Cachexia: A systemic consequence of progressive, unresolved disease.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.

Approaches and advances in the genetic causes of autoimmune disease and their implications.

Genome-wide association studies are transformative in revealing the polygenetic basis of common diseases, with autoimmune diseases leading the charge. Although the field is just over 10 years old, advances in understanding the underlying mechanistic pathways of these conditions, which result from a dense multifactorial blend of genetic, developmental and environmental factors, have already been informative, including insights into therapeutic possibilities. Nevertheless, the challenge of identifying the actual causal genes and pathways and their biological effects on altering disease risk remains for many identified susceptibility regions. It is this fundamental knowledge that will underpin the revolution in patient stratification, the discovery of therapeutic targets and clinical trial design in the next 20 years. Here we outline recent advances in analytical and phenotyping approaches and the emergence of large cohorts with standardized gene-expression data and other phenotypic data that are fueling a bounty of discovery and improved understanding of human physiology.

Infection perturbs Bach2- and Bach1-dependent erythroid lineage 'choice' to cause anemia.

Elucidation of how the differentiation of hematopoietic stem and progenitor cells (HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesis by regulating heme metabolism in committed erythroid cells to sustain erythroblast maturation and by reinforcing erythroid commitment at the erythro-myeloid bifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPß, as well as that of its target genes encoding molecules important for myelopoiesis and inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPß. Lipopolysaccharide diminished the expression of Bach TFs in progenitor cells and promoted myeloid differentiation. Overexpression of Bach2 in HSPCs promoted erythroid development and inhibited myelopoiesis. Knockdown of BACH1 or BACH2 in human CD34+ HSPCs impaired erythroid differentiation in vitro. Thus, Bach TFs accelerate erythroid commitment by suppressing the myeloid program at steady state. Anemia of inflammation and myelodysplastic syndrome might involve reduced activity of Bach TFs.

Common ground: shared risk factors for type 1 diabetes and celiac disease.

Risk factors for most autoimmune diseases are multifactorial genetic variants modified by environmental risk factors. Type 1 diabetes and celiac disease share high-risk HLA haplotypes, and the prevalence of both diseases has increased in many regions during the past half century. Unknown environmental factors are suspected to have increased the disease penetrance. Celiac disease depends on immune responses to dietary gluten, whereas the environmental risk factors for type 1 diabetes are not yet clear. Here, we consider the shared heritable genetic factors and review evidence of the dietary and microbial exposures, particularly in early life, that might influence the pathogenesis of one or both diseases. A deeper mechanistic understanding of the environmental factors responsible for increased risk of these diseases should provide opportunities to manipulate exposure in children carrying defined risk markers and thus prevent and attenuate disease, as well as to identify new therapeutic strategies for patients.

The Integrative Human Microbiome Project.

The NIH Human Microbiome Project (HMP) has been carried out over ten years and two phases to provide resources, methods, and discoveries that link interactions between humans and their microbiomes to health-related outcomes. The recently completed second phase, the Integrative Human Microbiome Project, comprised studies of dynamic changes in the microbiome and host under three conditions: pregnancy and preterm birth; inflammatory bowel diseases; and stressors that affect individuals with prediabetes. The associated research begins to elucidate mechanisms of host-microbiome interactions under these conditions, provides unique data resources (at the HMP Data Coordination Center), and represents a paradigm for future multi-omic studies of the human microbiome.

Diabetes and infection: review of the epidemiology, mechanisms and principles of treatment.

An association between diabetes and infection has been recognised for many years, with infection being an important cause of death and morbidity in people with diabetes. The COVID-19 pandemic has re-kindled an interest in the complex relationship between diabetes and infection. Some infections occur almost exclusively in people with diabetes, often with high mortality rates without early diagnosis and treatment. However, more commonly, diabetes is a complicating factor in many infections. A reciprocal relationship occurs whereby certain infections and their treatments may also increase the risk of diabetes. People with diabetes have a 1.5- to 4-fold increased risk of infection. The risks are the most pronounced for kidney infection, osteomyelitis and foot infection, but are also increased for pneumonia, influenza, tuberculosis, skin infection and general sepsis. Outcomes from infection are worse in people with diabetes, with the most notable example being a twofold higher rate of death from COVID-19. Hyperglycaemia has deleterious effects on the immune response. Vascular insufficiency and neuropathy, together with altered skin, mucosal and gut microbial colonisation, contribute to the increased risk of infection. Vaccination is important in people with diabetes although the efficacy of certain immunisations may be compromised, particularly in the presence of hyperglycaemia. The principles of treatment largely follow those of the general population with certain notable exceptions.

