The immunology of B-1 cells: from development to aging.

B-1 cells have intricate biology, with distinct function, phenotype and developmental origin from conventional B cells. They generate a B cell receptor with conserved germline characteristics and biased V(D)J recombination, allowing this innate-like lymphocyte to spontaneously produce self-reactive natural antibodies (NAbs) and become activated by immune stimuli in a T cell-independent manner. NAbs were suggested as "rheostats" for the chronic diseases in advanced age. In fact, age-dependent loss of function of NAbs has been associated with clinically-relevant diseases in the elderly, such as atherosclerosis and neurodegenerative disorders. Here, we analyzed comprehensively the ontogeny, phenotypic characteristics, functional properties and emerging roles of B-1 cells and NAbs in health and disease. Additionally, after navigating through the complexities of B-1 cell biology from development to aging, therapeutic opportunities in the field are discussed.

Systemic mechanisms of necrotic cell debris clearance.

Necrosis is an overarching term that describes cell death modalities caused by (extreme) adverse conditions in which cells lose structural integrity. A guaranteed consequence of necrosis is the production of necrotic cell remnants, or debris. Necrotic cell debris is a strong trigger of inflammation, and although inflammatory responses are required for tissue healing, necrotic debris may lead to uncontrolled immune responses and collateral damage. Besides local phagocytosis by recruited leukocytes, there is accumulating evidence that extracellular mechanisms are also involved in necrotic debris clearance. In this review, we focused on systemic clearance mechanisms present in the bloodstream and vasculature that often cooperate to drive the clearance of cell debris. We reviewed the contribution and cooperation of extracellular DNases, the actin-scavenger system, the fibrinolytic system and reticuloendothelial cells in performing clearance of necrotic debris. Moreover, associations of the (mis)functioning of these clearance systems with a variety of diseases were provided, illustrating the importance of the mechanisms of clearance of dead cells in the organism.

Office- versus home-based evaluation of quality of life in heart failure with reduced ejection fraction: A randomized study.

BACKGROUND: Heart failure (HF) patients often experience poor health-related quality-of-life (HR-QoL). The Kansas City Cardiomyopathy Questionnaire (KCCQ) is frequently used for assessing HR-QoL in HF. Whether KCCQ scores vary in a clinical meaningful manner according to the setting (home vs office) where patients respond to the questionnaire is currently unknown. AIMS: Assess the differences in the responses to KCCQ-23 questionnaire when completed at home or office. METHODS: Randomized parallel-group study, including patients with HF with reduced ejection fraction (HFrEF). Primary outcome was home vs office comparison of overall summary score (KCCQ-OSS). Main secondary outcomes were clinical summary score (KCCQ-CSS) and total symptom score (KCCQ-TSS). RESULTS: A total of 100 patients were included in the study: 50 home vs 50 office. Mean age was 71 yrs. Most baseline characteristics were well balanced between groups, except male sex, MRA use, and prior HF hospitalizations which were more frequent in the home group. No statistically-significant between-group differences were found regarding KCCQ-OSS (median [percentile25-75]) scores: home 69.1 (42.0-86.5) vs office 63.1 (44.3-82.3) points, P-value = 0.59, or main secondary outcomes: KCCQ-CSS home 62.2 (46.5-79.9) vs office 68.1 (51.9-79.2) points, P-value = 0.69, and KCCQ-TSS home 84.7 (59.7-97.2) vs office 76.4 (66.7-94.4) points, P-value = 0.85. Results remained similar after adjustment for differences in baseline characteristics and using non-parametric regressions. CONCLUSIONS: No major differences were found in KCCQ-23 scores regardless of whether the questionnaire was completed at home or office. These findings can be useful to make HR-QoL more accessible, allowing patients to respond at home using email or cell-phone applications.

Information in Healthcare - From Data to Knowledge: Improving Data Literacy Competencies.

Digitalization in healthcare and the increasing availability of data demand data literacy competences of nurses and other healthcare professionals including technical, ethical and communication skills. The international Spring School 2023 "Information in Healthcare - From Date to Knowledge" aimed at these competences covering interoperability, data protection and security, data analytics and ethical issues. These topics were embedded in the overall case of data-driven quality improvement for diabetes patients in a region. The curriculum includes an online preparation-phase and a five-days attendance week, incorporating problem-based and group work approaches. According to the studentt's evaluation, the awareness of the importance of the topics was raised and theoretical as well as practical application skills were improved. The Spring School enhanced data literacy competences, critical thinking, problem-solving, interprofessional und intercultural skills among healthcare professionals. Such course offering can contribute to meeting the increasing challenges of digitalization in healthcare.

