Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure.

BACKGROUND: Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals. METHODS: We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods. To identify causal genes, we performed a gene-wise association test. We conducted analyses in 2 separate large-scale cohorts: 77 822 individuals from the Genetic Epidemiology Research on Adult Health and Aging and 315 270 individuals from the UK Biobank. RESULTS: We identified 309, 259, 331, and 367 genes (false discovery rate <0.05) for diastolic BP and 191, 184, 204, and 204 genes for systolic BP in the artery, kidney, heart, and adrenal, respectively, in Genetic Epidemiology Research on Adult Health and Aging; 50% to 70% of these genes were replicated in the UK Biobank, significantly higher than the 12% to 15% expected by chance (P<0.0001). These results enabled tissue expression prediction of these 988 to 2875 putative BP genes in individuals of both cohorts to construct an expression polygenic score. This score explained ≈27% of the reported single-nucleotide variant heritability, substantially higher than expected from prior studies. CONCLUSIONS: Our work demonstrates the power of tissue-restricted comprehensive CRE analysis, followed by CRE-based expression prediction, for understanding BP regulation in relevant tissues and provides dual-modality supporting evidence, CRE and expression, for the causality genes.

Increase in acute mastoiditis at the end of the COVID-19 pandemic.

PURPOSE: Common respiratory infections were significantly reduced during the COVID-19 pandemic due to general protective and hygiene measures. The gradual withdrawal of these non-pharmaceutical interventions (NPI) was associated with a notable increase in these infections, particularly in pediatric and adult otorhinolaryngology. The aim of this retrospective monocentric study was to evaluate the impact of NPI during the COVID-19 pandemic on the incidence and severity of acute mastoiditis (AM). METHODS: Pre-pandemic clinical data of AM cases from 2011 to 2019 were compared with infection counts from January 2020 to June 2023 for seasonal periodicity, age-specific differences, pathogens, and complication rates in a German third-level hospital. RESULTS: Out of 196 patients with AM 133 were children, the majority between 1 and 5 years of age. Complications of AM, such as meningitis, brain abscess, and sinus vein thrombosis, were more common in adults (87%) than in children (17%). Morbidity and mortality rates were similar before, during and after the pandemic. Pneumococci were the most common pathogen in both age groups, with a post-pandemic cumulation of Streptococcus pyogenes infections in children. While pre-pandemic cases clustered in spring, seasonality was absent in all age groups during the main phase of the pandemic. The cessation of NPI caused a steep rise in AM cases in both age groups starting from December 2022. CONCLUSION: NPI during the COVID-19 pandemic reduced the incidence of AM. Their reversal led to a substantial increase in the incidence of AM during the post-pandemic period, which may be due to a general increase in viral respiratory infections and an insufficiently trained immune system.

Partial recovery of peripheral blood monocyte subsets in head and neck squamous cell carcinoma patients upon radio(chemo)therapy is associated with decreased plasma CXCL11.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) represents a common and heterogeneous malignancy of the oral cavity, pharynx and larynx. Surgery and radio(chemo)therapy are the standard treatment options and also have great influence on the composition of the tumor microenvironment and immune cell functions. However, the impact of radio(chemo)therapy on the distribution and characteristics of circulating monocyte subsets in HNSCC are not fully understood. METHODS: Expression patterns of adhesion molecules and chemokine receptors CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and checkpoint molecule PD-L1 (programmed cell death ligand-1) were investigated upon radio(chemo)therapeutic treatment using flow cytometry. Furthermore, comprehensive analysis of plasma cytokines was performed before and after treatment using ELISA measurements. RESULTS: Our data reveal a partial recovery of circulating monocytes in HNSCC patients upon radio(chemo)therapeutic treatment, with differential effects of the individual therapy regimen. PD-L1 expression on non-classical monocytes significantly correlates with the individual plasma levels of chemokine CXCL11 (C-X-C motif chemokine 11). CONCLUSIONS: Further comprehensive investigations on larger patient cohorts are required to elucidate the meaningfulness of peripheral blood monocyte subsets and chemokine CXCL11 as potential bioliquid indicators in HNSCC with regard to therapy response and the individual immunological situation.