Management of postinfectious inflammatory arthritis.

PURPOSE OF REVIEW: Postinfectious inflammatory arthritis can result from various pathogens, including bacteria, viruses, fungi, and parasites. Prompt identification and treatment of acute infection is vital, but some cases progress to chronic arthritis despite successful treatment of infection. Postinfectious inflammatory arthritis varies from mild, self-limited arthralgia to severe, refractory arthritis, necessitating ongoing disease-modifying treatment. This review explores the spectrum of postinfectious inflammatory arthritis to provide insights into effective management. RECENT FINDINGS: Research continues regarding the benefit of antimicrobial therapy, beyond treatment of the acute infection, to diminish the severity of postinfectious inflammatory arthritis. Following treatment of acute infection, most cases are self-limited so treatment is symptomatic. However, a difficult-to-predict fraction of cases develop chronic postinfectious inflammatory arthritis that can be challenging to manage. Recently, as more biologic, and targeted synthetic DMARDs have become available, treatment options have expanded. SUMMARY: In this article, we use the term 'postinfectious inflammatory arthritis' rather than 'reactive arthritis' because it describes a broader spectrum of diseases and emphasizes the common pathogenesis of a postinfectious inflammatory process. We summarize the conventional therapies and recent management developments for the most frequently encountered postinfectious inflammatory arthritides.

How I manage infection risk and prevention in patients with lymphoid cancer.

Infections are a common cause of morbidity and mortality in patients with lymphoid cancer. Because cancer therapeutics, including new targeted therapies and immunotherapies, are evolving, clinicians need to be aware of additional risk factors and infections that may arise in patients treated with these agents. This article highlights fundamental issues in treating patients with lymphoid cancer, including risk factors for infection, screening for infectious diseases, and recommendations for antimicrobial prophylaxis in patients with lymphoid cancers. We present 4 scenarios of patients with lymphoid cancers who have various infections, and we describe a treatment approach based on a combination of evidence-based data and experience because objective data are limited regarding infections, especially with newer agents. The goal of this discussion is to provide a framework for institutions and health care providers to help them develop their own approach to preventing and treating infections in patients with lymphoid cancer.

Acting on non-communicable diseases in low- and middle-income tropical countries.

The classical portrayal of poor health in tropical countries is one of infections and parasites, contrasting with wealthy Western countries, where unhealthy diet and behaviours cause non-communicable diseases (NCDs) such as heart disease and cancer. Using international mortality data, we show that most NCDs cause more deaths at every age in low- and middle-income tropical countries than in high-income Western countries. Causes of NCDs in low- and middle-income countries include poor nutrition and living environment, infections, insufficient taxation and regulation of tobacco and alcohol, and under-resourced and inaccessible healthcare. We identify a comprehensive set of actions across health, social, economic and environmental sectors that could confront NCDs in low- and middle-income tropical countries and reduce global health inequalities.

Updated Recommendations on the Prevention and Treatment of Infections in Children With Asplenia/Hyposplenism.

Children with congenital or acquired asplenia or hyposplenism have an increased risk for severe and even life-threatening infections mainly due to encapsulated bacteria. Current practice focuses on preventing severe infections with timely administration of vaccinations, antibacterial prophylaxis when indicated, and urgent evaluation and treatment of febrile events. As new vaccines are now available for both children and adults with asplenia/hyposplenism, we present an up-to-date recommendation on the prevention and management of acute infections in children with asplenia/hyposplenism.

Methylobacterium infection-induced peritonitis in a patient with renal insufficiency: A case report and literature review.

Clinical pharmacists participated in the drug therapy of peritonitis caused by Methylobacterium infection in a patient with renal insufficiency. Based on the knowledge of clinical pharmacy, the patient's condition and laboratory parameters, the literature, and the pharmacokinetic/pharmacodynamic characteristics of antibiotics, amikacin in combination with ciprofloxacin was suggested for anti-infection therapy. During the treatment, clinical pharmacists timely evaluated the efficacy of antibiotics, monitored the adverse reactions, and provided individualized pharmaceutical care in the patient.