Utilizing synchronous care to improve cardiovascular and renal health among patients with type 2 diabetes: Proof-of-concept results from the DECIDE-CV clinical programme.

AIM: The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline-directed medical therapy (GDMT). METHODS: We retrospectively analysed consecutive patients assessed in the 'synchronized' DECIDE-CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, renin-angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline-to-last-visit change in surrogate laboratory biomarkers. RESULTS: The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin-to-creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium-glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon-like peptide 1 receptor agonists (from 8% to 45%), renin-angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p < .01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin-to-creatinine ratio and N-terminal proB-type natriuretic peptide levels significantly dropped from baseline (p < .05 for all). CONCLUSIONS: Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers.

The Role of Programmed Cell Death Ligand 1 Expression in Pituitary Tumours: Lessons from the Current Literature.

BACKGROUND: Programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) expression predict the biological behaviour, aggressiveness, and response to immune checkpoint inhibitors in different cancers. We reviewed the published data on PD-L1 expression in pituitary tumours from the perspective of its biological role and prognostic usefulness. SUMMARY: A literature review focused on PD-L1 expression in pituitary tumours was performed. Six immunohistochemistry-based studies which assessed PD-L1 positivity in pituitary tumours were included, encompassing 704 patients. The cohort consisted of 384 (54.5%) nonfunctioning tumours and 320 (43.5%) functioning pituitary tumours. PD-L1 expression was positive in 248 cases (35.2%). PD-L1 positivity rate was higher in functioning than in nonfunctioning tumours (46.3% vs. 26.0%; p < 0.001) but also higher in growth hormone-secreting tumours (56.7%) and prolactinomas (53.6%) than in thyrotroph (33.3%) or corticotroph tumours (20.6%). While proliferative pituitary tumours showed higher rate of PD-L1 positivity than non-proliferative tumours (p < 0.001), no association with invasion or recurrence was found. KEY MESSAGES: PD-L1 is expressed in a substantial number of pituitary tumours, predominantly in the functioning ones. PD-L1 positivity rates were significantly higher in proliferative pituitary tumours in comparison to non-proliferative tumours, but no differences were found concerning invasive or recurrent pituitary tumours. More studies following homogeneous and standardised methodologies are needed to fully elucidate the role and usefulness of PD-L1 expression in pituitary tumours.

Impact of age and comorbid heart failure on the utility of smart voice-assistant devices.

Aims: The accuracy of voice-assisted technologies, such as Amazon Alexa, to collect data in patients who are older or have heart failure (HF) is unknown. The aim of this study is to analyse the impact of increasing age and comorbid HF, when compared with younger participants and caregivers, and how these different subgroups classify their experience using a voice-assistant device, for screening purposes. Methods and results: Subgroup analysis (HF vs. caregivers and younger vs. older participants) of the VOICE-COVID-II trial, a randomized controlled study where participants were assigned with subsequent crossover to receive a SARS-CoV2 screening questionnaire by Amazon Alexa or a healthcare personnel. Overall concordance between the two methods was compared using unweighted kappa scores and percentage of agreement. From the 52 participants included, the median age was 51 (34-65) years and 21 (40%) were HF patients. The HF subgroup showed a significantly lower percentage of agreement compared with caregivers (95% vs. 99%, P = 0.03), and both the HF and older subgroups tended to have lower unweighted kappa scores than their counterparts. In a post-screening survey, both the HF and older subgroups were less acquainted and found the voice-assistant device more difficult to use compared with caregivers and younger individuals. Conclusion: This subgroup analysis highlights important differences in the performance of a voice-assistant-based technology in an older and comorbid HF population. Younger individuals and caregivers, serving as facilitators, have the potential to bridge the gap and enhance the integration of these technologies into clinical practice. Study Registration: ClinicalTrials.gov Identifier: NCT04508972.

Acromegaly in humans and cats: Pathophysiological, clinical and management resemblances and differences.

