Diabetes mellitus affects over 500 million people globally, with current insulin therapies relying on subcutaneous injections that compromise the liver's natural role in glucose regulation and suffer from poor patient compliance. Oral insulin delivery offers a physiological alternative but faces challenges, including gastrointestinal degradation and poor absorption. Here, we engineered Saccharomyces boulardii, a probiotic yeast with established gastrointestinal survival capabilities, to secrete a long-acting Insulin-Fc fusion protein (Ins/Fc). Using strong constitutive promoters (TDH3 and TEF1), we achieved stable expression in lead strains FZ030 and FZ032. The secreted Ins/Fc fusion protein demonstrated functional bioactivity in cultured cells and in diabetic mice. This represents the first successful engineering of S. boulardii to produce a functional insulin and establishes a promising platform for developing oral insulin delivery systems.

A systematic review of the economic burden of advanced non-small-cell lung cancer (NSCLC).

Articles from 2011 onwards reporting the economic burden of locally advanced (stage IIIB/C)/metastatic (stage IV) NSCLC were identified through systematic and supplementary searches. Outcomes included hospitalizations, emergency department (ED) and outpatient visits, and direct and indirect costs, amongst others.

Across 50 publications (43 studies), patients with advanced NSCLC had high rates of healthcare resource utilization (HCRU), with most reporting hospitalization (ranging from 13.0% to 98.2% of patients), ED visits (2.5% to 83.1%), outpatient visits (74.6% to 100.0%), and diagnostic or monitoring tests (45.9% to 92.0%). HCRU (hospitalizations, ED visits and pharmacy visits) appeared to be lower with immunotherapy as compared to chemotherapy. Brain/central nervous system (CNS) metastases were the major clinical factor influencing HCRU. Mean direct costs ranged from US$5,647 (Brazil) to US$158,908 (US) over 12-24 months, and were generally higher in the US, Korea, Germany, and the UK (vs. Brazil, France, and Italy). The main direct cost drivers were drug-related costs (9.5-76.0% of total), overall outpatient costs (39-70.6%), and inpatient costs (5.0-58.1%). Costs were higher for chemotherapy than for immunotherapy. In China, indirect medical costs were US$1,413 per case. In general, mean total healthcare costs were higher for metastatic disease. Disease severity/diagnosis, presence of brain/CNS metastases, targeted therapy and chemotherapy (vs. immunotherapy) and the presence of comorbidities were the main factors influencing higher costs.

Patients with advanced NSCLC had high rates of HCRU, and costs were substantial, though varying greatly across countries. HCRU and costs were higher in patients with brain/CNS metastases. Since this was a qualitative review, no formal quantitative synthesis was attempted. Costs reported in different currencies and heterogeneity across studies limited comparability. Finally, a single reviewer extracted data.

The article considers results of studying dynamic shifts in morbidity of the population attached to the N. A. Semashko Northern Medical Clinical Center of the Federal Medical Biological Agency of Russia over ten-years period. The results testify increasing of morbidity of the attached contingent during studied period. In overall, the number of registered diseases increased by 4 866 cases (49.5%) as compared to the level of 2014, that is 1.5 times higher than the initial level. In quantitative terms, diseases of the eye and its appendage (2097±29), digestive organs (1671±173), circulatory system (1154±100) predominated. The analysis of gender differences testifies that percentage of neoplasms in the structure of morbidity of women (4.5%) is significantly higher than the one of men (1.4%) (plt;0.001). However, the rate of increase of oncological diseases was significantly higher among men (73.3%) as compared with women (20.7%)/ The rate of increase of endocrine diseases among men made up 714.0% and among women 210.3%. The study results can be used in planning the organization of medical care of population attached to the medical institution mentioned above.

Tumor-associated macrophages (TAMs) and monocytes that accumulate in colorectal cancer (CRC) play a crucial role in shaping the tumor microenvironment (TME) and anti-tumor immune responses. Although TAMs have been linked to both pro- and anti-tumor functions, our understanding of the cues instructing their heterogeneous phenotypes and function in cancer patients remains limited. Here, we established co-cultures comprising primary human monocytes and patient-derived organoids (PDOs) from patients with microsatellite-stable CRC to emulate myeloid/tumor cell interactions in vitro. Upon encountering PDOs, monocytes acquire phenotypic changes that are distinct from those induced by typical polarization protocols. Single-cell RNA sequencing revealed that PDO-exposed monocytes transcriptionally resembled IL1B-programmed monocytes previously identified in the tumor tissues of CRC patients. This phenotype emerged independently of tumor mutational profiles or consensus molecular subtypes. Mechanistically, soluble PDO-derived mediators induced the production of CXCL2, CXCL5 and CXCL7 chemokines, whereas the phagocytic uptake of tumor debris impaired the MHC class II-mediated antigen presentation capabilities of monocytes in co-culture. In addition, our in vitro system allowed functional assessment of PDO-exposed monocytes demonstrating a compromised capacity to mount an inflammatory response upon TLR stimulation. Together, PDO-monocyte co-cultures offer a platform to dissect the interplay between cancer cells and monocytes, and advance our understanding of myeloid plasticity and function in cancer patients.