Sex-specific genetic architecture of blood pressure.

The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (Pfemale ≤ 5 × 10-8; Pmale > 5 × 10-8) and 142 were male-specific (Pmale ≤ 5 × 10-8; Pfemale > 5 × 10-8); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1. Analyses of gene-by-sex interactions and sexually dimorphic effects identified four genomic regions, showing female-specific associations with diastolic BP or pulse pressure, including the chromosome 13q34-COL4A1/COL4A2 locus. Notably, female-specific pulse pressure-associated loci exhibited enriched acetylated histone H3 Lys27 modifications in arterial tissues and a female-specific association with fibromuscular dysplasia, a female-biased vascular disease; colocalization signals included Chr13q34: COL4A1/COL4A2, Chr9p21: CDKN2B-AS1 and Chr4q32.1: MAP9 regions. Sex-specific and sex-biased polygenic associations of BP traits were associated with multiple cardiovascular traits. These findings suggest potentially clinically significant and BP sex-specific pleiotropic effects on cardiovascular diseases.

Monitoring mepolizumab treatment in chronic rhinosinusitis with nasal polyps (CRSwNP): Discontinue, change, continue therapy?

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL-5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy should be monitored, what follow-up documentation is necessary, and when it should be discontinued if necessary. MATERIALS AND METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries, and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals, and possible therapy breaks as well as discontinuation of therapy when using mepolizumab for the indication CRSwNP in the German healthcare system are given on the basis of a documentation sheet. CONCLUSION: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

An epidemiological qualitative/quantitative SWOT-AHP analysis in order to highlight the positive or critical aspects of dental implants: A pilot study.

OBJECTIVES: In recent years, dental implants are increasing in popularity due to their high success rate, demonstrated functionality, and aesthetic treatment results. Scientific research is very active in proposing improvements in the quality and survival of implants, taking into consideration various aspects. The objective of this study was to provide a holistic epidemiologic view of the state of dental implants, using a systematic approach based on a multimethod SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis and AHP (analytical hierarchical process) qualitative-quantitative analysis to identify the characteristics that can determine their success or failure. MATERIALS AND METHODS: The study used the hybrid method of SWOT-AHP. RESULTS: Analysis of the results showed that among strengths, the skill of the dentist was considered the most important factor, followed by the success of dental implants in the old people; among weaknesses, bruxism and chronic diseases were highlighted; for opportunities, biomechanical behavior, in terms of good mechanical strength and good tribological resistance to chemical and physical agents in the oral cavity, were considered the most important factors; finally, among threats, medical liability and biomechanical problems had equal weight. CONCLUSIONS: This study applied a multimethod SWOT-AHP approach to bring out favorable or critical evidence on the topic of dental implants. In accordance with the result of the strategic vector identified in the Twisting zone Adjustment type section, showed that implant surgery is a widespread technique but always needs improvement to increase the likelihood of success and reduce the complications that can lead to implant failure.

The Relationship Between Barriers to Physical Activity and Depressive Symptoms in Community-Dwelling Women.

