mucosal vaccines, specifically a rice-based oral vaccine (MucoRice) and a nanogel-based nasal vaccine, with the aim of preventing and controlling gastrointestinal and respiratory infectious diseases using the interdisciplinary fusion of mucosal immunology with agricultural science and biomaterial engineering, respectively.

Introduction Exercise is one of several factors known to lower the risk of developing cancer, as well as improve outcomes in patients already diagnosed. People who exercise after cancer have lower rates of cancer complications, treatment toxicities, relapse and improved survival. This review highlights the supportive data and biochemical processes, which explain these potential benefits. Sources of data PubMed, Embase, Medline and Cochrane libraries were searched for papers which addressed the effects of exercise and physical activity on cancer for this review. The search terms used were physical activity, exercise and cancer up to February 2021. We also referred to the background research required for international exercise intervention study involving men with prostate cancer (INTERVAL-GAP4) and scrutinized references within the robust papers published on this subject to ensure we did not miss any clinically studies. One hundred and eighty eight papers were included. Areas of agreement Exercise programmes mitigate many of the complications and risks associated with cancer, particularly thromboembolism, fatigue, weight gain, arthralgia, cognitive impairment and depression. Areas of controversy Molecular and biomarker changes, resulting from exercise, suggest that exercise elicits beneficial changes in insulin-related pathways, down-regulates inflammation and serum oestrogen levels, and enhances oxidative, immune and cellular repair pathways. Nonetheless, the evidence remains preliminary. Growing points The timing, intensity and challenges of prehabilitation, adjunct and rehabilitation exercise programmes are being increasingly understood but their implementation remains sporadic. Areas for developing research More robust clinical trial data are needed to substantiate a causal effect of exercise on overall and cancer-specific survival. These studies are ongoing. Research evaluating the most cost-efficient ways of incorporating prehabilitation, adjunct and rehabilitation programmes into routine practice would be helpful to funding bodies and health care strategists.

In recent years, epidemiological studies have consistently demonstrated that the coexistence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) is strongly associated with increased mortality and morbidity related to hepatic- and extrahepatic causes. Indeed, compared with the general population, patients with T2DM are more likely to be diagnosed with more severe forms of NAFLD (i.e., nonalcoholic steatohepatitis (NASH) with liver fibrosis). There is an ongoing debate whether NALFD is a consequence of diabetes or whether NAFLD is simply a component and manifestation of the metabolic syndrome, since liver fat (steatosis) and even more advanced stages of liver fibrosis can occur in the absence of diabetes. Nevertheless, insulin resistance is a key component of the mechanism of NAFLD development; furthermore, therapies that lower blood glucose concentrations also appear to be effective in the treatment of NAFLD. Here, we will discuss the pathophysiological and epidemiological associations between NAFLD and T2DM. We will also review currently available anti-diabetic agents with their regard to their efficacy of NAFLD/NASH treatment. Open Access funding enabled and organized by Projekt DEAL

Amino acid supplementation may be indicated to correct for insufficient amino acid intake in healthy individuals, and in specific physiological or pathophysiological situations. However, there is a concern to not supplement beyond the tolerable upper intake level (UL) by determining parameters of no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for each amino acid. Since the NOAEL and LOAEL values are at least one order of magnitude different when comparing the values obtained in rats and humans, the aim of this review is to evaluate to what extent the amino acid UL measured in the rat model, when referenced to the dietary usual consumption (UC) and dietary requirement (RQ) for indispensable amino acids, may be used as an approximation of the UL in humans. This review then compares the ratios of the NOAEL or LOAEL over UC and RQ in the rat model with the same ratios calculated in humans for the nine amino acids (arginine, serine, glycine, histidine, leucine, lysine, methionine, phenylalanine, and tryptophan) for which this comparison can be done. From the calculations made, it appears that for these 9 amino acids, the calculated ratios for rats and humans, although rather different for several amino acids, remains for all of them in the same order of magnitude. For tryptophan, tyrosine, and valine, the ratios calculated in rats are markedly different according to the sex of animals, raising the view that it may be also the case in humans.

