Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype.

Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function. Furthermore, we identified the activity of nitric oxide synthase 2 (NOS2, also known as iNOS) originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to a reduction in both microglia recruitment and tumor expansion, whereas depletion of microglial caspase-3 gene promoted tumor growth. Our results provide evidence that inhibition of the denitrosylation of S-nitrosylated procaspase-3 mediated by the redox protein Trx2 is a part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.

Evidence of human occupation in Mexico around the Last Glacial Maximum.

The initial colonization of the Americas remains a highly debated topic1, and the exact timing of the first arrivals is unknown. The earliest archaeological record of Mexico-which holds a key geographical position in the Americas-is poorly known and understudied. Historically, the region has remained on the periphery of research focused on the first American populations2. However, recent investigations provide reliable evidence of a human presence in the northwest region of Mexico3,4, the Chiapas Highlands5, Central Mexico6 and the Caribbean coast7-9 during the Late Pleistocene and Early Holocene epochs. Here we present results of recent excavations at Chiquihuite Cave-a high-altitude site in central-northern Mexico-that corroborate previous findings in the Americas10-17of cultural evidence that dates to the Last Glacial Maximum (26,500-19,000 years ago)18, and which push back dates for human dispersal to the region possibly as early as 33,000-31,000 years ago. The site yielded about 1,900 stone artefacts within a 3-m-deep stratified sequence, revealing a previously unknown lithic industry that underwent only minor changes over millennia. More than 50 radiocarbon and luminescence dates provide chronological control, and genetic, palaeoenvironmental and chemical data document the changing environments in which the occupants lived. Our results provide new evidence for the antiquity of humans in the Americas, illustrate the cultural diversity of the earliest dispersal groups (which predate those of the Clovis culture) and open new directions of research.

A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve.

BACKGROUND: The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes. METHODS: We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3, APCDD1, TMX3, CEP192, and BCL7A genes identified in these LVNC families by whole exome sequencing. Histological, developmental, and functional analyses of these mouse models were carried out by echocardiography and cardiac magnetic resonance imaging, together with gene expression profiling by RNA sequencing of both selected engineered mouse models and human induced pluripotent stem cell-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot. RESULTS: Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 missense allele leads to bicuspid aortic valve in a NOTCH-sensitized genetic background. These data suggest that development of LVNC is influenced by genetic modifiers present in affected families, whereas valve defects are highly sensitive to NOTCH haploinsufficiency. Whole exome sequencing of LVNC families revealed single-nucleotide gene variants of ASXL3, APCDD1, TMX3, CEP192, and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice developed bicuspid aortic valve and other valve-associated defects. Biochemical analysis suggested interactions between CEP192, BCL7A, and NOTCH. Gene expression profiling of mutant mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation. CONCLUSIONS: These findings reveal a shared genetic substrate underlying LVNC and bicuspid aortic valve in which MIB1-NOTCH variants plays a crucial role in heterozygous combination with cosegregating genetic modifiers.

Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Agreement between the perception of colon cleansing reported by patients and colon cleansing assessed by a validated colon cleansing scale.

AIMS: Patients' perception of their cleansing quality can guide strategies to improve cleansing during colonoscopy. There are no studies assessing the agreement between the quality of cleansing perceived by patients and cleansing quality assessed during colonoscopy using validated bowel preparation scales. The main aim of this study was to compare the cleansing quality reported by patients with the quality during colonoscopy using the Boston Bowel Preparation Scale (BBPS). PATIENTS AND METHODS: Consecutive patients referred to an outpatient colonoscopy were included. Four drawings representing different degrees of cleansing were designed. Patients chose the drawing that most resembled the last stool. The predictive ability of the patient's perception and agreement between the patient's perception and the BBPS were calculated. A BBPS score of <2 points in any segment was considered inadequate. RESULTS: Six hundred and thirty-three patients were included (age: 62.8±13.7 years, male: 53.4%). Overall, 107 patients (16.9%) had inadequate cleansing during colonoscopy, and in 12.2% of cases, the patient's perception was poor. The patient's perception compared to the quality of cleanliness during colonoscopy presented a positive and negative predictive value of 54.6% and 88.3%, respectively. The agreement between patient perception and the BBPS was significant (P<0.001), although fair (k=0.37). The results were similar in a validation cohort of 378 patients (k=0.41). CONCLUSIONS: The cleanliness perceived by the patient and the quality of cleanliness using a validated scale were correlated, although fair. However, this measure satisfactorily identified patients with adequate preparation. Cleansing rescue strategies may target patients who self-report improper cleaning. Registration number of the trial: NCT03830489.

