Clinical-based phenotypes in children with pediatric post-COVID-19 condition.

BACKGROUND: Pediatric post coronavirus disease 2019 (COVID-19) condition (PPCC) is a heterogeneous syndrome, which can significantly affect the daily lives of children. This study aimed to identify clinically meaningful phenotypes in children with PPCC, to better characterize and treat this condition. METHODS: Participants were children with physician-diagnosed PPCC, referred to the academic hospital Amsterdam UMC in the Netherlands between November 2021 and March 2023. Demographic factors and information on post-COVID symptoms, comorbidities, and impact on daily life were collected. Clinical clusters were identified using an unsupervised and unbiased approach for mixed data types. RESULTS: Analysis of 111 patients (aged 3-18 years) revealed three distinct clusters within PPCC. Cluster 1 (n = 62, median age = 15 years) predominantly consisted of girls (74.2%). These patients suffered relatively more from exercise intolerance, dyspnea, and smell disorders. Cluster 2 (n = 33, median age = 13 years) contained patients with an even gender distribution (51.5% girls). They suffered from relatively more sleep problems, memory loss, gastrointestinal symptoms, and arthralgia. Cluster 3 (n = 16, median age = 11 years) had a higher proportion of boys (75.0%), suffered relatively more from fever, had significantly fewer symptoms (median age of 5 years compared to 8 and 10 years for clusters 1 and 2 respectively), and experienced a lower impact on daily life. CONCLUSIONS: This study identified three distinct clinical PPCC phenotypes, with variations in sex, age, symptom patterns, and impact on daily life. These findings highlight the need for further research to understand the potentially diverse underlying mechanisms contributing to post-COVID symptoms in children.

Molecular recording of calcium signals via calcium-dependent proximity labeling.

Calcium ions serve as key intracellular signals. Local, transient increases in calcium concentrations can activate calcium sensor proteins that in turn trigger downstream effectors. In neurons, calcium transients play a central role in regulating neurotransmitter release and synaptic plasticity. However, it is challenging to capture the molecular events associated with these localized and ephemeral calcium signals. Here we present an engineered biotin ligase that generates permanent molecular traces in a calcium-dependent manner. The enzyme, calcium-dependent BioID (Cal-ID), biotinylates nearby proteins within minutes in response to elevated local calcium levels. The biotinylated proteins can be identified via mass spectrometry and visualized using microscopy. In neurons, Cal-ID labeling is triggered by neuronal activity, leading to prominent protein biotinylation that enables transcription-independent activity labeling in the brain. In summary, Cal-ID produces a biochemical record of calcium signals and neuronal activity with high spatial resolution and molecular specificity.

The virtual pivot point concept improves predictions of ground reaction forces.

Ground reaction forces (GRFs) are essential for the analysis of human movement. To measure GRFs, 3D force plates that are fixed to the floor are used with large measuring ranges, excellent accuracy and high sample frequency. For less dynamic movements, like walking or squatting, portable 3D force plates are used, while if just the vertical component of the GRFs is of interest, pressure plates or in-shoe pressure measurements are often preferred. In many cases, however, it is impossible to measure 3D GRFs, e.g., during athletic competitions, at work or everyday life. It is still challenging to predict the horizontal components of the GRFs from kinematics using biomechanical models. The virtual pivot point (VPP) concept states that measured GRFs during walking intercept in a point located above the center of mass, while during running, the GRFs cross each other at a point below the center of mass. In the present study, this concept is used to compare predicted GRFs from measured kinematics with measured 3D-GRFs, not only during walking but also during more static movements like squatting and inline lunge. To predict the GRFs a full-body biomechanical model was used while gradually changing the positions of the VPP. It is shown that an optimal VPP improves the prediction of GRFs not only for walking but also for inline lunge and squats.

The Impact of High Adiposity on Endometrial Progesterone Response and Metallothionein Regulation.