Clinical and Prognostic Features of Diabetic Ketoacidosis According to the Trigger of the Syndrome.

BACKGROUND: Diabetic ketoacidosis (DKA) is an acute metabolic, life-threatening complication of diabetes mellitus with a mortality rate that now stand at less than 1%. Although mortality is coupled with the etiology of DKA, literature on the influence of DKA etiology on patient outcome is scarce. OBJECTIVES: To study different triggers for DKA and their effect on outcomes. METHODS: We conducted a retrospective study that include 385 DKA patients from 2004 to 2017. The study compared demographics, clinical presentation, and mortality rates by different precipitating factors. RESULTS: Patients with DKA due to infections had a higher risk to develop in-hospital mortality after controlling for age and sex (odds ratio 4.40, 95% confidence interval 1.35-14.30), had a higher Charlson Comorbidity Index score, a higher risk of being mechanical ventilated (14% vs. 3%, P < 0.01), and a longer duration of hospitalization (5 days vs. 3 days, P < 0.001). CONCLUSIONS: It is crucial to find the triggers that precipitate DKA and start the treatment as early as possible in addition to the metabolic aspect of the treatment especially when the trigger is an infectious disease.

[Advances in the role of infection in the development of benign tracheal stenosis].

Benign tracheal stenosis (BTS) is a refractory disease with a complex pathogenesis and limited therapeutic drug effects. The management of benign tracheal stenosis remains a major challenge for the interventional physiologist. In recent years, the role of infection in the occurrence and development of tracheal stenosis has attracted some attention, but there is still some controversy. A clear understanding of the relationship between infection and tracheal stenosis is essential to elucidate the pathogenic mechanism of BTS, and then to improve early prevention and management of BTS. This article reviewed the research progress on BTS associated with infection to explore new effective interventions that can reduce the BTS.

Toward prevention of childhood ALL by early-life immune training.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common form of childhood cancer. Chemotherapy is associated with life-long health sequelae and fails in ∼20% of cases. Thus, prevention of leukemia would be preferable to treatment. Childhood leukemia frequently starts before birth, during fetal hematopoiesis. A first genetic hit (eg, the ETV6-RUNX1 gene fusion) leads to the expansion of preleukemic B-cell clones, which are detectable in healthy newborn cord blood (up to 5%). These preleukemic clones give rise to clinically overt leukemia in only ∼0.2% of carriers. Experimental evidence suggests that a major driver of conversion from the preleukemic to the leukemic state is exposure to immune challenges. Novel insights have shed light on immune host responses and how they shape the complex interplay between (1) inherited or acquired genetic predispositions, (2) exposure to infection, and (3) abnormal cytokine release from immunologically untrained cells. Here, we integrate the recently emerging concept of "trained immunity" into existing models of childhood BCP-ALL and suggest future avenues toward leukemia prevention.

Inflammation, Infection and Venous Thromboembolism.

The association between inflammation, infection, and venous thrombosis has long been recognized; yet, only in the last decades have we begun to understand the mechanisms through which the immune and coagulation systems interact and reciprocally regulate one another. These interconnected networks mount an effective response to injury and pathogen invasion, but if unregulated can result in pathological thrombosis and organ damage. Neutrophils, monocytes, and platelets interact with each other and the endothelium in host defense and also play critical roles in the formation of venous thromboembolism. This knowledge has advanced our understanding of both human physiology and pathophysiology, as well as identified mechanisms of anticoagulant resistance and novel therapeutic targets for the prevention and treatment of thrombosis. In this review, we discuss the contributions of inflammation and infection to venous thromboembolism.

The association between hypogammaglobulinemia severity and infection risk in rituximab-treated patients with childhood-onset idiopathic nephrotic syndrome.