Design and validation of an artificial intelligence system to detect the quality of colon cleansing before colonoscopy.

BACKGROUND AND AIMS: Patients' perception of their bowel cleansing quality may guide rescue cleansing strategies before colonoscopy. The main aim of this study was to train and validate a convolutional neural network (CNN) for classifying rectal effluent during bowel preparation intake as "adequate" or "inadequate" cleansing before colonoscopy. PATIENTS AND METHODS: Patients referred for outpatient colonoscopy were asked to provide images of their rectal effluent during the bowel preparation process. The images were categorized as adequate or inadequate cleansing based on a predefined 4-picture quality scale. A total of 1203 images were collected from 660 patients. The initial dataset (799 images), was split into a training set (80%) and a validation set (20%). The second dataset (404 images) was used to develop a second test of the CNN accuracy. Afterward, CNN prediction was prospectively compared with the Boston Bowel Preparation Scale (BBPS) in 200 additional patients who provided a picture of their last rectal effluent. RESULTS: On the initial dataset, a global accuracy of 97.49%, a sensitivity of 98.17% and a specificity of 96.66% were obtained using the CNN model. On the second dataset, an accuracy of 95%, a sensitivity of 99.60% and a specificity of 87.41% were obtained. The results from the CNN model were significantly associated with those from the BBPS (P<0.001), and 77.78% of the patients with poor bowel preparation were correctly classified. CONCLUSION: The designed CNN is capable of classifying "adequate cleansing" and "inadequate cleansing" images with high accuracy.

Usefulness of a novel computer-aided detection system for colorectal neoplasia: a randomized controlled trial.

BACKGROUND AND AIMS: Artificial intelligence-based computer-aid detection (CADe) devices have been recently tested in colonoscopies, increasing the adenoma detection rate (ADR), mainly in Asian populations. However, evidence for the benefit of these devices in the occidental population is still low. We tested a new CADe device, namely, ENDO-AID (OIP-1) (Olympus, Tokyo, Japan), in clinical practice. METHODS: This randomized controlled trial included 370 consecutive patients who were randomized 1:1 to CADe (n = 185) versus standard exploration (n = 185) from November 2021 to January 2022. The primary endpoint was the ADR. Advanced adenoma was defined as ≥10 mm, harboring high-grade dysplasia, or with a villous pattern. Otherwise, the adenoma was nonadvanced. ADR was assessed in both groups stratified by endoscopist ADR and colon cleansing. RESULTS: In the intention-to-treat analysis, the ADR was 55.1% (102/185) in the CADe group and 43.8% (81/185) in the control group (P = .029). Nonadvanced ADRs (54.8% vs 40.8%, P = .01) and flat ADRs (39.4 vs 24.8, P = .006), polyp detection rate (67.1% vs 51%; P = .004), and number of adenomas per colonoscopy were significantly higher in the CADe group than in the control group (median [25th-75th percentile], 1 [0-2] vs 0 [0-1.5], respectively; P = .014). No significant differences were found in serrated ADR. After stratification by endoscopist and bowel cleansing, no statistically significant differences in ADR were found. CONCLUSIONS: Colonoscopy assisted by ENDO-AID (OIP-1) increases ADR and number of adenomas per colonoscopy, suggesting it may aid in the detection of colorectal neoplastic lesions, especially because of its detection of diminutive and flat adenomas. (Clinical trial registration number: NCT04945044.).

Clustering of systemic lupus erythematosus mortality in southwestern Spain.