CONTEXT: Obesity is a disease with deleterious effects on the female reproductive tract, including the endometrium. OBJECTIVE: We sought to understand the effects of excess adipose on the benign endometrium. DESIGN: A physiologic in vitro coculture system was developed, consisting of multicellular human endometrial organoids, adipose spheroids, and menstrual cycle hormones. Native human endometrial tissue samples women with and without obesity were also analyzed. SETTING: Academic institution. PATIENTS: Benign endometrial tissues from premenopausal women were obtained following written consent. MAIN OUTCOME MEASURES: Gene expression, protein expression, chromatin binding, and expression of DNA damage and oxidative damage markers were measured. RESULTS: Under high-adiposity conditions, endometrial organoids downregulated endometrial secretory phase genes, suggestive of an altered progesterone response. Progesterone specifically upregulated the metallothionein (MT) gene family in the epithelial cells of endometrial organoids, while high adiposity significantly downregulated the MT genes. Silencing MT genes in endometrial epithelial cells resulted in increased DNA damage, illustrating the protective role of MTs. Native endometrium from women with obesity displayed increased MT expression and oxidative damage in the stroma and not in the epithelium, indicating the cell-specific impact of obesity on MT genes. CONCLUSIONS: Taken together, the in vitro and in vivo systems used here revealed that high adiposity or obesity can alter MT expression by decreasing progesterone response in the epithelial cells and increasing oxidative stress in the stroma.

Exposure of Peregrine Falcons to Halogenated Flame Retardants: A 30 Year Retrospective Biomonitoring Study across North America.

Compared to aquatic ecosystem, terrestrial systems have been subjected to fewer investigations on the exposure to halogenated flame retardants (HFRs). Our study utilized peregrine falcon eggs collected from multiple habitats across North America to retrospectively explore both spatial distribution and temporal changes in legacy (e.g., polybrominated diphenyl ethers) and alternative HFRs over a 30 year period (1984-2016). The results reveal intensive HFR exposure in terrestrial ecosystems and chemical-specific spatiotemporal distribution patterns. The correlations between egg levels of the selected HFRs and human population density clearly illustrated a significant urban influence on the exposure of this wildlife species to these HFRs and subsequent maternal transfer to their eggs. Temporal analyses suggest that, unlike aquatic systems, terrestrial ecosystems may undergo continual exposure to consistently high levels of legacy HFRs for a long period of time. Our findings collectively highlight the effectiveness of using peregrine eggs to monitor terrestrial exposure to HFRs and other bioaccumulative chemicals and the need for continuous monitoring of HFRs in terrestrial ecosystems.

A European survey of older peoples' preferences, and perceived barriers and facilitators to inform development of a medication-related fall-prevention patient portal.

PURPOSE: Falls are a major and growing health care problem in older adults. A patient portal has the potential to provide older adults with fall-prevention advice to reduce fall-risk. However, to date, the needs and preferences regarding a patient portal in older people who have experienced falls have not been explored. This study assesses content preferences, potential barriers and facilitators with regard to using a patient portal, as perceived by older people who have experienced falls, and explores regional differences between European participants. METHODS: We conducted a survey of older adults attending an outpatient clinic due to a fall or fall-related injury, to explore their content preferences, perceived barriers, and facilitators with respect to a fall-prevention patient portal. Older adults (N = 121, 69.4% female, mean age: 77.9) were recruited from seven European countries. RESULTS: Almost two-thirds of respondents indicated they would use a fall-prevention patient portal. The portal would preferably include information on Fall-Risk-Increasing Drugs (FRIDs), and ways to manage other related/relevant medical conditions. Facilitators included a user-friendly portal, with easily accessible information and physician recommendations to use the portal. The most-commonly-selected barriers were privacy issues and usage fees. A family member's recommendation to use the portal was seemingly more important for Southern and Eastern European participants compared to the other regions. CONCLUSION: The majority of older people with lived falls experience expressed an interest in a fall-prevention patient portal providing personalized treatment advice to prevent further falls. The results will be used to inform the development of a fall-prevention patient portal. The fall-prevention patient portal is intended to be used in addition to a consultation with a physician. Future research is needed to explore how to prevent falls in older patients who are not interested in a fall-prevention patient portal.

Feed restriction of lactating cows triggers acute downregulation of mammary mTOR signaling and chronic reduction of mammary epithelial mass.

