LC3-Associated Endocytosis Facilitates ß-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease.

The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer's Disease. We have identified a novel non-canonical function of several autophagy proteins in the conjugation of LC3 to Rab5+, clathrin+ endosomes containing ß-amyloid in a process of LC3-associated endocytosis (LANDO). We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic ß-amyloid. This inflammation and ß-amyloid deposition were associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from ß-amyloid deposition.

LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance.

Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here, we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single-cell RNA sequencing (RNA-seq) analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti-tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP.

The clearance of dead cells by efferocytosis.

Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis. Efferocytosis is performed by macrophages and to a lesser extent by other 'professional' phagocytes (such as monocytes and dendritic cells) and 'non-professional' phagocytes, such as epithelial cells. Recent discoveries have shed light on this process and how it functions to maintain tissue homeostasis, tissue repair and organismal health. Here, we outline the mechanisms of efferocytosis, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and highlight the pathophysiological consequences that can arise when this process is abrogated.

Stable germline transgenesis using the Minos Tc1/mariner element in the sea urchin, Lytechinus pictus.

Stable transgenesis is a transformative tool in model organism biology. While the sea urchin is one of the oldest animal models in cell and developmental biology, studies in this animal have largely relied on transient manipulation of wild animals, without a strategy for stable transgenesis. Here we build on recent progress to develop a more genetically tractable sea urchin species, Lytechinus pictus and establish a robust transgene integration method. Three commonly used transposons (Minos, Tol2, piggyBac) were tested for non-autonomous transposition, using plasmids containing a polyubiquitin promoter upstream of a H2B-mCerulean nuclear marker. Minos was the only transposable element that resulted in significant expression past metamorphosis. F0 animals were raised to sexual maturity and spawned to determine germline integration, transgene inheritance frequency, and to characterize expression patterns of the transgene in F1 progeny. The results demonstrated transgene transmission through the germline, the first example of a germline transgenic sea urchin, and indeed of any echinoderm. This milestone paves the way for the generation of diverse transgenic resources that will dramatically enhance the utility, reproducibility, and efficiency of sea urchin research.

First Report of Watermelon Crinkle Leaf-Associated Virus-2 (WCLaV-2) in Watermelon (Citrullus lanatus) in Georgia, USA.

Watermelon (Citrullus lanatus) is a key horticultural crop in Georgia with farmgate value of 142 million USD (2022 Farm Gate Value Report), yet faces challenges from whitefly-transmitted viruses, especially during periods of elevated whitefly populations in the fall. Foliar symptoms on watermelon plants including yellow mottling and chlorosis, wrinkling, bunching, and upward curling, were observed in experimental fields at UGA Tifton and commercial fields in Colquitt County in the fall of 2023. These were similar to those described for watermelon crinkle leaf-associated viruses (WCLaV-1 and WCLaV-2) from Florida (Hendrick et al, 2021) and Texas (Hernandez et al., 2021). The disease incidence reached 100% in both locations. WCLaV-1 was previously identified in Georgia (Adeleke et al., 2022a); however, WCLaV-2 remained undetected in further surveys (Adeleke et al., 2022b). Total nucleic acid was extracted from symptomatic leaf tissues with the MagMAXTM 96 Viral RNA isolation kit (ThermoFisher Scientific, USA), following the manufacturer's guidelines, with the omission of DNAse treatment. The presence of WCLaV-1 was identified through reverse transcription-polymerase chain reaction (RT-PCR) (Hernandez et al., 2021) in 17 out of 24 samples in Tift County, and 12 out of 15 samples from Colquitt County. Within the same set of samples, WCLaV-2 was identified in three samples from Tift County and four samples from Colquitt County by RT-PCR directed at the RdRp gene (Hernandez et al., 2021). WCLaV-1 was not detected in the three samples from Tift County that had WCLaV-2, while mixed infections of WCLaV-2 and WCLaV-1 were observed in the samples form Colquitt County. Two whitefly transmitted viruses, previously reported in Georgia were also identified as mixed infection in these samples (Table S1). The presence of WCLaV-2 was further confirmed by amplifying the movement protein (MP) gene of WCLaV-2 by RT-PCR assays (Hernandez et al., 2021). The amplicons, with expected sizes of 968bp for the RdRp gene and 562bp for the MP gene of WCLaV-2, located on RNA 1 and RNA 2 segments respectively, were directly sequenced from both directions (Genewiz, USA) from a sample collected in Tift County. The resulting data were analyzed via BLASTn search. The MP gene fragment (PP178543) shared 100% identity with isolates from Brazil (LC636074.1), Texas (MW559086.1), and Florida (MZ325858.1). RdRp gene (PP178542) shared >99.7% identity with isolates from Brazil (LC636073.1), Texas (MW559083.1) and Florida (MZ325855.1). WCLaV-1 and WCLaV-2, initially discovered in Asia (Xin et al., 2017), have been assigned to the genus Coguvirus, in the family Phenuiviridae (Walker et al., 2022). Subsequent reports from the USA (Hendrick et al., 2021; Hernandez et al., 2021), Australia (Mulholland et al., 2023), and Brazil (Maeda et al., 2022) indicate the global spread of these viruses. Watermelon is the primary host of WCLaV-2. Despite these findings, biological information, including vector relations, for both viruses and other members of the genus Coguvirus remains elusive. The impact of these viruses on watermelon production and yield in the identified regions remains largely unknown, underscoring the need for further investigations.