Background: Women are less physically active, report greater perceived barriers for exercise, and show higher levels of depressive symptoms. This contributes to high global disability. The relationship between perceived barriers for physical activity and depressive symptoms in women remains largely unexplored. The aims of this cross-sectional analysis were to examine the association between physical activity barriers and depressive symptoms, and identify types of barriers in physically inactive community-dwelling women. Methods: Three hundred eighteen physically inactive women aged 25-65 years completed the Barriers to Being Active Quiz (BBAQ) developed by the Centers for Disease Control and Prevention, and the Center for Epidemiological Studies Depression Scale at the baseline visit of the mobile phone-based physical activity education trial. The BBAQ consists of six subscales (lack of time, social influence, lack of energy, lack of willpower, fear of injury, lack of skill, and lack of resources). We used multivariate regression analyses, correcting for sociodemographics. Results: Higher physical activity barriers were associated with greater depressive symptoms scores (linear effect, estimate = 0.75, 95% confidence interval [CI]: 0.39-1.12, p < 0.001). This effect appeared to taper off for the higher barrier scores (quadratic effect, estimate: -0.02, 95% CI: -0.03 to -0.01, p = 0.002). Exploratory analyses indicated that these associations were most driven by the social influence (p = 0.027) and lack of energy subscales (p = 0.017). Conclusions: Higher depression scores were associated with higher physical activity barriers. Social influence and lack of energy were particularly important barriers. Addressing these barriers may improve the efficacy of physical activity interventions in women with higher depressive symptoms. Future research should assess this in a randomized controlled trial. Trial Registration ClinicalTrialsgov#: NCTO1280812 registered January 21, 2011.

Establishment of the deuterium oxide dilution method as a new possibility for determining the transendothelial water permeability.

Increase in transendothelial water permeability is an essential etiological factor in a variety of diseases like edema and shock. Despite the high clinical relevance, there has been no precise method to detect transendothelial water flow until now. The deuterium oxide (D2O) dilution method, already established for measuring transepithelial water transport, was used to precisely determine the transendothelial water permeability. It detected appropriate transendothelial water flow induced by different hydrostatic forces. This was shown in four different endothelial cell types. The general experimental setup was verified by gravimetry and absorbance spectroscopy. Determination of transendothelial electrical resistance (TEER) and immunocytochemical staining for proteins of the cell-cell contacts were performed to ensure that no damage to the endothelium occurred because of the measurements. Furthermore, endothelial barrier function was modulated. Measurement of transendothelial water flux was verified by measuring the TEER, the apparent permeability coefficient and the electrical capacity. The barrier-promoting substances cyclic adenosine monophosphate and iloprost reduced TEER and electrical capacity and increased permeability. This was accompanied by a reduced transendothelial water flux. In contrast, the barrier-damaging substances thrombin, histamine and bradykinin reduced TEER and electrical capacity, but increased permeability. Here, an increased water flow was shown. This newly established in vitro method for direct measurement of transendothelial water permeability was verified as a highly precise technique in various assays. The use of patient-specific endothelial cells enables individualized precision medicine in the context of basic edema research, for example regarding the development of barrier-protective pharmaceuticals.

[Online survey to determine realistic success rates and trends in surgical septal perforation repair]. / Online-Befragung: realistische Erfolgsquoten und Trends beim operativen Septumperforationsverschluss.

OBJECTIVE: High success rates (SR) for surgical septal perforation repair (SPR) of over 90 % are reported in the literature. We think that realistic SR are significantly lower and wanted to confirm this thesis with the help of a survey among ear, nose, throat ENT specialists from Germany. Surgical trends were also queried. MATERIAL AND METHODS: An anonymous online survey among ENT specialists in Germany was conducted. 356 doctors participated. The collected SR were statistically evaluated, and the operative trends were analysed. It applies a significance level α = 0.05. The SR were collected for 3 different size categories (<1 cm, 1-2 cm, >2 cm). RESULTS: The SR for SPR <1 cm (median 79 %) was higher than that for 1-2 cm (60 %) and >2 cm (40 %). Surgeons estimated SR significantly higher (90 %, 75 %, 50 %; p-value <0.001 each) than non-surgeons (80 %, 50 %, 25 %). Hospital-based physicians (90 %, 70 %, 50 %) reported significantly higher SR than ambulatory physicians (80 %, 50 %, 30 %, p-value <0.001 each). No linear relationship was found between the total number of SPR performed and SR (r <1cm = 0.16, r1-2cm = 0.18, r >2cm = 0.19). Most SPR were performed with the bridge flap technique (73 %), a closed surgical approach (85 %), an interposition graft (74 %) and postoperative splinting (94 %). CONCLUSIONS: The subjective SR suggest that the SR of SPR is lower than described in the literature. This may be due to short follow-up times, small patient populations and a retrospective design of existing studies. The variety of surgical possibilities confirms the complexity of SPR. Optimising the design of future studies could help to collect realistic SR.