OBJECTIVE: Acromegaly is a disorder associated with excessive levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). In general, GH/IGF-1 excess leads to morphologic craniofacial and acral changes as well as cardiometabolic complications, but the phenotypic changes and clinical presentation of acromegaly differ across species. Here, we review the pathophysiology, clinical presentation and management of acromegaly in humans and cats, and we provide a systematic comparison between this disease across these different species. DESIGN: A comprehensive literature review of pathophysiology, clinical features, diagnosis and management of acromegaly in humans and in cats was performed. RESULTS: Acromegaly is associated with prominent craniofacial changes in both species: frontal bossing, enlarged nose, ears and lips, and protuberant cheekbones are typically encountered in humans, whereas increased width of the head and skull enlargement are commonly found in cats. Malocclusion, prognathism, dental diastema and upper airway obstruction by soft tissue enlargement are reported in both species, as well as continuous growth and widening of extremities resulting in osteoarticular compromise. Increase of articular joint cartilage thickness, vertebral fractures and spine malalignment is more evident in humans, while arthropathy and spondylosis deformans may also occur in cats. Generalized organomegaly is equally observed in both species. Other similarities between humans and cats with acromegaly include heart failure, ventricular hypertrophy, diabetes mellitus, and an overall increased cardiometabolic risk. In GH-secreting pituitary tumours, local compressive effects and behavioral changes are mostly observed in humans, but also present in cats. Cutis verticis gyrata and skin tags are exclusively found in humans, while palmigrade/plantigrade stance may occur in some acromegalic cats. Serum IGF-1 is used for acromegaly diagnosis in both species, but an oral glucose tolerance test with GH measurement is only useful in humans, as glucose load does not inhibit GH secretion in cats. Imaging studies are regularly performed in both species after biochemical diagnosis of acromegaly. Hypophysectomy is the first line treatment for humans and cats, although not always available in veterinary medicine. CONCLUSION: Acromegaly in humans and cats has substantial similarities, as a result of common pathophysiological mechanisms, however species-specific features may be found.

Bacillus velezensis iturins inhibit the hemolytic activity of Staphylococcus aureus.

Bovine mastitis caused by S. aureus has a major economic impact on the dairy sector. With the crucial need for new therapies, anti-virulence strategies have gained attention as alternatives to antibiotics. Here we aimed to identify novel compounds that inhibit the production/activity of hemolysins, a virulence factor of S. aureus associated with mastitis severity. We screened Bacillus strains obtained from diverse sources for compounds showing anti-hemolytic activity. Our results demonstrate that lipopeptides produced by Bacillus spp. completely prevented the hemolytic activity of S. aureus at certain concentrations. Following purification, both iturins, fengycins, and surfactins were able to reduce hemolysis caused by S. aureus, with iturins showing the highest anti-hemolytic activity (up to 76% reduction). The lipopeptides showed an effect at the post-translational level. Molecular docking simulations demonstrated that these compounds can bind to hemolysin, possibly interfering with enzyme action. Lastly, molecular dynamics analysis indicated general stability of important residues for hemolysin activity as well as the presence of hydrogen bonds between iturins and these residues, with longevous interactions. Our data reveals, for the first time, an anti-hemolytic activity of lipopeptides and highlights the potential application of iturins as an anti-virulence therapy to control bovine mastitis caused by S. aureus.

Exploring Aromatherapy as a Complementary Approach in Palliative Care: A Systematic Review.

Background: Palliative care, a cornerstone of comprehensive healthcare, prioritizes quality of life for individuals with life-threatening illnesses. Aromatherapy, with its holistic approach and patient-reported benefits, emerges as a promising complementary therapy for managing symptoms and enhancing well-being in palliative care. Objective: The objective of this systematic review is to assess the efficacy of aromatherapy interventions in symptom management, with a focus on pain, anxiety, nausea, and sleep disturbances among palliative care patients. Design: A comprehensive search was conducted across various databases to identify relevant studies. Eligibility criteria were applied, resulting in the inclusion of eight studies for analysis. The review assessed the efficacy of aromatherapy interventions, primarily through massage, in symptom management. Variations in intervention procedures and outcome measures were noted, necessitating a critical examination of the findings. Results: The review's findings suggest promising outcomes associated with aromatherapy in palliative care. Aromatherapy interventions demonstrated significant efficacy in reducing pain, anxiety, nausea, and improving sleep quality among patients. However, considerable heterogeneity was observed across studies, highlighting the need for standardized methodologies and larger-scale trials. Conclusion: This systematic review underscores the potential of aromatherapy as a complementary intervention in palliative care. While the findings support its efficacy in symptom management, methodological inconsistencies across studies warrant further research. Standardized approaches and larger trials are essential to validate the tailored effectiveness of aromatherapy for different symptoms encountered in palliative care, ultimately enhancing its clinical utility and integration into therapeutic practices.