While there is generally no consensus about how nutrients determine milk synthesis in the mammary gland, it is likely that the mechanistic target of rapamycin complex 1 (mTORC1) plays a role as a key integrator of nutritional and mitogenic signals that can influence a multitude of catabolic and anabolic pathways. The objectives of this study were to evaluate acute changes (<24 h) in translational signaling, in addition to chronic changes (14 d) in mammary gland structure and composition, in response to a severe feed restriction. Fourteen lactating Holstein dairy cows were assigned to either ad libitum feeding (n = 7), or a restricted feeding program (n = 7). Feed-restricted cows had feed removed after the evening milking on d 0. Mammary biopsies and blood samples were collected 16 h after feed removal, after which cows in the restricted group were fed 60% of their previously observed ad lib intake for the remainder of the study. On d 14, animals were sacrificed and mammary glands dissected. In response to feed removal, an acute increase in plasma nonesterified fatty acid concentration was observed, concurrent to a decrease in milk yield. In mammary tissue, we observed downregulation of the mTORC1-S6K1 signaling cascade, in addition to reductions in mRNA expression of markers of protein synthesis, endoplasmic reticulum biogenesis, and cell turnover (i.e., transcripts associated with apoptosis or cell proliferation). During the 14 d of restricted feeding, animals underwent homeorhetic adaptation to 40% lower nutrient intake, achieving a new setpoint of 14% reduced milk yield with 18% and 29% smaller mammary secretory tissue dry matter and crude protein masses, respectively. On d 14, no treatment differences were observed in markers of protein synthesis or mammary cell turnover evaluated using gene transcripts and immunohistochemical staining. These findings implicate mTORC1-S6K1 in the early phase of the adaptation of the mammary gland's capacity for milk synthesis in response to changes in nutrient supply. Additionally, changes in rates of mammary cell turnover may be transient in nature, returning to basal levels following brief alterations that have sustained effects.

The weather as a determinant of farmer's mental health: A dependent, interacting, cumulative and escalating model (DICE) of the effects of extreme weather events.

This perspective paper presents a conceptual, theoretical framework of the weather as a determinant of mental health for farmers. This model proposes that the effects of extreme weather events have interacting and cumulative effects for farmers, who are dependent on the land.

COVID-19 and beyond: A systematic review of adaptations to psychosocial support in oncology.

AIMS: To understand the strategies used to continue providing psychosocial support to cancer patients during the pandemic, including outcomes and implications beyond the pandemic. DESIGN: A systematic review of original research. DATA SOURCES: ProQuest Health & Medicine, CINAHL Complete (via EBSCOhost), Scopus, and PubMed were searched for original work published between January 2020 and December 2022. METHODS: Abstract and title screening identified eligible articles for full-text review. Following a full-text review, data were extracted from eligible articles, and a risk of bias assessment was conducted. A synthesis without meta-analysis was performed. RESULTS: Thirty-four articles met the selection criteria. These articles provide evidence that systematic adaptations during the pandemic improved the assessment and screening of psychological needs and/or increased the number of clients accessing services. Additionally, while the pandemic was associated with decreased psychosocial well-being for cancer patients, five intervention studies reported improvements in psychosocial well-being. Barriers, strategies, and recommendations were described. CONCLUSION: Adapting psychosocial support during a pandemic can be successful, achieved relatively quickly, and can increase the uptake of support for people experiencing cancer. IMPLICATIONS FOR PATIENT CARE: It is imperative that these adaptations continue beyond the pandemic to maximize adaptive psychosocial outcomes for a group vulnerable to ongoing mental health concerns. IMPACT: While the COVID-19 pandemic was associated with increased psychosocial need for cancer patients, evidence in the review suggested that adaptations made to service delivery facilitated increased access for patients who may not previously have been able to access support. Additionally, improvements in psychosocial well-being were achieved. These findings are relevant for clinicians and decision-makers who fund and design psychosocial support services for cancer patients. REPORTING METHOD: The review was guided by PRISMA Guidelines and the SWiM Reporting Guideline. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Effect of postbiotic Lactiplantibacillus plantarum LRCC5314 supplemented in powdered milk on type 2 diabetes in mice.