Attitudes and experiences related to the deaths of COVID-19 patients among nursing staff: A qualitative evidence synthesis.

AIM: To identify and synthesize the experiences and attitudes of nursing staff regarding the deaths of COVID-19 patients. REVIEW METHODS: A qualitative evidence synthesis was carried out, using Noblit and Hare's meta-ethnographic approach. The review protocol was listed in PROSPERO (CRD42022330928). Studies published from January 2020 to January 2022 that met the criteria were searched in PubMed, Web of Science, Scopus, CINAHL, CUIDEN and PsycInfo. A total of 12 articles were included. RESULTS: Thirty-three metaphors emerged, which were grouped into three main themes: Determining factors of care, Feelings about death and Strategies for coping with death. Nurses reported the high emotional toll, the absence of family and the lack of staff, protocol and training as determining factors. Furthermore, staff had doubts about the quality of care that COVID-19 patients received. As coping strategies, nurses developed avoidance behaviours towards COVID-19 patients, selective memories, resilience, and/or leaving the profession. CONCLUSIONS: The difficulty in providing adequate nursing care and the high number of deaths has increased anxiety and stress among nurses. These factors, alongside their lived experiences of seeing patients suffering, many dying alone without family members, have had psychological repercussions on nursing staff. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The results demonstrate a high emotional toll and doubts surrounding their caregiving role caused by the lack of professional training needed to face a pandemic. This research shows what has been learned for future pandemics and highlights basic components that could provide a foundation for coping interventions for healthcare professionals. IMPACT: WHAT PROBLEM DID THE STUDY ADDRESS?: The challenges posed by COVID-19 patient deaths for nursing staff around the world and also by the pandemic circumstances in which those deaths occurred. WHAT WERE THE MAIN FINDINGS?: The high number of deceased patients who were isolated from family members, communication with family members and doubts surrounding care given during the pandemic have created feelings of fear, stress and anxiety, as well as obsessive thoughts that have changed nursing staff's perception of death due to COVID-19. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: Results will be useful for preparing for future pandemics, and for policymakers and health staff in supporting healthcare professionals by creating programmes to help them cope with the emotional toll they have felt after dealing with death in such unprecedented circumstances. REPORTING METHOD: The authors have adhered to the PRISMA guidelines and the eMERGe Reporting Guidance. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Impact of mesalazine on the response to COVID-19 vaccination in patients with inflammatory bowel disease: Results of a prospective multicentre study of GETECCU (VACOVEII study). / Impacto de la mesalazina en la respuesta a la vacunación contra la COVID-19 en pacientes con enfermedad inflamatoria intestinal. Resultados de un estudio prospectivo multicéntrico de GETECCU (VACOVEII).