To evaluate a multidisciplinary therapy program with a neurological focus for individuals with post-COVID-19 condition, aiming to reduce symptom burden and improve functioning.

Non-experimental prospective before-after study.

Individuals diagnosed with post-COVID-19 condition, defined as experiencing persistent signs and symptoms for more than 12 weeks after initial SARS-CoV-2 infection.

We conducted a 2 week multidisciplinary rehabilitation program at the Schoen Clinic Bad Aibling, Germany. The intervention included multi-professional therapies. Assessments were conducted at six time points: baseline at the start of the 2-week control period, pre- and post-intervention, and at 2, 8, and 24 weeks post-intervention. Mixed-effects regression models were used to analyze changes over time. Outcome measures included health-related quality of life (HRQoL; EQ-5D-5L), fatigue, anxiety, depression, symptom severity, breathing difficulties, cognitive function, functional disability, and performance measures.

A total of 47 participants (60% female; mean age 49 years; range 21-80) were enrolled, with a median of 220 days (Q1: 156-Q3: 376) since initial infection. No significant improvement in HRQoL, grip strength, cognitive function, walking capacity, or balance was observed during the intervention compared to the control period. Fatigue, anxiety, depression, symptom severity, functional disability, and dyspnea improved significantly.

This study indicates beneficial effects of a 2 week multidisciplinary therapy program on symptom burden and functional outcomes of the post-COVID-19 condition. Further research including randomized controlled trials is warranted.

German Clinical Trials Register, DRKS00029415. Registered 04 July, 2022. Retrospectively registered. https://drks.de/search/en/trial/DRKS00029415.

Kidney transplant recipients (KTRs) exhibit impaired immune responses to vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, remaining vulnerable to severe coronavirus disease 2019 (COVID-19) even after multiple vaccine doses. We hypothesized that repeated SARS-CoV-2 vaccinations in KTRs might promote remodeling of the adaptive immune repertoire. In order to address this hypothesis and gain insight into adaptive immune dynamics in this population, we employed next-generation sequencing (NGS) to determine longitudinal alterations in immunoglobulin (IG) and T cell receptor (TR) gene repertoires following multiple mRNA vaccinations and functional experiments to assess lymphocyte signaling capacity. TR gene repertoire analysis revealed increased diversity and reduced clonality after booster immunizations, indicative of substantial repertoire renewal. Although the relative frequency of SARS-CoV-2-specific TR clonotypes remained stable over time, significant shifts in TRBV gene usage reflected dynamic reshaping of the TR clonal architecture. Parallel IG gene repertoire profiling demonstrated increased diversity and limited oligoclonal expansions after booster mRNA vaccination. These changes were accompanied by elevated levels of somatic hypermutation in IG clonotypes similar to published SARS-CoV-2-specific clonotypes, suggestive of more efficient humoral responses following repeated antigenic exposure. Phospho-specific flow cytometry analysis revealed initially diminished B cell receptor signaling, which was restored following multiple immunizations, consistent with reversal of B cell anergy status. Altogether, our findings support the notion that repeated SARS-CoV-2 vaccinations drive the remodeling of cellular and humoral immune landscapes in KTRs. These results underscore the importance of tailored vaccination strategies to optimize immune protection in immunocompromised individuals.

Using State-level surveillance records we assessed disparities in premature mortality among people with HIV (PWH) in Florida during pre- (2019) and early COVID-19 pandemic (2020).

We calculated age-standardized rates of years of potential life lost per 100 persons (aYPLL) stratified by sex, race and ethnicity, rural/urban residence, and social vulnerability index (SVI).

PWH in Florida during 2020 experienced a significant increase in aYPLL (2019: 29.0, 95% CI [28.1, 30.0]; 2020: 32.8, 95% CI [31.8, 33.9]). HIV/AIDS contributed the most aYPLL in 2020 (13.4, 95% CI [12.4, 14.4]), especially among females (15.8, 95% CI [15.2, 16.4]), rural communities (14.5, 95% CI [12.7, 17.6]), and high SVI communities (12.5, 95% CI [11.9, 13.2]). aYPLL due to external causes increased significantly from 2019 to 2020 (4.1, 95% CI [4.0, 4.3] vs 5.4, 95% CI [5.2, 5.5]), especially for females (3.6, 95% CI [3.3, 3.9] vs 7.8, 95% CI [7.4, 8.3]) and those living in low SVI communities (3.1, 95% CI [2.7, 3.8] vs 7.1, 95% CI [6.5, 8.1]). aYPLL due to COVID-19 was greatest for females (2.3, 95% CI [2.1, 2.6]) and residents of high SVI communities (2.0, 95% CI [1.9, 2.1]).