OBJECTIVE: To analyse time trends in systemic lupus erythematosus (SLE) mortality and explore possible provincial clustering of SLE mortality in Spain (2001-2020). METHODS: We conducted an ecological study using deaths registered in SLE at the Spanish National Institute of Statistics between 2001 and 2020. Jointpoint regression models have been used to evaluate temporal trends. To analyse the spatial pattern of SLE mortality in men and women in Spain, crude rates, age-standardised mortality rates (ASMRs), smooth relative risk (RR) and posterior probabilities (PP) for RR greater than one for the period 2001-2020 were calculated. The Global Moran I index was used to assess the existence of global spatial autocorrelation. Local indicators of spatial association (LISA) and Kulldorff's spatial scan statistic were used to identify clusters. RESULTS: Over the 20 years analyzed in this study, the SLE average ASMR for the period was 2.7 for women and 0.7 for men, with a sex ratio (female/male) of 3.8. In men, no province showed a RR>1. Conversely, in women, eight provinces showed values of RR> 1 with a PP greater than 0.8 (Seville, Cadiz, Huelva and Murcia in the south, Barcelona, Zaragoza, Huesca and Leon in the north). In men, neither of the two methods detected a clustering of provinces. However, in women, both methods identified a cluster of provinces located in the southwest of the country (Huelva, Cádiz, Seville and Malaga) as a cluster with significant excess mortality. In the second cluster (centred on the province of Huelva) obtained with the Kulldorff method, two more provinces were added (Badajoz and Cordoba, also located in the southwest). CONCLUSIONS: We detected a cluster of provinces with an excess risk of female SLE mortality in the southwest of Spain.

Hidden Markov Modeling with HMMTeacher.

Is it possible to learn and create a first Hidden Markov Model (HMM) without programming skills or understanding the algorithms in detail? In this concise tutorial, we present the HMM through the 2 general questions it was initially developed to answer and describe its elements. The HMM elements include variables, hidden and observed parameters, the vector of initial probabilities, and the transition and emission probability matrices. Then, we suggest a set of ordered steps, for modeling the variables and illustrate them with a simple exercise of modeling and predicting transmembrane segments in a protein sequence. Finally, we show how to interpret the results of the algorithms for this particular problem. To guide the process of information input and explicit solution of the basic HMM algorithms that answer the HMM questions posed, we developed an educational webserver called HMMTeacher. Additional solved HMM modeling exercises can be found in the user's manual and answers to frequently asked questions. HMMTeacher is available at https://hmmteacher.mobilomics.org, mirrored at https://hmmteacher1.mobilomics.org. A repository with the code of the tool and the webpage is available at https://gitlab.com/kmilo.f/hmmteacher.

Cranial and extracranial large-vessel giant cell arteritis share a genetic pattern of interferon-gamma pathway.

OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.

Cranial and extracranial giant cell arteritis do not exhibit differences in the IL6 -174 G/C gene polymorphism.

OBJECTIVES: Since interleukin-6 (IL-6) is a pivotal proinflammatory cytokine implicated in the pathogenesis of giant cell arteritis (GCA), we aimed to determine the potential association of the functional IL6 -174 G/C polymorphism with GCA as well as if the single base change variation at the promoter region in the human IL-6 gene may account for differences in the clinical spectrum of GCA between cranial and extracranial large vessel vasculitis (LVV)-GCA. METHODS: The IL6 -174 G/C polymorphism (rs1800795) was genotyped in 191 patients with biopsy-proven GCA who had typical cranial manifestations of the disease, 109 patients with extracranial LVV-GCA, without cranial ischaemic manifestations of GCA, and 877 ethnically matched unaffected controls. A comparative study was carried out between patients with cranial and extracranial LVV-GCA and controls. RESULTS: No significant differences in genotype and allele frequencies of IL6 -174 G/C polymorphism were found between the whole cohort of GCA patients and healthy controls. It was also the case when cranial and extracranial LVV-GCA were compared or when each of these subgroups was compared to controls. Moreover, no significant results in genotype and allele frequencies of IL6 -174 G/C polymorphism were disclosed when the whole cohort of GCA patients were stratified according to the presence of polymyalgia rheumatica, severe ischaemic manifestations, including permanent visual loss and peripheral arteriopathy, and HLA-DRB1*04:01 status. CONCLUSIONS: Our results show that the IL6 -174 G/C polymorphism does not influence the phenotypic expression of GCA.

Ultrafast fluorescence depolarisation in green fluorescence protein tandem dimers as hydrophobic environment sensitive probes.