OBJECTIVE: The recommendations of the Spanish Ministry of Health on vaccination in risk groups include mesalazine among the treatments with a possible negative effect on its effectiveness. However, this is not the recommendation of most experts. Our objective was to evaluate the effect of mesalazine on the humoral response to the SARS-CoV-2 vaccine in patients with inflammatory bowel disease (IBD). METHODS: VACOVEII is a Spanish, prospective, multicenter study promoted by GETECCU, which evaluates the effectiveness of the SARS-CoV-2 vaccine in patients with IBD. This study includes IBD patients who have recieved the full vaccination schedule and without previous COVID-19 infection. Seroconversion was set at 260BAU/mL (centralized determination) and was assessed 6 months after full vaccination. In this subanalysis of the study, we compare the effectiveness of the vaccine between patients treated with mesalazine and patients without treatment. RESULTS: A total of 124 patients without immunosuppressive therapy were included, of which 32 did not receive any treatment and 92 received only mesalazine. Six months after full vaccination, no significant differences are observed in the mean concentrations of IgG anti-S between both groups. In the multivariate analysis, antibody titers were independently associated with the use of mRNA vaccines and with SARS-CoV-2 infection. CONCLUSION: Mesalazine does not have a negative effect on the response to SARS-CoV-2 vaccines in IBD patients.

The prognostic value of the NECPAL instrument, Palliative Prognostic Index, and PROFUND index in elderly residents of nursing homes with advanced chronic condition.

BACKGROUND: It is essential to assess the need for palliative care and the life prognosis of elderly nursing home residents with an advanced chronic condition, and the NECPAL ICO-CCOMS©4.0 prognostic instrument may be adequate for both purposes. The objective of this study was to examine the predictive capacity of NECPAL, the Palliative Prognosis Index, and the PROFUND index in elderly residents with advanced chronic condition with and without dementia, comparing their results at different time points. METHODS: This prospective observational study was undertaken in eight nursing homes, following the survival of 146 residents with advanced chronic condition (46.6% with dementia) at 3, 6, 12, and 24 months. The capacity of the three instruments to predict mortality was evaluated by calculating the area under the receiver operating characteristic curve (AUC), with 95% confidence interval, for the global population and separately for residents with and without dementia. RESULTS: The mean age of residents was 84.63 years (± 8.989 yrs); 67.8% were female. The highest predictive capacity was found for PROFUND at 3 months (95%CI: 0.526-0.756; p = 0.016), for PROFUND and NECPAL at 12 months (non-significant; AUC > 0.5), and NECPAL at 24 months (close-to-significant (AUC = 0.624; 95% CI: 0.499-0.750; p = 0.053). The highest capacity at 12 months was obtained using PROFUND in residents with dementia (AUC = 0.698; 95%CI: 0.566-0.829; p = 0.003) and NECPAL in residents without dementia (non-significant; AUC = 0.649; 95%CI: 0.432-0.867; p = 0.178). Significant differences in AUC values were observed between PROFUND at 12 (p = 0.017) and 24 (p = 0.028) months. CONCLUSIONS: PROFUND offers the most accurate prediction of survival in elderly care home residents with advanced chronic condition overall and in those with dementia, especially over the short term, whereas NECPAL ICO-CCOMS©4.0 appears to be the most useful to predict the long-term survival of residents without dementia. These results support early evaluation of the need for palliative care in elderly care home residents with advanced chronic condition.

A booster dose of SARS-COV-2 vaccine improves suboptimal seroconversion rates in patients with inflammatory bowel disease. Results of a prospective multicenter study of GETECCU (VACOVEII study).