PWH experienced increased individual- and neighborhood-level disparities in premature mortality from HIV/AIDS from 2019 to 2020, especially among females and those in rural and socially vulnerable communities. External causes and COVID-19 were also associated with an increased premature mortality during this time frame, with disparities noted by sex and community social vulnerability. Pandemic planning should include targeted outreach programs which prepare for vulnerable populations' healthcare needs and mitigate mortality.

BACKGROUND Lipomatous atrial septal hypertrophy (LASH) is a benign but uncommon condition characterized by excessive adipose tissue accumulation within the interatrial septum. Although most cases remain asymptomatic, large lesions may produce superior vena cava (SVC) obstruction. Acute pulmonary embolism as an initial presentation is rare. CASE REPORT A 75-year-old woman with a history of chronic obstructive pulmonary disease and hypertension experienced 7 days of progressively worsening exertional dyspnea, orthopnea, and lower-extremity edema, without chest pain, cough, or fever. Physical examination findings included tachypnea, hypertension, bilateral lower-extremity edema, elevated jugular venous pressure, and bibasilar crackles. Computed tomography pulmonary angiography - prompted by elevated D-dimer - demonstrated bilateral pulmonary emboli and a large LASH causing SVC obstruction with near-complete obliteration of the right atrium. Transthoracic echocardiography confirmed the presence of LASH. The absence of personal or family history of inherited thrombophilia, along with negative deep venous thrombosis findings on lower-extremity Doppler ultrasonography, suggested that pulmonary embolism and right heart failure were related to sluggish right atrial flow secondary to LASH-induced mechanical SVC obstruction. Clinical improvement was achieved with anticoagulation and diuretic therapy, followed by partial surgical resection of the interatrial septum in conjunction with coronary artery bypass grafting. Histopathologic examination confirmed LASH without evidence of inflammation or malignancy. CONCLUSIONS Symptomatic LASH causing SVC obstruction is extremely uncommon and rarely associated with pulmonary embolism. This case underscores the importance of recognizing LASH as a potential contributor to right heart failure and thromboembolism; it highlights echocardiography as an essential diagnostic modality when pulmonary embolism is suspected.

Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite significant progress in identifying and managing traditional risk factors such as hyperlipidemia, hypertension, and diabetes. While targeted therapies addressing these factors reduce the risk of primary and secondary cardiac events, a substantial "residual risk" persists even after successful clinical intervention. This residual risk has prompted renewed interest in understanding the long-term biological effects of cardiovascular risk factors, particularly through the lens of chronic inflammation. Recent advances highlight a pivotal role for trained immunity-a form of innate immune memory driven by epigenetic and metabolic reprogramming-in driving this inflammation. Unlike adaptive immune memory, trained immunity occurs in innate immune cells and enhances their responsiveness to subsequent, unrelated stimuli. Emerging evidence suggests that various cardiovascular risk states, including hypercholesterolemia, obesity, and diabetes, can induce trained immunity, leading to heightened inflammatory tone that persists over time. Cardiac macrophages, as central mediators of tissue homeostasis and inflammation in the heart, are increasingly recognized as critical targets of this phenomenon. In this review, we explore how established cardiovascular risk factors can induce trained immunity on cardiac macrophages and examine the implications for disease progression, myocardial remodeling, and post-injury repair. Finally, we discuss emerging therapeutic strategies aimed at modulating trained immunity to reduce residual cardiovascular risk, offering a new frontier in the prevention and treatment of CVD.

Self-measured blood pressure (SMBP) monitoring is an evidence-based practice effective for improving the diagnosis and control of hypertension. Healthcare settings face challenges integrating it into clinical care.

This study applied behavior change theory to design a clinic-based intervention to integrate SMBP within safety net primary care settings.

We conducted multi-phase, mixed methods research to adapt a clinic-level intervention across 25 safety net primary care clinics within three California public healthcare systems as part of the Championing Hypertension Remote Monitoring for Equity and Dissemination (CHARMED) Study. From February to August 2024, clinic champions participated in surveys and focus groups to assess: (i) current practices in hypertension management, (ii) implementation barriers, and (iii) strategies for optimizing the use of SMBP within clinics. Using the Behavior Change Wheel, we designed and tailored the intervention to improve clinical practices for SMBP.

Over 50 clinicians/staff participated. Surveys revealed varying SMBP use due to knowledge gaps, lack of standardized processes, and insufficient financial and human resources. Focus groups highlighted the importance of increasing SMBP knowledge among patients and care teams (capability); promoting structured workflows/templates for documenting and acting on SMBP data (opportunity); and building care team buy-in for SMBP (motivation). These insights guided the final intervention activities.

Using behavior change theory and stakeholder-engaged methods, we developed a multi-component clinic-focused intervention to promote tailored SMBP implementation within safety net primary care clinics. This evidence-based, adaptable approach may inform future efforts to implement SMBP at multiple levels of care.

The Clinical Trials Registration #NCT06113458.