Prenatal exposure to social adversity and infant cortisol in the first year of life.

Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman's reports of social adversity during the third trimester were associated with their infant's resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants' cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

INHBA is Enriched in HPV-negative Oropharyngeal Squamous Cell Carcinoma and Promotes Cancer Progression.

Patients with oropharyngeal squamous cell carcinoma (OPSCC) caused by human papilloma virus (HPV) exhibit a better prognosis than those with HPV-negative OPSCC. This study investigated the distinct molecular pathways that delineate HPV-negative from HPV-positive OPSCC to identify biologically relevant therapeutic targets. Bulk mRNA from 23 HPV-negative and 39 HPV-positive OPSCC tumors (n = 62) was sequenced to uncover the transcriptomic profiles. Differential expression followed by gene set enrichment analysis was performed to outline the top enriched biological process in the HPV-negative compared with HPV-positive entity. INHBA, the highest overexpressed gene in the HPV-negative tumor, was knocked down. Functional assays (migration, proliferation, cell death, stemness) were conducted to confirm the target's oncogenic role. Correlation analyses to reveal its impact on the tumor microenvironment were performed. We revealed that epithelial-to-mesenchymal transition (EMT) is the most enriched process in HPV-negative compared with HPV-positive OPSCC, with INHBA (inhibin beta A subunit) being the top upregulated gene. INHBA knockdown downregulated the expression of EMT transcription factors and attenuated migration, proliferation, stemness, and cell death resistance of OPSCC cells. We uncovered that INHBA associates with a pro-tumor microenvironment by negatively correlating with antitumor CD8+ T and B cells while positively correlating with pro-tumor M1 macrophages. We identified three miRNAs that are putatively involved in repressing INHBA expression. Our results indicate that the upregulation of INHBA is tumor-promoting. We propose INHBA as an attractive therapeutic target for the treatment of INHBA-enriched tumors in patients with HPV-negative OPSCC to ameliorate prognosis. SIGNIFICANCE: Patients with HPV-negative OPSCC have a poorer prognosis due to distinct molecular pathways. This study reveals significant transcriptomic differences between HPV-negative and HPV-positive OPSCC, identifying INHBA as a key upregulated gene in HPV-negative OPSCC's oncogenic pathways. INHBA is crucial in promoting EMT, cell proliferation, and an immunosuppressive tumor environment, suggesting its potential as a therapeutic target for HPV-negative OPSCC.

Genetic risk score for Alzheimer's disease predicts brain volume differences in mid and late life in UK biobank participants.

INTRODUCTION: We estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle-aged and older adults. METHODS: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume. RESULTS: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm3 [-0.42, -0.40]); hippocampus (-0.45 mm3 [-0.45, -0.44]), nucleus accumbens (-0.55 mm3 [-0.56, -0.54]), thalamus (-0.38 mm3 [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm3 [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices. DISCUSSION: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.

Association between water insecurity and antiretroviral therapy adherence among pregnant and postpartum women in Greater Accra region of Ghana.