BACKGROUND: The response to SARS-CoV-2 vaccination decreases in inflammatory bowel disease (IBD) patients, specially under anti-TNF treatment. However, data on medium-term effectiveness are limited, specially using new recommended seroconversion rate (>260BAU/mL). Our aim was to evaluate the 6-month>260 BAU-seroconversion rate after full vaccination and after booster-dose. METHODS: VACOVEII is a Spanish multicenter, prospective study promoted by GETECCU. IBD patients full vaccinated against SARS-CoV-2 and without previous COVID-19 infection, treated or not with immunosuppressants, were included. The booster dose was administered 6 months after the full vaccination. Seroconversion was set at 260BAU/mL, according to most recent recommendations and was assessed 6 months after the full vaccination and 6 months after booster-dose. RESULTS: Between October 2021 and March 2022, 313 patients were included (124 no treatment or mesalazine; 55 immunomodulators; 87 anti-TNF; 19 anti-integrin; and 28 ustekinumab). Most patients received mRNA-vaccines (86%). Six months after full vaccination, overall seroconversion rate was 44.1%, being significantly lower among patients on anti-TNF (19.5%, p<0.001) and ustekinumab (35.7%, p=0.031). The seroconversion rate after booster was 92%. Again, anti-TNF patients had a significantly lower seroconversion rate (67%, p<0.001). mRNA-vaccine improved seroconversion rate (OR 11.720 [95% CI 2.26-60.512]). CONCLUSION: The full vaccination regimen achieves suboptimal response in IBD patients, specially among those anti-TNF or ustekinumab. The booster dose improves seroconversion rate in all patients, although it remains limited in those treated with anti-TNF. These results reinforce the need to prioritize future booster doses in patients on immunosuppressants therapy, specially under anti-TNF, and using mRNA-vaccines.

Cultural adaptation and validation of the Quality of Dying in Long-term Care (QoD-LTC and QoD-LTC-C) scales by caregivers in nursing homes.

BACKGROUND: There is a lack of tools that can evaluate quality of dying in nursing homes from the perspective of deceased patients' caregivers. The aim of this study was to adapt and validate the caregivers' versions of the Quality of Dying in Long-Term Care (QoD-LTC) and Quality of Dying in Long-Term Care Complete (QoD-LTC-C) scales in the Spanish context. METHODS: This was a cultural adaptation and validation study. The scales were translated from English to Spanish and vice versa, and 13 experts in end-of-life care participated in a two-round Delphi panel. Caregivers of 69 deceased residents from seven nursing homes in southern Spain completed both scales. Reliability, feasibility, and concurrent validity with global quality of dying perception and symptom burden (Edmonton Symptom Assessment Scale), were evaluated. RESULTS: Spanish caregivers' version of the QoD-LTC scale showed good internal consistency for the total scale (α = 0.74) and each of its three factors, and good inter-rater reliability (ICC = 0.50) and test-retest reliability (ICC = 0.81). The Spanish QoD-LTC-C scale for caregivers showed good internal consistency for the total scale (α = 0.81) and for its component factors, and good test-retest reliability (ICC = 0.89) and inter-rater reliability (ICC = 0.66). Both scales correlated with family caregivers' global perception of deceased residents' quality of dying (r = 0.39; r = 0.32), but not with the ESAS score. CONCLUSIONS: Both scales presented an adequate factorial structure, internal consistency, and reliability to assess caregivers' perception of the quality of dying in Spanish nursing homes.

Inadequate human resources, equipment and training: A qualitative assessment of the objectives of the NUHELP end-of-life care programme in the context of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic had a particularly severe impact on nursing homes, exposing numerous pre-existing deficiencies in end-of-life care. AIM: To describe how the COVID-19 pandemic affected nursing home and primary care professionals' attempts to achieve the objectives of a pre-existing end-of-life programme and to explore their personal experiences of end-of-life care in these facilities. DESIGN: A qualitative descriptive study using thematic analysis. SETTING/PARTICIPANTS: Twenty semi-structured interviews were conducted from March to November 2020 with professionals from nursing homes and primary care facilities who participated in the development of the NUHELP programme. RESULTS: Six main themes were identified: (1) Comprehensive assessments of residents at the homes were not conducted due to excessive workload and high staff turnover. (2) New technologies and changes to professional roles were used to meet relatives' needs for information. Residents only received information when they requested it. (3) Advance care planning was not carried out and was limited to potential hospital transfer. (4) Arrangements were made to allow relatives to spend time with residents during their final moments, but complicated grief among relatives and professionals is anticipated. (5) Management of complexity varied depending on the degree of coordination with primary care facilities. (6) Nursing home professionals felt abandoned, with a lack of human resources, equipment and training. CONCLUSIONS: The pandemic cast light on existing shortcomings in nursing homes in terms of comprehensive assessments, communication, decision making, grief management and palliative care complexity. Nursing homes need more human, material and training resources, as well as improved coordination with the public healthcare system.