As a nitric oxide (NO) enhancer, citrulline malate (CM) has recently been touted as a potential ergogenic aid to both resistance and high-intensity exercise performance, as well as the recovery of muscular performance. The mechanism has been associated with enhanced blood flow to active musculature, however, it might be more far-reaching as either ammonia homeostasis could be improved, or ATP production could be increased via greater availability of malate. Moreover, CM might improve muscle recovery via increased nutrient delivery and/or removal of waste products. To date, a single acute 8 g dose of CM on either resistance exercise performance or cycling has been the most common approach, which has produced equivocal results. This makes the effectiveness of CM to improve exercise performance difficult to determine. Reasons for the disparity in conclusions seem to be due to methodological discrepancies such as the testing protocols and the associated test–retest reliability, dosing strategy (i.e., amount and timing), and the recent discovery of quality control issues with some manufacturers stated (i.e., citrulline:malate ratios). Further exploration of the optimal dose is therefore required including quantification of the bioavailability of NO, citrulline, and malate following ingestion of a range of CM doses. Similarly, further well-controlled studies using highly repeatable exercise protocols with a large aerobic component are required to assess the mechanisms associated with this supplement appropriately. Until such studies are completed, the efficacy of CM supplementation to improve exercise performance remains ambiguous.

Sexual selection is a key component of evolutionary biology. However, from the very formulation of sexual selection by Darwin, the nature and extent of sexual selection have been controversial. Recently, such controversy has led back to the fundamental question of just what sexual selection is. This has included how we incorporate female-female reproductive competition into sexual or natural selection. In this review, we do four things. First, we examine what we want a definition to do. Second, we define sexual selection: sexual selection is any selection that arises from fitness differences associated with nonrandom success in the competition for access to gametes for fertilization. An important outcome of this is that as mates often also offer access to resources, when those resources are the targets of the competition, rather than their gametes, the process should be considered natural rather than sexual selection. We believe this definition encapsulates both much of Darwin’s original thinking about sexual selection, and much of how contemporary biologists use the concept of sexual selection. Third, we address alternative definitions, focusing in some detail on the role of female reproductive competition. Fourth, we challenge our definition with a number of scenarios, for instance where natural and sexual selection may align (as in some forms of endurance rivalry), or where differential allocation means teasing apart how fecundity and access to gametes influence fitness. In conclusion, we emphasize that whilst the ecological realities of sexual selection are likely to be complex, the definition of sexual selection is rather simple., Sexual selection is a crucial component of evolutionary biology yet debate over what forms of selection do or don’t comprise sexual selection have re-surfaced over the last couple of decades. Here we provide and justify a definition of sexual selection, that is focused on competition for access to gametes, and challenge that definition with ecologically complex scenarios. We hope this will allow the field to move forward, building on a firm conceptual basis.

Immunoglobulin G (IgG) therapy is an established long‐term treatment in chronic inflammatory demyelinating polyneuropathy (CIDP) that is commonly administered intravenously (IVIg). The subcutaneous immunoglobulin (SCIg) administration route is a safe and effective alternative option, approved by the United States Food and Drug Administration (FDA) in 2018, for maintenance treatment of adults with CIDP. Physicians and patients alike need to be aware of all their treatment options in order to make informed decisions and plan long‐term treatment strategies. In this review, we collate the evidence for SCIg in CIDP from all published studies and discuss their implications and translation to clinical practice. We also provide guidance on the practicalities of how and when to transition patients from IVIg to SCIg and ongoing patient support. Evidence suggests that IVIg and SCIg have comparable long‐term efficacy in CIDP. However, SCIg can provide additional benefits for some patients, including no requirement for venous access or premedication, and reduced frequency of systemic adverse events. Local‐site reactions are more common with SCIg than IVIg, but these are mostly well‐tolerated and abate with subsequent infusions. Data suggest that many patients prefer SCIg following transition from IVIg. SCIg preference may be a result of the independence and flexibility associated with self‐infusion, whereas IVIg preference may be a result of familiarity and reliance on a healthcare professional for infusions. In practice, individualizing maintenance dosing based on disease behavior and determining the minimally effective IgG dose for individuals are key considerations irrespective of the administration route chosen.