BACKGROUND: Adherence to antiretroviral therapy (ART) can substantially reduce morbidity and mortality among women living with HIV (WLWH) and prevent vertical transmission of HIV. However, in sub-Saharan Africa (SSA), more than 50% of new mothers discontinue ART and HIV care after childbirth. The role of water insecurity (WI) in ART adherence is not well-explored. We examined the relationship between WI and ART adherence among pregnant and postpartum WLWH in Greater Accra region of Ghana. METHODS: Using a cross-sectional survey, we recruited 176 pregnant and postpartum WLWH on ART across 11 health facilities. We examined the association between WI (measured using the Household Water Insecurity Experience Scale, and categorized as moderate and severe WI compard to low WI) and poor ART adherence (defined as scoring a below average observed CASE index score). Bivariate analysis was performed using chi-square test followed by multivariate logistic regression models. We included all variables with p-values less than 0.20 in the multivariate analysis. RESULTS: Most (79.5%) of the pregnant and postpartum WLWH enrolled on ART, were urban residents. Over 2/3 were aged 30 years and older. Overall, 33.5% of respondents had poor ART adherence. Proportion of poor ART adherence was 19.4% among those with low WI, 44.4% in those with moderate WI, and 40.0% among those with high WI. Respondents with moderate household water insecurity had a greater odds of reporting poor ART adherence, as compared to those with low water insecurity (adjusted Odds ratio (aOR) = 2.76, 95%CI: 1.14-6.66, p = 0.024), even after adjusting for food insecurity. Similarly, respondents with high WI had a greater odds of reporting poor ART adherence, as compared to those with low water insecurity (aOR = 1.49, 95%CI: 0.50-4.48, p = 0.479), even after adjusting for food insecurity. CONCLUSION: Water insecurity is prevalent among pregnant and postpartum WLWH and is a significant risk factor for poor ART adherence. Governments and other stakeholders working in HIV care provision should prioritize water security programming for WLWH along the HIV care continuum.

Multi-ancestry genome-wide meta-analysis identifies novel basal cell carcinoma loci and shared genetic effects with squamous cell carcinoma.

Basal cell carcinoma (BCC) is one of the most common malignancies worldwide, yet its genetic determinants are incompletely defined. We perform a European ancestry genome-wide association (GWA) meta-analysis and a Hispanic/Latino ancestry GWA meta-analysis and meta-analyze both in a multi-ancestry GWAS meta-analysis of BCC, totaling 50,531 BCC cases and 762,234 controls from four cohorts (GERA, Mass-General Brigham Biobank, UK Biobank, and 23andMe research cohort). Here we identify 122 BCC-associated loci, of which 36 were novel, and subsequently fine-mapped these associations. We also identify an association of the well-known pigment gene SLC45A2 as well as associations at RCC2 and CLPTM1L with BCC in Hispanic/Latinos. We examine these BCC loci for association with cutaneous squamous cell carcinoma (cSCC) in 16,407 SCC cases and 762,486 controls of European ancestry, and 33 SNPs show evidence of association. Our study findings provide important insights into the genetic basis of BCC and cSCC susceptibility.

[Fundamentals and practice of the application of nasal packing in sinonasal surgery]. / Grundlagen und Praxis der Anwendung von Nasentamponaden in der endonasalen Chirurgie.

BACKGROUND AND OBJECTIVES: This paper presents an overview on nasal packing materials which are available in Germany. The current literature is analyzed whether there are robust criteria regarding use nasal packing after sinonasal surgery, whether there are fundamental and proven advantages or disadvantages of products, and what this means in clinical practice. MATERIALS AND METHODS: Selective literature analysis using the PubMed database (key words "nasal packing", "nasal tamponade", "nasal surgery", "sinonasal surgery", or "sinus surgery"), corresponding text books and resulting secondary literature. RESULTS AND CONCLUSIONS: Because of systematic methodological shortcomings, the literature does not help in the decision-making about which nasal packing should be used after which kind of sinonasal surgery. In fact, individual approaches for the many different clinical scenarios are recommended. In principle, nasal packing aims in hemostasis, should promote wound healing, and should not result in secondary morbidity. Nasal packing materials should be smooth (non-absorbable materials), inert (absorbable materials), and should not exert excessive pressure. Using non-absorbable packing entails the risk of potentially lethal aspiration and ingestion. For safety reasons inpatient control is recommended as long as this packing is in situ. With other, uncritical packing materials and in patients with special conditions, outpatient control could be justified.

Tumor-Infiltrating CD103+ Tissue-Resident Memory T Cells and CD103-CD8+ T Cells in HNSCC Are Linked to Outcome in Primary but not Metastatic Disease.