NUrsing Homes End of Life care Program (NUHELP): developing a complex intervention.

BACKGROUND: Nursing homes are likely to become increasingly important as end-of-life care facilities. Previous studies indicate that individuals residing in these facilities have a high prevalence of end-of-life symptoms and a significant need for palliative care. The aim of this study was to develop an end-of-life care program for nursing homes in Spain based on previous models yet adapted to the specific context and the needs of staff in nursing homes in the country. METHODS: A descriptive study of a complex intervention procedure was developed. The study consisted of three phases. The first phase was a prospective study assessing self-efficacy in palliative care (using the SEPC scale) and attitudes towards end-of-life care (using the FATCOD-B scale) among nursing home staff before and after the completion of a basic palliative care training program. In the second phase, objectives were selected using the Delphi consensus technique, where nursing home and primary care professionals assessed the relevance, feasibility, and level of attainment of 42 quality standards. In phase 3, interventions were selected for these objectives through two focus group sessions involving nursing home, primary care, and palliative care professionals. RESULTS: As a result of the training, an improvement in self-efficacy and attitudes towards end-of-life care was observed. In phase 2, 14 standards were selected and grouped into 5 objectives: to conduct a comprehensive assessment and develop a personalized care plan adapted to the palliative needs detected; to provide information in a clear and accessible way; to request and record advance care directives; to provide early care with respect to loss and grief; to refer patients to a specialized palliative care unit if appropriate, depending on the complexity of the palliative care required. Based on these objectives, the participants in the focus group sessions designed the 22 interventions that make up the program. CONCLUSIONS: The objectives and interventions of the NUHELP program constitute an end-of-life care program which can be implemented in nursing homes to improve the quality of end-of-life care in these facilities by modifying their clinical practice, organization, and relationship with the health system as well as serving as an example of an effective health intervention program.

Frailty, Complexity, and Priorities in the Use of Advanced Palliative Care Resources in Nursing Homes.

Background and objectives: This study aimed to determine the frailty, prognosis, complexity, and palliative care complexity of nursing home residents with palliative care needs and define the characteristics of the cases eligible for receiving advanced palliative care according to the resources available at each nursing home. Materials and Methods: In this multi-centre, descriptive, and cross-sectional study, trained nurses from eight nursing homes in southern Spain selected 149 residents with palliative care needs. The following instruments were used: the Frail-VIG index, the case complexity index (CCI), the Diagnostic Instrument of Complexity in Palliative Care (IDC-Pal), the palliative prognosis index, the Barthel index (dependency), Pfeiffer's test (cognitive impairment), and the Charlson comorbidity index. A consensus was reached on the complexity criteria of the Diagnostic Instrument of Complexity in Palliative Care that could be addressed in the nursing home (no priority) and those that required a one-off (priority 2) or full (priority 1) intervention of advanced palliative care resources. Non-parametric tests were used to compare non-priority patients and patients with some kind of priority. Results: A high percentage of residents presented frailty (80.6%), clinical complexity (80.5%), and palliative care complexity (65.8%). A lower percentage of residents had a poor prognosis (10.1%) and an extremely poor prognosis (2%). Twelve priority 1 and 14 priority 2 elements were identified as not matching the palliative care complexity elements that had been previously identified. Of the studied cases, 20.1% had priority 1 status and 38.3% had priority 2 status. Residents with some kind of priority had greater levels of dependency (p < 0.001), cognitive impairment (p < 0.001), and poorer prognoses (p < 0.001). Priority 1 patients exhibited higher rates of refractory delirium (p = 0.003), skin ulcers (p = 0.041), and dyspnoea (p = 0.020). Conclusions: The results indicate that there are high levels of frailty, clinical complexity, and palliative care complexity in nursing homes. The resources available at each nursing home must be considered to determine when advanced palliative care resources are required.