BACKGROUND: Hypogammaglobulinemia is a major adverse effect from rituximab. However, the association between rituximab-induced hypogammaglobulinemia and infection frequency is unknown. METHODS: Patients who received rituximab for complicated nephrotic syndrome between February 2006 and October 2020 were enrolled in this retrospective observational study. Infections requiring antibacterial or antiviral agents or hospitalization were identified, and the characteristics of infections were compared according to infection type. RESULTS: One hundred and forty patients were enrolled. Fifty infection events were detected in 36 patients, 45 infection events in 32 patients required hospitalization, and 1 severe infection event required intensive care unit admission. In eight patients who developed severe hypogammaglobulinemia (serum IgG level < 200 mg/dL) for more than 1 year after rituximab treatment, eight infections occurred in six patients; six of these infections did not occur during the period of severe hypogammaglobulinemia. Febrile neutropenia accounted for 54.2% (13/24) of all infections among the patients with hypogammaglobulinemia. The incidence of infections was 0.028 (95% confidence interval = 0.017-0.448), 0.071 (95% [CI] = 0.041-0.114), and 0.096 (95% [CI] = 0.019-0.282) patient-years in patients with normal serum IgG levels and those with mild and severe hypogammaglobulinemia, respectively. Immunoglobulin replacement therapy was not administered to any patients except for the treatment of infection. CONCLUSIONS: Our results showed no statistically significant association between hypogammaglobulinemia severity and infection rate. In addition, the frequency of infection was relatively low even in patients with severe hypogammaglobulinemia, suggesting that immunoglobulin replacement therapy may not be necessary for rituximab-treated patients with severe hypogammaglobulinemia. A higher resolution version of the Graphical abstract is available as Supplementary information.

Protothecosis in four dogs in New Zealand.

CASE HISTORIES: Medical records of four dogs diagnosed with protothecosis in New Zealand were reviewed. The dogs were aged between 4 and 9 years and three of the four dogs were female. Breeds were one Labrador, one Miniature Schnauzer and two crossbreeds. The reasons for initial veterinary evaluation were a cough and opaque appearance of the right eye (Case 1), diarrhoea (Cases 2 and 3), and cutaneous disease (Case 4). CLINICAL FINDINGS: The ocular signs were characterised by panuveitis, retinal detachment and secondary glaucoma. Gastrointestinal signs included chronic haemorrhagic diarrhoea due to colitis. Three cases had disseminated infection and developed both bilateral, blinding, ocular disease and chronic gastrointestinal disease. Cutaneous signs consisted of draining fistulae over the olecranon, multifocal cutaneous nodules, and ulceration and tracts of the foot pads. Disseminated protothecosis was confirmed by histopathology of biopsied ocular tissues in Cases 1 and 2 and by gastrointestinal biopsies in Case 3. Prototheca spp. were also identified in cytological specimens from Cases 1 and 4 and recovered by culture in Cases 2 and 4. Cutaneous protothecosis was diagnosed in Case 4 initially by cytology and histopathology of skin lesions, and Prototheca zopfii was confirmed by PCR of cultured organisms. TREATMENT AND OUTCOME: Prior to diagnosis of protothecosis, a variety of treatments were prescribed to treat the gastrointestinal and ocular signs. After diagnosis, only Cases 2 and 4 received medication aimed at treating the protothecal infection, which was itraconazole in both cases. Following the progression of clinical signs and concerns about quality of life, all four dogs were euthanised. DIAGNOSIS: Disseminated protothecosis in three dogs, cutaneous protothecosis in one dog. CLINICAL RELEVANCE: Canine protothecosis is rarely reported, despite the ubiquity of the causal algae, and the disease usually carries an extremely grave prognosis when infection is generalised. In New Zealand, protothecosis should be considered as a differential diagnosis in dogs with panuveitis, chorioretinitis or retinal detachment, colitis, or nodular, ulcerative or fistulating cutaneous lesions.

Potential mechanisms of tumor progression associated with postoperative infectious complications.