Type 2 diabetes (T2D) is a chronic multifactorial disease characterized by a combination of insulin resistance and impaired glucose regulation. The alleviative effects of probiotics on T2D have been widely studied. However, studies on the effects of postbiotics, known as inactivated probiotics, on dairy products are limited. This study aimed to evaluate the effectiveness of postbiotic Lactiplantibacillus plantarum LRCC5314 in milk powder (MP-LRCC5314) in a stress-T2D mouse model. Compared with probiotic MP-LRCC5314, postbiotic MP-LRCC5314 significantly influenced stress-T2D-related factors. The administration of heat-killed MP-LRCC5314 reduced corticosterone levels, increased short-chain fatty acid production by modulating gut microbiota, and regulated immune response, glucose metabolism, stress-T2D-related biomarkers in the brain, gut, and adipose tissues, as well as glucose and insulin sensitivity. Additionally, heat-killed MP-LRCC5314 treatment led to a decrease in pro-inflammatory cytokine levels and an increase in anti-inflammatory cytokine levels. Overall, these findings suggest that adding postbiotic MP-LRCC5314 to milk powder could serve as a potential supplement for stress-T2D mitigation.

Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity.

Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena3. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory4. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer5. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.

Oncolytic vaccinia virus immunotherapy antagonizes image-guided radiotherapy in mouse mammary tumor models.

Ionizing radiation (IR) and oncolytic viruses are both used to treat cancer, and the effectiveness of both agents depends upon stimulating an immune response against the tumor. In this study we tested whether combining image guided ionizing radiation (IG-IR) with an oncolytic vaccinia virus (VACV) could yield a better therapeutic response than either treatment alone. ΔF4LΔJ2R VACV grew well on irradiated human and mouse breast cancer cells, and the virus can be combined with 4 or 8 Gy of IR to kill cells in an additive or weakly synergistic manner. To test efficacy in vivo we used immune competent mice bearing orthotopic TUBO mammary tumors. IG-IR worked well with 10 Gy producing 80% complete responses, but this was halved when the tumors were treated with VACV starting 2 days after IG-IR. VACV monotherapy was ineffective in this model. The antagonism was time dependent as waiting for 21 days after IG-IR eliminated the inhibitory effect but without yielding any further benefits over IR alone. In irradiated tumors, VACV replication was also lower, suggesting that irradiation created an environment that did not support infection as well in vivo as in vitro. A study of how four different treatment regimens affected the immune composition of the tumor microenvironment showed that treating irradiated tumors with VACV altered the immunological profiles in tumors exposed to IR or VACV alone. We detected more PD-1 and PD-L1 expression in tumors exposed to IR+VACV but adding an αPD-1 antibody to the protocol did not change the way VACV interferes with IG-IR therapy. VACV encodes many immunosuppressive gene products that may interfere with the ability of radiotherapy to induce an effective anti-tumor immune response through the release of danger-associated molecular patterns. These data suggest that infecting irradiated tumors with VACV, too soon after exposure, may interfere in the innate and linked adaptive immune responses that are triggered by radiotherapy to achieve a beneficial impact.

Ameliorating effect of 2'-Fucosyllactose and 6'-Sialyllactose on lipopolysaccharide-induced intestinal inflammation.

Human milk oligosaccharides (HMO) affect gut microbiota during neonatal development, particularly with respect to the immune system. Bovine milk-based infant formulas have low oligosaccharide contents. Thus, efforts to fortify infant formulas with HMO are being undertaken. Two major HMO, 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL), exert anti-inflammatory effects; however, the associations between anti-inflammatory effects induced by 2'-FL and 6'-SL co-treatment and gut microbiota composition and metabolite modulation remain unclear. Therefore, in this study, we evaluated the effects of a mixture of these HMO. To determine the optimal HMO ratio for anti-inflammatory effects and elucidate its mode of action, LPS-induced inflammatory HT-29 epithelial cells and intestinal inflamed suckling mice were treated with various mixtures of 2'-FL and 6'-SL. 2'-FL:6'-SL ratio of 5:1 was identified as the most effective pre-treatment HMO mixture in vitro; thus, this ratio was selected and used for low, middle, and high-dose treatments for subsequent in vivo studies. In vivo, high-dose HMO treatment restored LPS-induced inflammation symptoms, such as body weight loss, colon length reduction, histological structural damage, and intestinal gene expression related to inflammatory responses. High-dose HMO was the only treatment that modulated the major phyla Bacteroidetes and Firmicutes and the genera Ihubacter, Mageeibacillus, and Saccharofermentans. These changes in microbial composition were correlated with intestinal inflammation-related gene expression and short-chain fatty acid production. To our knowledge, our study is the first to report the effects of Ihubacter, Mageeibacillus, and Saccharofermentans on short chain fatty acid levels, which can subsequently affect inflammatory cytokine and tight junction protein levels. Conclusively, the HMO mixture exerted anti-inflammatory effects through changes in microbiota and metabolite production. These findings suggested that supplementation of infant formula with HMO may benefit formula-fed infants by forming unique microbiota contributing to neonatal development.