PURPOSE: High numbers of tumor-infiltrating lymphocytes (TIL) are linked to better survival in patients with cancer. Tissue-resident memory T cells (TRM; CD8+CD103+) are recognized as a key player of anticancer immune response. To assess TRM cells in primary, metastatic, and recurrent head and neck squamous cell carcinoma (HNSCC), we developed a tissue microarray (TMA) and used multiplex IHC (MxIHC). EXPERIMENTAL DESIGN: Samples from primary tumors of 379 HNSCC cases treated at Southampton Hospitals between 2000 and 2016 were collected and analyzed. Of these, 105 cases had lymph node metastases and 82 recurrences. A TMA was generated with triplicate cores for each sample. MxIHC with a stain-and-strip approach was performed using CD8, CD103, and TIM3. Scanned slides were analyzed (digital image analysis) and quality checked (QC). RESULTS: After QC, 194 primary tumors, 76 lymph node metastases, and 65 recurrences were evaluable. Alcohol consumption was statistically significantly correlated with a reduction of TRM cells in primary tumors (nondrinker vs. heavy drinker: P = 0.0036). The known survival benefit of TRM cell infiltration in primary tumors was not found for lymph node metastasis. In recurrences, a high TRM cell number led to a favorable outcome after 12 months. The checkpoint molecule TIM3, was expressed significantly higher on TRM and non-TRM cells in the lymph node compared with primary tumors (P < 0.0001), which was also seen in recurrences (P = 0.0134 and P = 0.0007, respectively). CONCLUSIONS: We confirm the prognostic impact of TIL in primary tumors and in recurrences. TRM cell density in lymph node metastases was not linked to outcome. The role of TIM3, as a therapeutic target remains to be defined.

["Radical" versus "functional" surgery of the paranasal sinuses-A contradiction?] / "Radikale" vs. "funktionelle" Chirurgie der Nasennebenhöhlen ­ ein Widerspruch?

BACKGROUND AND OBJECTIVE: The terms "functional" and "radical" paranasal sinus surgery were often considered to be different operations which were mutually exclusive. This overview aims to look at the basics of these terms and surgical procedures and to work out the resulting surgical concepts for clinically relevant indications. MATERIAL AND METHODS: Selective literature analysis using the data base PubMed, corresponding textbooks and resulting secondary literature regarding functional and radical or extended paranasal sinus surgery. Similarly, the current literature regarding clinically relevant indications for sinus surgery were analyzed. RESULTS AND CONCLUSION: Modern pathophysiological knowledge, anatomically and pathophysiologically substantiated endoscopic surgical procedures and the usage of up to date technical possibilities have resulted in concepts which combine functional and so-called radical or extended surgery of the paranasal sinuses that complement each other and sometimes even overlap. The preoperative diagnosis and definition of underlying diseases are decisive and should be as precise as possible, as the extent and surgical details mainly depend on them: a sole creation of free drainage pathways, an additional creation of anatomical access for subsequent topical treatment or a complete (radical) removal of a pathological process.

A clinical evaluation of patients with known mutations (plasminogen and factor XII) with a focus on prophylactic treatment.

BACKGROUND: Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease. The symptoms can resemble other forms of hereditary angioedema (HAE), but the specific laboratory values are inconspicuous. The knowledge about treatment strategies in HAE-nC1-INH remains insufficient; most of the drugs are only licensed and approved for other types of HAE. METHODS: An analysis of all patients with HAE-nC1-INH was carried out in a certified angioedema treatment center in southern Germany. Only patients with a confirmed HAE-nC1-INH mutation were included. The impact of disease was monitored with validated questionnaires. RESULTS: Eighteen patients were included: two families with a factor XII mutation and seven families with a plasminogen mutation. All individuals received icatibant for on-demand therapy-efficient treatment response was reported. Three patients were severely affected, and prophylaxis was initiated with lanadelumab. According to the questionnaires, the clinical course and symptoms improved significantly under this prophylactic regime. CONCLUSION: This is one of the first descriptions of the clinical outcomes as a response to prophylactic treatment with lanadelumab in HAE-nC1-INH patients with a known mutation. The therapeutic management of HAE-1 and HAE-2 should also be the basis of HAE-nC1-INH, including prophylaxis.