Discovering the importance of health informatics education competencies in healthcare practice. A focus group interview.

BACKGROUND: As healthcare and especially health technology evolve rapidly, new challenges require healthcare professionals to take on new roles. Consequently, the demand for health informatics competencies is increasing, and achieving these competencies using frameworks, such as Technology Informatics Guiding Reform (TIGER), is crucial for future healthcare. AIM: The study examines essential health informatics and educational competencies and health informatics challenges based on TIGER Core Competency Areas. Rather than examine each country independently, the focus is on uncovering commonalities and shared experiences across diverse contexts. METHODS: Six focus group interviews were conducted with twenty-one respondents from three different countries (Germany (n = 7), Portugal (n = 6), and Finland (n = 8)). These interviews took place online in respondents' native languages. All interviews were transcribed and then summarized by each country. Braun and Clarke's thematic analysis framework was applied, which included familiarization with the data, generating initial subcategories, identifying, and refining themes, and conducting a final analysis to uncover patterns within the data. RESULTS: Agreed upon by all three countries, competencies in project management, communication, application in direct patient care, digital literacy, ethics in health IT, education, and information and knowledge management were identified as challenges in healthcare. Competencies such as communication, information and communication technology, project management, and education were identified as crucial for inclusion in educational programs, emphasizing their critical role in healthcare education. CONCLUSIONS: Despite working with digital tools daily, there is an urgent need to include health informatics competencies in the education of healthcare professionals. Competencies related to application in direct patient care, IT-background knowledge, IT-supported and IT-related management are critical in educational and professional settings are seen as challenging but critical in healthcare.

Feasibility and Acceptability of Pediatric Smartphone Lung Auscultation by Parents: Cross-Sectional Study.

Background: The use of a smartphone built-in microphone for auscultation is a feasible alternative to the use of a stethoscope, when applied by physicians. Objective: This cross-sectional study aims to assess the feasibility of this technology when used by parents-the real intended end users. Methods: Physicians recruited 46 children (male: n=33, 72%; age: mean 11.3, SD 3.1 y; children with asthma: n=24, 52%) during medical visits in a pediatric department of a tertiary hospital. Smartphone auscultation using an app was performed at 4 locations (trachea, right anterior chest, and right and left lung bases), first by a physician (recordings: n=297) and later by a parent (recordings: n=344). All recordings (N=641) were classified by 3 annotators for quality and the presence of adventitious sounds. Parents completed a questionnaire to provide feedback on the app, using a Likert scale ranging from 1 ("totally disagree") to 5 ("totally agree"). Results: Most recordings had quality (physicians' recordings: 253/297, 85.2%; parents' recordings: 266/346, 76.9%). The proportions of physicians' recordings (34/253, 13.4%) and parents' recordings (31/266, 11.7%) with adventitious sounds were similar. Parents found the app easy to use (questionnaire: median 5, IQR 5-5) and were willing to use it (questionnaire: median 5, IQR 5-5). Conclusions: Our results show that smartphone auscultation is feasible when performed by parents in the clinical context, but further investigation is needed to test its feasibility in real life.

Pseudoacromegaly-A challenging entity in the endocrine clinic: A systematic review.