Advances in ultra-fast photonics have enabled monitoring of biochemical interactions on a sub nano-second time scale. In addition, picosecond dynamics of intermolecular energy transfer in fluorescent proteins has been observed. Here, we present the development of a genetically encoded fluorescent sensor that can detect changes in hydrophobicity by monitoring ultrafast fluorescence depolarisation. Our sensor is composed of a pair of dimeric enhanced green fluorescent proteins (dEGFPs) linked by a flexible amino-acid linker. We show dimerisation is perturbed by the addition of glycerol which interferes with the hydrophobic interaction of the two proteins. Time-resolved fluorescence anisotropy revealed a systematic attenuation of ultrafast fluorescence depolarisation when the sensor was exposed to increasing glycerol concentrations. This suggests that as hydrophobicity increases, dEGFP pairing decreases within a tandem dimer. Un-pairing of the protein fluorophores dramatically alters the rate of energy transfer between the proteins, resulting in an increase in the limiting anisotropy of the sensor.

Continuous time recurrent neural networks: Overview and benchmarking at forecasting blood glucose in the intensive care unit.

OBJECTIVE: Blood glucose measurements in the intensive care unit (ICU) are typically made at irregular intervals. This presents a challenge in choice of forecasting model. This article gives an overview of continuous time autoregressive recurrent neural networks (CTRNNs) and evaluates how they compare to autoregressive gradient boosted trees (GBT) in forecasting blood glucose in the ICU. METHODS: Continuous time autoregressive recurrent neural networks (CTRNNs) are a deep learning model that account for irregular observations through incorporating continuous evolution of the hidden states between observations. This is achieved using a neural ordinary differential equation (ODE) or neural flow layer. In this manuscript, we give an overview of these models, including the varying architectures that have been proposed to account for issues such as ongoing medical interventions. Further, we demonstrate the application of these models to probabilistic forecasting of blood glucose in a critical care setting using electronic medical record and simulated data and compare with GBT and linear models. RESULTS: The experiments confirm that addition of a neural ODE or neural flow layer generally improves the performance of autoregressive recurrent neural networks in the irregular measurement setting. However, several CTRNN architecture are outperformed by a GBT model (Catboost), with only a long short-term memory (LSTM) and neural ODE based architecture (ODE-LSTM) achieving comparable performance on probabilistic forecasting metrics such as the continuous ranked probability score (ODE-LSTM: 0.118 ± 0.001; Catboost: 0.118 ± 0.001), ignorance score (0.152 ± 0.008; 0.149 ± 0.002) and interval score (175 ± 1; 176 ± 1). CONCLUSION: The application of deep learning methods for forecasting in situations with irregularly measured time series such as blood glucose shows promise. However, appropriate benchmarking by methods such as GBT approaches (plus feature transformation) are key in highlighting whether novel methodologies are truly state of the art in tabular data settings.

Antibacterial and Cytotoxic Study of Hybrid Films Based on Polypropylene and NiO or NiFe2O4 Nanoparticles.

This study presents an in vitro analysis of the bactericidal and cytotoxic properties of hybrid films containing nickel oxide (NiO) and nickel ferrite (NiFe2O4) nanoparticles embedded in polypropylene (PP). The solvent casting method was used to synthesize films of PP, PP@NiO, and PP@NiFe2O4, which were characterized by different spectroscopic and microscopic techniques. The X-ray diffraction (XRD) patterns confirmed that the small crystallite sizes of NiO and NiFe2O4 NPs were maintained even after they were incorporated into the PP matrix. From the Raman scattering spectroscopy data, it was evident that there was a significant interaction between the NPs and the PP matrix. Additionally, the Scanning Electron Microscopy (SEM) analysis revealed a homogeneous dispersion of NiO and NiFe2O4 NPs throughout the PP matrix. The incorporation of the NPs was observed to alter the surface roughness of the films; this behavior was studied by atomic force microscopy (AFM). The antibacterial properties of all films were evaluated against Pseudomonas aeruginosa (ATCC®: 43636™) and Staphylococcus aureus (ATCC®: 23235™), two opportunistic and nosocomial pathogens. The PP@NiO and PP@ NiFe2O4 films showed over 90% bacterial growth inhibition for both strains. Additionally, the effects of the films on human skin cells, such as epidermal keratinocytes and dermal fibroblasts, were evaluated for cytotoxicity. The PP, PP@NiO, and PP@NiFe2O4 films were nontoxic to human keratinocytes. Furthermore, compared to the PP film, improved biocompatibility of the PP@NiFe2O4 film with human fibroblasts was observed. The methodology utilized in this study allows for the production of hybrid films that can inhibit the growth of Gram-positive bacteria, such as S. aureus, and Gram-negative bacteria, such as P. aeruginosa. These films have potential as coating materials to prevent bacterial proliferation on surfaces.