The Impact of Baseline PSMA PET/CT Versus CT on Outcomes of 223Ra Therapy in Metastatic Castration-Resistant Prostate Cancer Patients.

Imaging before 223Ra-dichloride (223Ra) therapy is crucial for selecting metastatic castration-resistant prostate cancer (mCRPC) patients with bone-only disease. The purpose of this study was to evaluate if baseline prostate-specific membrane antigen (PSMA) PET/CT (bPSMA) versus CT is associated with outcomes of 223Ra therapy. Methods: A secondary analysis of the data of a prospective observational study (NCT04995614) was performed. Patients received a maximum of 6 223Ra cycles and were retrospectively divided into the bPSMA or baseline CT (bCT) groups. All patients received baseline bone scintigraphy. Primary endpoints were alkaline phosphatase and prostate-specific antigen response. Secondary endpoints were overall survival (OS) and radiologic response. Results: Between 2017 and 2020, 122 mCRPC patients were included: 18 (14.8%) in the bPSMA group and 104 (85.2%) in the bCT group. All baseline characteristics were comparable. No significant differences in alkaline phosphatase or prostate-specific antigen response were found. The bCT group showed an OS significantly shorter than that of the bPSMA group (12.4 vs. 19.9 mo, P = 0.038). In 31 of 76 patients (40.1%) in the bCT group who also received posttherapy CT, lymph node or visceral metastases (soft-tissue involvement [STI]) were detected after 223Ra therapy, compared with 0 of 15 patients in the bPSMA group who received posttherapy PSMA PET/CT or CT. No significant difference in OS was found between patients in the bCT or posttherapy CT subgroup without STI (46/76) and the bPSMA group. Conclusion: bPSMA versus CT does not seem to impact biochemical response during 223Ra therapy in mCRPC patients. Nevertheless, patients in the bCT group had a significantly shorter OS, most likely due to underdetection of STI in this group. Therefore, replacing bCT with PSMA PET/CT appears to be a valuable screening method for identifying patients who will benefit most from 223Ra therapy.

Patient Impression of Improvement 1 year After Sacrospinous Hysteropexy Versus Vaginal Hysterectomy in Women with Pelvic Organ Prolapse Stage 2 or Higher.

INTRODUCTION AND HYPOTHESIS: Patient-reported outcomes are relevant outcomes in studies on pelvic organ prolapse (POP) surgery, as anatomical recurrence alone does not have a significant correlation with perceived improvement. In the present study, the patient's impression of improvement after 1 year is studied after vaginal hysterectomy (VH) versus sacrospinous hysteropexy (SSH) in large cohorts from daily clinical practice. We hypothesize that there is no difference between the groups. METHODS: This is a secondary analysis on prospectively collected data in a multicenter cohort of patients who underwent VH or SSH for symptomatic POP. All patients had a POP-Q stage ≥ 2 in at least one compartment at baseline and were treated with VH or SSH between 2002 and 2019. The primary outcome was the patient-reported score on the patient global impression of improvement index (PGI-I) 1 year after surgery. The secondary outcome was a composite outcome of surgical success, defined as the absence of recurrent POP beyond the hymen with bothersome bulge symptoms and/or repeat surgery. RESULTS: A total of 378 women (196 VH and 182 SSH) were included. The median score on the PGI-I did not differ between VH and SSH. At 1 year post-operatively, 77 women after VH (73%) and 77 women after SSH (75%) considered their condition (very) much improved (p = 0.86). There was no difference in composite outcome of surgical success (126 out of 137 women [92%] after VH, 118 out of 125 women [94%] after SSH; p = 0.44). CONCLUSIONS: Our study shows that there was no difference in the type of surgery, VH or SSH, with regard to the patient's impression of improvement 1 year postoperatively in a large cohort from daily clinical practice.

Compliance with maternal sepsis guidelines in a tertiary hospital in the Netherlands.