OBJECTIVE: Pseudoacromegaly encompasses conditions with features of acromegaly/gigantism, but no growth hormone (GH) or insulin-like growth factor-1 (IGF-1) excess. We aimed to review published pseudoacromegaly cases evaluated due to clinical suspicion of acromegaly. DESIGN/PATIENTS: PubMed/Medline search was conducted to identify reported pseudoacromegaly cases, which were systematically reviewed to ensure they met eligibility criteria: (1) presentation suggestive of acromegaly; (2) acromegaly excluded based on normal GH, IGF-1 and/or GH suppression on oral glucose tolerance test (OGTT-GH); (3) diagnosis of the pseudoacromegaly condition was established. Data were retrieved from each case and analysed collectively. RESULTS: Of 76 cases, 47 were males, mean ages at presentation and at first acromegaloid symptoms were 28 ± 16 and 17 ± 10 years, respectively. Most common conditions were pachydermoperiostosis (47%) and insulin-mediated pseudoacromegaly (IMP) (24%). Acromegaloid facies (75%) and acral enlargement (80%) were the most common features. Measurement of random GH was reported in 65%, IGF-1 in 79%, OGTT-GH in 51%. GH excess was more frequently excluded based on two tests (53%). Magnetic resonance imaging (MRI) was performed in 30 patients, with pituitary adenoma or hyperplasia being reported in eight and three patients, respectively. Investigations differed between cases managed by endocrine and non-endocrine specialists, the former requesting more often IGF-1, OGTT-GH and pituitary MRI. CONCLUSIONS: Pseudoacromegaly is a challenging entity that may be encountered by endocrinologists. Pachydermoperiostosis and IMP are the conditions most often mimicking acromegaly. Adequate assessment of GH/IGF-1 is crucial to exclude acromegaly, which may be better performed by endocrinologists. Pituitary incidentalomas are common and require careful judgement to prevent unnecessary pituitary surgery.

Multidisciplinary Team Care in Pituitary Tumours.

The optimal care for patients with pituitary tumours is best provided in a multidisciplinary and collaborative environment, which requires the contribution of multiple medical specialties working together. The benefits and advantages of the pituitary multidisciplinary team (MDT) are broad, and all relevant international consensus and guidelines in the field recommend that patients with pituitary tumours should always be managed in a MDT. Endocrinologists and neurosurgeons are normally the leading specialties within the pituitary MDT, supported by many other specialties with significant contributions to the diagnosis and management of pituitary tumours, including neuropathology, neuroradiology, neuro-ophthalmology, and otorhinolaryngology, among others. Here, we review the literature concerning the concepts of Pituitary MDT/Pituitary Tumour Centre of Excellence (PTCOE) in terms of their mission, goals, benefits, structure, proposed models of function, and barriers, and we also provide the views of different specialists involved in our Pituitary MDT.

Natural antibodies are required for clearance of necrotic cells and recovery from acute liver injury.

Background & Aims: Hepatocellular necrosis is common in both acute and chronic liver injury and may evolve to fibrosis and liver failure. Injury leads to accumulation of necrotic cell debris in the liver, which drives persistent inflammation and poor recovery. This study investigated the role of natural antibodies (NAbs) in the clearance of necrotic cells in the injured liver, their impact on tissue regeneration and their potential as a therapy for acute liver injury. Methods: We used murine models of drug-induced liver injury and focal thermal injury in immunocompetent and antibody-deficient mice (Rag2-/- and IgMi). Intravital microscopy was used to investigate the role of NAbs in the phagocytosis of necrotic cells in the liver in vivo. Immunostainings were used to quantify the extent of liver necrosis (fibrin), antibody deposition (IgM and IgG) and cellular proliferation (Ki67). Results: Both IgM and IgG NAbs bound necrotic liver areas and opsonized multiple debris molecules released during hepatocellular necrosis such as DNA, histones, actin, phosphoinositides and mitochondrial cardiolipin, but not phosphatidylserine. Rag2-/- and IgMi mice presented impaired recovery from liver injury, which was correlated to the sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. These defects were rescued by treating mice with NAbs after the induction of injury. Mechanistically, in vitro and in vivo, phagocytosis of necrotic debris was dependent on NAbs via Fcγ receptors and CD11b. Moreover, NAb-mediated phagocytosis of necrotic cell debris occurs in two waves, firstly driven by neutrophils and then by recruited monocytes. Importantly, supplementation of immunocompetent mice with NAbs also improved liver regeneration significantly, demonstrating the therapeutic potential of natural IgM and IgG. Conclusion: NAbs drive the phagocytosis of necrotic cells in liver injury and promote liver regeneration and recovery. Impact and implications: Treatment with natural antibodies after acute liver injury improved recovery by increasing the clearance of necrotic debris and by improving cellular proliferation in the liver. This preclinical study provides a basis for the development of an immunotherapy for patients with early-stage, reversible, liver injury that aims to prevent disease chronification into fibrosis and liver failure.