Re-analysis of genomic data: An overview of the mechanisms and complexities of clinical adoption.

Re-analyzing genomic information from a patient suspected of having an underlying genetic condition can improve the diagnostic yield of sequencing tests, potentially providing significant benefits to the patient and to the health care system. Although a significant number of studies have shown the clinical potential of re-analysis, less work has been performed to characterize the mechanisms responsible for driving the increases in diagnostic yield. Complexities surrounding re-analysis have also emerged. The terminology itself represents a challenge because "re-analysis" can refer to a range of different concepts. Other challenges include the increased workload that re-analysis demands of curators, adequate reimbursement pathways for clinical and diagnostic services, and the development of systems to handle large volumes of data. Re-analysis also raises ethical implications for patients and families, most notably when re-classification of a variant alters diagnosis, treatment, and prognosis. This review highlights the possibilities and complexities associated with the re-analysis of existing clinical genomic data. We propose a terminology that builds on the foundation presented in a recent statement from the American College of Medical Genetics and Genomics and describes each re-analysis process. We identify mechanisms for increasing diagnostic yield and provide perspectives on the range of challenges that must be addressed by health care systems and individual patients.

Low-Temperature Photophysics of Single Nitrogen-Vacancy Centers in Diamond.

We investigate the magnetic field dependent photophysics of individual nitrogen-vacancy (NV) color centers in diamond under cryogenic conditions. At distinct magnetic fields, we observe significant reductions in the NV photoluminescence rate, which indicate a marked decrease in the optical readout efficiency of the NV's ground state spin. We assign these dips to excited state level anticrossings, which occur at magnetic fields that strongly depend on the effective, local strain environment of the NV center. Our results offer new insights into the structure of the NVs' excited states and a new tool for their effective characterization. Using this tool, we observe strong indications for strain-dependent variations of the NV's orbital g factor, obtain new insights into NV charge state dynamics, and draw important conclusions regarding the applicability of NV centers for low-temperature quantum sensing.

Vascular endothelial growth factor haplotypes are associated with severe ischaemic complications in giant cell arteritis regardless of the disease phenotype.

OBJECTIVES: To determine whether functional vascular endothelial growth factor (VEGF) polymorphisms influence the expression of the clinical phenotype of giant cell arteritis (GCA). We also evaluated whether VEGF polymorphism is associated with the development of severe ischaemic manifestations in patients with GCA regardless of the clinical phenotype, classic cranial GCA or predominantly extracranial GCA large vessel vasculitis (LVV). METHODS: VEGF rs833061 T/C, rs2010963 G/C and rs3025039 C/T polymorphisms were genotyped in 185 patients with biopsy-proven cranial GCA, 105 with extracranial LVV-GCA and 490 healthy controls. Allelic combinations (haplotypes) of VEGF were carried out. Comparisons were performed between patients with GCA and healthy controls as well as between patients with GCA stratified according to the clinical phenotype and the presence of severe ischaemic manifestations. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of VEGF were found between patients with GCA and healthy controls as well as between GCA patients with the classic cranial pattern and the extracranial LVV-GCA pattern of the disease. However, the VEGF CGC haplotype (OR= 1.63 [1.05-2.53]) and the CGT haplotype (OR= 2.55 [1.10-5.91]) were significantly more frequent in GCA patients with severe ischaemic complications compared to those patients without these complications. CONCLUSIONS: VEGF haplotypes seem to play a role in the development of severe ischaemic manifestations in GCA patients, regardless of the clinical phenotype of expression of the disease.

Mortality prediction by serum melatonin levels of patients with spontaneous intracerebral hemorrhage.