D-dimer and high-sensitivity C-reactive protein levels to predict venous thromboembolism recurrence after discontinuation of anticoagulation for cancer-associated thrombosis.

BACKGROUND: Optimal duration of anticoagulation for cancer-associated thrombosis (CAT) remains unclear. This study assessed D-dimer (DD) and high-sensitivity C-reactive protein (hs-CRP) levels after the withdrawal of anticoagulation treatment to predict the risk of venous thromboembolism (VTE) recurrence among patients with CAT. METHODS: Prospective, multicentre study to evaluate CAT with ≥3 months of anticoagulation that was subsequently discontinued. Blood samples were taken when patients stopped the anticoagulation and 21 days later to determine the DD and hs-CRP levels. All patients were followed up for 6 months to detect VTE recurrence. RESULTS: Between 2013 and 2015, 325 patients were evaluated and 114 patients were ultimately enrolled in the study. The mean age was 62 ± 14 years and nearly 40% had metastasis. Ten patients developed VTE recurrence within 6 months (8.8%, 95% confidence interval [CI]: 4.3-15.5%). The DD and hs-CRP levels after 21 days were associated with VTE recurrence. The subdistribution hazard ratios were 9.82 for hs-CRP (95% CI: 19-52) and 5.81 for DD (95% CI: 1.1-31.7). CONCLUSIONS: This study identified that hs-CRP and DD were potential biomarkers of VTE recurrence after discontinuation of anticoagulation in CAT. A risk-adapted strategy could identify low-risk patients who may benefit from discontinuation of anticoagulation.

TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3.

Selective autophagy underlies many of the important physiological roles that autophagy plays in multicellular organisms, but the mechanisms involved in cargo selection are poorly understood. Here we describe a molecular mechanism that can target conventional endosomes for autophagic degradation. We show that the human transmembrane protein TMEM59 contains a minimal 19-amino-acid peptide in its intracellular domain that promotes LC3 labelling and lysosomal targeting of its own endosomal compartment. Interestingly, this peptide defines a novel protein motif that mediates interaction with the WD-repeat domain of ATG16L1, thus providing a mechanistic basis for the activity. The motif is represented with the same ATG16L1-binding ability in other molecules, suggesting a more general relevance. We propose that this motif may play an important role in targeting specific membranous compartments for autophagic degradation, and therefore it may facilitate the search for adaptor proteins that promote selective autophagy by engaging ATG16L1. Endogenous TMEM59 interacts with ATG16L1 and mediates autophagy in response to Staphylococcus aureus infection.

Autochthonous acute hepatitis E: an increasingly frequent diagnosis. Clinical-epidemiological analysis of our experience.

BACKGROUND: In Europe, acute hepatitis caused by the hepatitis E virus (HEV) traditionally was an infection found in people who had travelled to endemic zones, mainly Asia and Africa. However, a growing number of sporadic autochthonous cases are now being diagnosed in the Western world. OBJECTIVE: To analyze the cases of acute HEV hepatitis diagnosed in our setting, with the identification of the clinical-epidemiological characteristics. MATERIAL AND METHODS: We included the cases of acute HEV hepatitis diagnosed (positive anti-HEV IgM and/or HEV RNA present in serum) between January 2008 and December 2014. Different clinical, epidemiological and evolutive parameters were analyzed. RESULTS: A total of 23 patients were identified, all originating from Spain. Fourteen cases (60.87%) presented jaundice and marked cytolysis at the time of diagnosis (aspartate aminotransferase [AST] 1,106.91 U/l and alanine aminotransferase [ALT] 1,407.04 U/l). Twenty-two cases were regarded as autochthonous, and one patient had travelled to China three months before. The mean time to resolution was 11.2 weeks. Some autoimmune markers were positive in 43.5% of the patients. Two subjects were diagnosed with previous chronic liver disease and were classified as "acute-on-chronic liver failure" (ACLF), one died and the other underwent liver transplantation. CONCLUSION: Acute HEV hepatitis in our setting is an autochthonous condition that is probably underdiagnosed, manifesting with jaundice and cytolysis. Autoimmune marker positivity is an epiphenomenon, which in some cases complicates the diagnosis.