Regional outcome disparities in German head and neck cancer patients: Shorter survival in Eastern Germany.

INTRODUCTION: Demographics are important prognostic factors in malignant diseases. A nationwide analysis concerning the prognostic impact of demographics in head and neck cancer (HNC) patients (HNCP) has not been performed previously. METHODS: A retrospective analysis of data from the Center for Cancer Registry Data (ZfKD) and the Federal Statistical Office (Destatis) between 2002 and 2017 was performed. A total of 212'920 HNCP were included. Incidence, tumor stage, age development, sex distribution, age-, residence-, and diagnosis-time-specific survival were examined. RESULTS: Mean age of HNCP increased more rapidly than in the general population (slope coefficient: 0.29 vs. 0.20; p < 0.0001). Higher age and male sex were associated with a worse prognosis. Whereas overall survival (OS) increased from the early to the later observation period for HNCP <70 years, no OS improvement for HNCP >70 years was found. Furthermore, an OS disadvantage was observed for East Germany compared to West Germany (median 47 vs. 60 months; p < 0.0001). This disparity was associated with a disproportionately high ratio of men in East Germany (men/women: 4.4 vs. 3.1; p < 0.0001) and a lower mean age (61 vs. 63 years; p < 0.0001). In addition to stage, age and sex, residence in East Germany were confirmed as an independent factor for OS in a multivariate analysis. CONCLUSION: Finally, three decades after the German reunion, a survival disadvantage for patients in East Germany still exists. This discrepancy may be a result of socioeconomic disparities.

"It has changed my life": unconditional cash transfers and personalized infant feeding support- a feasibility intervention trial among women living with HIV in western Kenya.

BACKGROUND: The syndemic effects of poverty, food insecurity and living with HIV are recognized as global health priorities, including through the United Nations Sustainability Goals 1, 2 and 3. Today, women and girls account for 63% of all new HIV infections in eastern and southern Africa, including Kenya. Pregnant and postpartum women living with HIV in this setting face unique challenges including increased financial insecurity as women leave the work force to care for their newborn infants. This contributes to poverty, food scarcity and stress. METHODS: To address financial insecurity, improve infant feeding and reduce stress among mothers living with HIV in this setting, we developed a multilevel intervention, Supporting Healthy Mothers, consisting of 10 monthly unconditional cash transfers (10,000 KES, ~$75 USD/month) and personalized infant feeding support from pregnancy to 7 months postpartum. We conducted a non-randomized feasibility trial of this intervention among women engaged in HIV care in Kisumu, Kenya. From February 23, 2022 to March 23, 2022, we enrolled a total of 40 women who were 20-35 weeks pregnant-20 women to the intervention group at a public clinic, and 20 women to the control group at a similar clinic. Our aim was to assess feasibility, acceptability, and the potential impact of the intervention on food security, infant feeding and maternal mental health. RESULTS: Analyzing data from all 40 participants, we found a significant reduction in food insecurity scores from baseline for the intervention group when compared to the control group at 6 weeks and 6 months postpartum (p = 0.0008 and p < 0.0001, respectively). Qualitative exit interviews with intervention group participants confirmed women felt more financially secure and had newly acquired practical knowledge and skills related to infant feeding. Women found the two intervention components highly acceptable and described an overall positive impact on wellbeing. CONCLUSIONS: The Supporting Healthy Mothers intervention has potential to positively impact women across the perinatal period and beyond by increasing financial security and supporting women to overcome infant feeding challenges and should be assessed in larger trials. TRIAL REGISTRATION: Supporting Healthy Mothers was registered with ClinicalTrials.gov Protocol Registration and Results System, initially published on February 1, 2022. CLINICALTRIALS: gov ID: NCT05219552 Protocol ID: K23MH116807.