OBJECTIVE: In one study, higher serum melatonin levels have been reported at diagnosis of spontaneous intracerebral hemorrhage (ICH) in non-surviving than in surviving patients. Now, we carried out this study with the aims to explore whether blood melatonin concentrations in the first 7 days of ICH are different in survivor and non-survivor patients and whether are useful in the prediction of mortality. METHODS: Six Spanish hospitals participated in this observational study of patients with severe supratentorial ICH (defining severe as Glasgow Coma Scale < 9). We determined serum melatonin levels during the first, fourth, and eighth day of severe ICH. RESULTS: Surviving (n = 64) compared to non-surviving (n = 53) patients showed lower serum melatonin levels during the first (p < 0.001), fourth (p < 0.001), and eighth day (p < 0.001) of severe ICH. We found in multiple logistic regression analysis an association between serum melatonin levels and 30-day mortality (odds ratio = 8.932; 95% CI = 2.442-32.665; p = 0.001) controlling for midline shift, ICH score, early evacuation of ICH, and glycemia. We found an AUC (95% CI) for the mortality prediction of 0.90 (0.83-0.95; p < 0.001), 0.94 (0.87-0.98; p < 0.001), and 0.90 (0.81-0.96; p < 0.001) by serum melatonin concentrations during the first, fourth, and eighth day. CONCLUSIONS: In our current study, it appears that novel findings of serum melatonin levels recollected at any moment during the first 7 days of a severe ICH were higher in non-survivor than in survivor patients and could help in mortality prediction.

Co-Development of a Web Application (COVID-19 Social Site) for Long-Term Care Workers ("Something for Us"): User-Centered Design and Participatory Research Study.

BACKGROUND: Improving confidence in and uptake of COVID-19 vaccines and boosters among long-term care workers (LTCWs) is a crucial public health goal, given their role in the care of elderly people and people at risk. While difficult to reach with workplace communication interventions, most LTCWs regularly use social media and smartphones. Various social media interventions have improved attitudes and uptake for other vaccines and hold promise for the LTCW population. OBJECTIVE: We aimed to develop a curated social web application (interactive website) to increase COVID-19 vaccine confidence (a 3-arm randomized trial is underway). METHODS: Following user-centric design and participatory research approaches, we undertook the following 3 steps: (1) content identification, (2) platform development, and (3) community building. A LTCW and stakeholder advisory group provided iterative input. For content identification (step 1), we identified topics of concern about COVID-19 vaccines via desktop research (published literature, public opinion polls, and social media monitoring), refined by interviewing and polling LTCWs. We also conducted a national online panel survey. We curated and fact-checked posts from popular social media platforms that addressed the identified concerns. During platform development (step 2), we solicited preferences for design and functionality via interviews and user experience testing with LTCWs. We also identified best practices for online community building (step 3). RESULTS: In the interviews (n=9), we identified 3 themes: (1) LTCWs are proud of their work but feel undervalued; (2) LTCWs have varying levels of trust in COVID-19-related information; and (3) LTCWs would welcome a curated COVID-19 resource that is easy to understand and use-"something for us". Through desktop research, LTCW interviews, and our national online panel survey (n=592) we found that participants are interested in information about COVID-19 in general, vaccine benefits, vaccine risks, and vaccine development. Content identification resulted in 434 posts addressing these topic areas, with 209 uploaded to the final web application. Our LTCW poll (n=8) revealed preferences for personal stories and video content. The platform we developed is an accessible WordPress-based social media web application, refined through formal (n=3) and informal user experience testing. Users can sort posts by topic or subtopic and react to or comment on posts. To build an online community, we recruited 3 LTCW "community ambassadors" and instructed them to encourage discussion, acknowledge concerns, and offer factual information on COVID-19 vaccines. We also set "community standards" for the web application. CONCLUSIONS: An iterative, user-centric, participatory approach led to the launch of an accessible social media web application with curated content for COVID-19 vaccines targeting LTCWs in the United States. Through our trial, we will determine if this approach successfully improves vaccine confidence. If so, a similar social media resource could be used to develop curated social media interventions in other populations and with other public health goals.

The Superficial Inferior Epigastric Artery Interpolated Flap for Closure of Large Anterolateral Thigh Flap Donor Site Defects.

ABSTRACT: The Anterolateral Thigh (ALT) flap has a critical role in head, neck, and extremity reconstruction. Unfortunately, when the ALT flap is dimensionally large, it leaves an open donor site that may not respond optimally to primary or secondary closure. Traditionally, skin grafting has been used to close large ALT flap donor site defects. However, skin grafting offers less than desirable aesthetic and functional results. The purpose of this article is to present the first reported case of a 70-year-old woman with a large ATL donor site defect, not responsive to direct primary closure, which was successfully reconstructed using a superficial inferior epigastric artery (SIEA) interpolated flap. After 3 weeks, the SIEA interpolated flap was divided, with the patient reporting good outcomes after a 3-month follow-up. The authors suggest that a SIEA interpolated flap as a novel potential approach to optimally repair large ALT donor site defects.