There is increasing evidence that postoperative infectious complications (PICs) are associated with poor prognosis after potentially curative surgery. However, the role that PICs play in tumor development remains unclear. In this article, we reviewed the literature for novel insights on the mechanisms of cancer progression associated with PICs. The Medline and EMBASE databases were searched for publications regarding the role of suppression of antitumor immunity by PIC in tumor progression and selected 916 manuscripts were selected for this review. In addition, a summary of the authors' own experimental data from this field was set in the context of current knowledge regarding cancer progression under septic conditions. Initially, sepsis/microbial infection dramatically activates the systemic immune system with increases in pro-inflammatory mediators, which results in the development of systemic inflammatory response syndrome; however, when sepsis persists in septic patients, a shift toward an anti-inflammatory immunosuppressive state, characterized by macrophage deactivation, reduced antigen presentation, T cell anergy, and a shift in the T helper cell pattern to a predominantly TH2-type response, occurs. Thus, various cytokine reactions and the immune status dynamically change during microbial infection, including PIC. We proposed three possible mechanisms for the tumor progression associated with PIC: first, a mechanism in which microbes and/or microbial PAMPs may be directly involved in cancer growth; second, a mechanism in which factors released from immunocompetent cells during infections may affect tumor progression; and third, a mechanism in which factors suppress host tumor immunity during infections, which may result in tumor progression. A more detailed understanding by surgeons of the immunological features in cancer patients with PIC can subsequently open new avenues for improving unfavorable long-term oncological outcomes associated with PICs.

The Effect of Early Infection on the Rate of Volitional Voiding after Spinal Cord Injury: A Potential Modifiable Risk Factor for Bladder Outcomes.

PURPOSE: Recently, it has been observed that early infections after spinal cord injury (SCI) are associated with decreased long-term motor and sensory recovery. We investigate the effects of early infection after SCI on long-term bladder function. MATERIALS AND METHODS: We assessed data for the years 1995 to 2006 using the National Spinal Cord Injury Database. Postoperative wound infections and pneumonia were used to classify infections during the acute inpatient and rehabilitation periods. The effect of early infections on volitional voiding status at 1-year followup was assessed. Age, gender and neurological status at rehabilitation discharge (level of injury, American Spinal Injury Association Impairment Scale [AIS] and bilateral lower extremity motor scores) were included in multivariate logistic regression modeling to control for confounding. RESULTS: Of the 3,561 persons studied, 1,233 (34.6%) had an early infection. Those with an infection during early recovery were less likely to void than their noninfected counterparts if in the AIS A (0.3% vs 1.9%, p=0.010), AIS B (3.8% vs 10.5%, p=0.018) and AIS C (29.1% vs 37.3%, p=0.071) classification, while those with less complete injuries (AIS D) did not appear to be affected (62.6% vs 65.4%, p=0.456). Similar findings were found when stratifying by lower extremity motor scores and persisted on multivariate analysis, where early infection decreased the odds of volitional voiding at 1-year followup (OR=0.79, p=0.042). CONCLUSIONS: Infections during the early recovery period may modify volitional voiding at 1-year followup by 20% or more. Future investigations to confirm our findings and potentially evaluate mitigation strategies are warranted.

Cervical suppurative lymphadenitis in children: microbiology, primary sites of infection, and evaluation of antibiotic treatment.

PURPOSE: The significant pathogens associated with paediatric cervical suppurative lymphadenitis (CSL) are unclarified, and there is a lack of clinical evaluations of antibiotic regimens in paediatric CSL. We aimed to (1) explore the bacterial findings and the associated primary sites of infection in paediatric cases of CSL and (2) evaluate the clinical outcomes in patients treated with different antibiotic regimens. METHODS: All children (< 18 years) treated for non-mycobacterium CSL at the Department of Otorhinolaryngology, Aarhus University Hospital, from 2001 to 2018 were retrospectively evaluated. RESULTS: Eighty-five patients were included in the study. The prevalent isolates were S. aureus (57%), S. pyogenes (17%), non-haemolytic streptococci (11%), and F. necrophorum (3%). The primary sites of infection were identified in 30 (35%) patients. The most common sites were the oropharynx (n = 15), the middle ear (n = 10), and the skin (n = 5). All patients were treated with surgical incision and antibiotics. No statistically significant differences were found between patients treated with antibiotics covering streptococci (n = 60) versus antibiotics covering streptococci and S. aureus (n = 25) in terms of duration of hospitalisation (median 4 vs 4 days, p = 0.26), altered antibiotic treatment because of insufficient clinical or biochemical progress (7% vs 12%, p = 0.41), and abscess recurrence (8% vs 12%, p = 0.69). CONCLUSION: S. aureus was the predominant pathogen in paediatric CSL at all cervical levels, and even in cases with evidence of primary site infection not normally associated with S. aureus. We were unable to underscore the importance of antibiotic treatment covering S. aureus based on evaluation of the clinical outcomes.