OBJECTIVES: Sepsis is a common cause of maternal mortality and morbidity. Early detection and rapid management are essential. In this study, we evaluate the compliance with the implemented maternity-specific Early Warning Score (EWS), Rapid Response Team (RRT) protocol and the Surviving Sepsis Campaign (SSC) Hour-1 Bundle in a tertiary hospital in the Netherlands. METHODS: We performed a retrospective patient chart review from July 2019 to June 2020 at the Leiden University Medical Centre. We included women who received therapeutic antibiotics and were admitted for at least 24 hours. RESULTS: We included 240 women: ten were admitted twice and one woman three times, comprising 252 admissions. A clinical diagnosis of sepsis was made in 22 women. The EWS was used in 29% (n = 73/252) of admissions. Recommendations on the follow-up of the EWS were carried out in 53% (n = 46/87). Compliance with the RRT protocol was highest for assessment by a medical doctor within 30 minutes (n = 98/117, 84%) and lowest for RRT involvement (n = 7/23, 30%). In women with sepsis, compliance with the SSC Bundle was highest for acquiring blood cultures (n = 19/22, 85%), while only 64% (n = 14/22) received antibiotics within 60 minutes of the sepsis diagnosis. CONCLUSION: The adherence to the maternity-specific EWS and the SSC Hour-1 bundle was insufficient, even within this tertiary setting in a high-income country.

A Well-Being Well-Check for Neurosurgery: Evidence-Based Suggestions for Our Specialty Based on a Systematic Review.

BACKGROUND: The path through neurosurgery is rigorous. Many neurosurgeons may experience burnout, depression, or suicide throughout training and practice. We review the literature to help foster a culture of awareness and self-care and arm trainees with coping skills to reduce burnout and, thus, suicidality during all phases of their medical careers. METHODS: A systematic search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using 4 databases. 7 studies were included. RESULTS: Overlying themes of interventions were to increase balance, mindfulness, and physical fitness. The most common interventions included in programs were educational and physical activity. We suggest a comprehensive wellness program emphasizing interventions from 4 wellness dimensions-physical, spiritual, mental, and emotional. CONCLUSIONS: Many neurosurgeons experience burnout, leading to a lack of satisfaction and early retirement; this necessitates a discipline-wide acknowledgment of endemic burnout among neurosurgeons. Systemic changes are needed to refine the training process and prioritize physician well-being- this cannot be left to chance.

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

[Cell-based influenza vaccines: an effective vaccine option for under 60-year-olds]. / Zellkulturbasierte Influenzaimpfstoffe: eine effektive Impfstoffoption für unter 60-Jährige.

The population < 60 years of age is also affected by a significant disease burden from seasonal influenza. It carries a high economic burden, mainly driven by influenza-associated productivity losses in the working population. Conventional egg-based influenza vaccines may experience reduced effectiveness due to antigen adaptation in eggs. In contrast, cell-based influenza vaccines are less likely to be affected by antigenic adaptations to the host system and showed better effectiveness in individuals 4-64 years old over several seasons compared to conventional egg-based influenza vaccines under real-world conditions. Preferential use of cell-based influenza vaccines, as opposed to conventional egg-based vaccines, could reduce the burden of influenza-related symptoms on individuals and alleviate the economic impact on the German population < 60 years of age.

Prevalence of swallowing difficulties and associated factors in older people with intellectual disabilities.

BACKGROUND: We investigated the prevalence of swallowing difficulties and associated factors in people with intellectual disability. METHODS: We included people aged 50+ receiving care for people with intellectual disabilities. The Dysphagia Disorder Survey (DDS) was used to assess swallowing difficulties. We determined the agreement between the DDS and swallowing difficulties in medical records. We used logistic regression analyses to explore associated factors. RESULTS: One thousand and fifty people were included. The prevalence of swallowing difficulties was 43.8%. Swallowing difficulties were not reported in the medical records of 83.3% of these cases. Frailty (odds ratio (OR) = 4.22, 95% CI = 2.05-8.71), mobility impairment (OR = 2.50, 95% CI = 1.01-6.19), and mealtime dependency (OR = 3.05, 95% CI = 1.10-8.47) were independently associated with swallowing difficulties. CONCLUSION: Swallowing difficulties are prevalent in older people with intellectual disability but may be under-recognised. Frailty may be a good indicator for population-based screening for swallowing difficulties.