Pulmonary fibrosis (PF) is a disease in which excessive extracellular matrix (ECM) accumulation occurs in the lungs, which induces thickening of the alveolar walls, ultimately leading to the destruction of alveolar structures and respiratory failure. Idiopathic PF, the cause of which is unknown, has a poor prognosis with a median survival of 2–4 years after diagnosis. There is currently no known curative treatment. The mechanism underlying PF is thought to be initiated by the dysfunction of type II alveolar epithelial cells, which leads to ECM overproduction through the activation of fibroblasts. In addition, it has been suggested that a variety of cells contribute to fibrotic processes. In particular, clinical and basic research findings examining the roles of macrophages suggest that they may be pivotal regulators of PF. In this review, we discuss the characteristics, functions and origins of subsets of macrophages involved in PF, including resident alveolar, interstitial and monocyte-derived macrophages.

Fibrosis results from aberrant wound healing and is characterized by an accumulation of extracellular matrix, impairing the function of an affected organ. Increased deposition of extracellular matrix proteins, disruption of matrix degradation, but also abnormal post‐translational modifications alter the biochemical composition and biophysical properties of the tissue microenvironment – the stroma. Macrophages are known to play an important role in wound healing and tissue repair, but the direct influence of fibrotic stroma on macrophage behaviour is still an under‐investigated element in the pathogenesis of fibrosis. In this review, the current knowledge on interactions between macrophages and (fibrotic) stroma will be discussed from biochemical, biophysical, and cellular perspectives. Furthermore, we provide future perspectives with regard to how macrophage–stroma interactions can be examined further to ultimately facilitate more specific targeting of these interactions in the treatment of fibrosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Contains fulltext : 234014.pdf (Publisher’s version ) (Open Access) Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Semaphorins were originally identified as axon-guidance molecules essential for neural development. In addition to their functions in the neural system, members of the semaphorin family have critical functions in many pathophysiological processes, including immune responses, bone homeostasis, cancer and metabolic disorders. In particular, several lines of evidence indicate that mammalian/mechanistic target of rapamycin (mTOR), a central regulator of cell metabolism, regulates the functions of semaphorins in various types of cells, revealing a novel link between semaphorins and cell metabolism. In this review, we discuss recent advances in the immunometabolic functions of semaphorins, with a particular focus on mTOR signaling.

Clonal haematopoiesis (CH) is a phenomenon whereby somatic mutations confer a fitness advantage to haematopoietic stem and progenitor cells (HSPCs) and thus facilitate their aberrant clonal expansion. These mutations are carried into progeny leucocytes leading to a situation whereby a substantial fraction of an individual’s blood cells originate from the HSPC mutant clone. Although this condition rarely progresses to a haematological malignancy, circulating blood cells bearing the mutation have the potential to affect other organ systems as they infiltrate into tissues under both homeostatic and disease conditions. Epidemiological and clinical studies have revealed that CH is highly prevalent in the elderly and is associated with an increased risk of cardiovascular disease and mortality. Recent experimental studies in murine models have assessed the most commonly mutated ‘driver’ genes associated with CH, and have provided evidence for mechanistic connections between CH and cardiovascular disease. A deeper understanding of the mechanisms by which specific CH mutations promote disease pathogenesis is of importance, as it could pave the way for individualized therapeutic strategies targeting the pathogenic CH gene mutations in the future. Here, we review the epidemiology of CH and the mechanistic work from studies using murine disease models, with a particular focus on the strengths and limitations of these experimental systems. We intend for this review to help investigators select the most appropriate models to study CH in the setting of cardiovascular disease.

With the advent of antiretroviral therapy (ART), the prognosis of people infected with human immunodeficiency virus (HIV) has improved, and the frequency of HIV-related central nervous system (CNS) diseases has decreased. Nevertheless, mortality from HIV-related CNS diseases, including those associated with ART (e.g., immune reconstitution inflammatory syndrome) remains significant. Magnetic resonance imaging (MRI) can improve the outlook for people with HIV through early diagnosis and prompt treatment. For example, HIV encephalopathy shows a diffuse bilateral pattern, whereas progressive multifocal leukoencephalopathy, HIV-related primary CNS lymphoma, and CNS toxoplasmosis show focal patterns on MRI. Among the other diseases caused by opportunistic infections, CNS cryptococcosis and CNS tuberculosis have extremely poor prognoses unless diagnosed early. Immune reconstitution inflammatory syndrome shows distinct MRI findings from the offending opportunistic infections. Although distinguishing between HIV-related CNS diseases based on imaging alone is difficult, in this review, we discuss how pattern recognition approaches can contribute to their early differentiation.