Differentiating Pressure Ulcer Risk Levels through Interpretable Classification Models Based on Readily Measurable Indicators.

Pressure ulcers carry a significant risk in clinical practice. This paper proposes a practical and interpretable approach to estimate the risk levels of pressure ulcers using decision tree models. In order to address the common problem of imbalanced learning in nursing classification datasets, various oversampling configurations are analyzed to improve the data quality prior to modeling. The decision trees built are based on three easily identifiable and clinically relevant pressure ulcer risk indicators: mobility, activity, and skin moisture. Additionally, this research introduces a novel tabular visualization method to enhance the usability of the decision trees in clinical practice. Thus, the primary aim of this approach is to provide nursing professionals with valuable insights for assessing the potential risk levels of pressure ulcers, which could support their decision-making and allow, for example, the application of suitable preventive measures tailored to each patient's requirements. The interpretability of the models proposed and their performance, evaluated through stratified cross-validation, make them a helpful tool for nursing care in estimating the pressure ulcer risk level.

Experiences in the use of multiple doses of convalescent plasma in critically ill patients with COVID-19: An early phase 1 descriptive study.

Background: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, transfusion of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) emerged as a potential therapeutic strategy to help patients severely afflicted by COVID-19. The efficacy of CCP has been controversial as it depends on many variables pertaining to the plasma donor and the patient with COVID-19, for example, time of convalescence or symptoms onset. This feasibility and descriptive study aimed to assess the safety of multiple doses of CCP in mechanically ventilated, intubated patients with respiratory failure due to COVID-19. Methods: A cohort of 30 patients all experiencing severe respiratory failure and undergoing invasive mechanical ventilation in an intensive care unit, received up to five doses of 300-600 mL of CCP on alternate days (0, 2, 4, 6, and 8) until extubation, futility, or death. Results: Nineteen patients received five doses, seven received four, and four received two or three doses. At 28-day follow-up mark, 57% of patients recovered and were sent home, and the long-term mortality rate was 27%. Ten severe adverse events reported in the study were unrelated to CCP transfusion. Independent of the number of transfused doses, most patients had detectable levels of total and neutralizing antibodies in plasma. Conclusion: This study suggests that transfusion of multiple doses of CCP is safe. This strategy may represent a viable option for future studies, given the potential benefit of CCP transfusions during the early stages of infection in unvaccinated populations and in settings where monoclonal antibodies or antivirals are contraindicated or unavailable.

Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion.

T cell exhaustion is linked to persistent antigen exposure and perturbed activation events, correlating with poor disease prognosis. Tumor-mediated T cell exhaustion is well documented; however, how the nutrient-deprived tumor niche affects T cell receptor (TCR) activation is largely unclear. We show that methionine metabolism licenses optimal TCR signaling by regulating the protein arginine methylome, and limiting methionine availability during early TCR signaling promotes subsequent T cell exhaustion. We discovered a novel arginine methylation of a Ca 2+ -activated potassium transporter, KCa3.1, prevention of which results in increased Ca 2+ -mediated NFAT1 activation, NFAT1 promoter occupancy, and T cell exhaustion. Furthermore, methionine supplementation reduces nuclear NFAT1 in tumor-infiltrating T cells and augments their anti-tumor activity. These findings demonstrate metabolic regulation of T cell exhaustion determined during TCR engagement.