Complement activation induces excessive T cell cytotoxicity in severe COVID-19.

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.

Examining the Interplay Between Preexposure Prophylaxis (PrEP) and Gender-Related Stigmas as Barriers for PrEP Uptake Among Transgender Women in Tijuana, Mexico: A Mixed-Methods Study.

HIV prevalence among transgender women (TW) in Tijuana, Mexico is estimated at 22%. Pre-exposure prophylaxis (PrEP) reduces the risk of HIV acquisition by > 90%, though uptake in Tijuana has been low due to limited availability. The interplay between PrEP and gender stigmas may also serve as a barrier to PrEP uptake among TW in Tijuana. Experiences of gender- and PrEP- stigmas were assessed quantitatively (Quan) among 110 HIV-negative TW and qualitatively (Qual) among 17 TW through semi-structured interviews guide by the Health Stigma and Discrimination Framework. Qual findings were triangulated with Quant data to identify factors that may support gender affirmation and reduce PrEP stigma in an explanatory sequential Quan → Qual fashion. Most participants were < 40 years of age (80%), while approximately half had at least a high school education (48.2%) and were accessing gender-affirming hormone therapy (56.4%). Mean expectations of gender stigma were greatest for endorsing negative future expectations from others (M = 17.69; possible range 0-36). PrEP stigma was prominent among those who associated negative stereotypes with PrEP users, such as poor judgment (M = 45.91; possible range 14-70) and high personal risk attributes (M = 28.61; possible range 12-60). While PrEP knowledge was low among the qualitative sample, participants identified gender-, PrEP-, and intersectional- stigmas as potential barriers to PrEP uptake. Participants suggested that resilience strategies used to combat gender stigma could also mitigate PrEP stigma. Enhancing resilience skills at the intersection of gender and PrEP stigma may reduce these barriers, facilitating greater PrEP uptake as it becomes more available in Mexico.

The increase in diaphragm thickness in preterm infants is related to birth weight: a pilot study.

Diaphragm ultrasound (DU) has been used in adult and pediatric critical patients in relation to prediction of extubation success or to detect diaphragm dysfunction, but there is a lack of evidence in neonates. Our aim is to study the evolution of diaphragm thickness in preterm infants, as well as related variables. This prospective monocentric observational study included preterm infants born before 32 weeks (PT32). We performed DU to measure right and left inspiratory and expiratory thickness (RIT, LIT, RET, and LET) and calculated the diaphragm-thickening fraction (DTF) in the first 24 h of life and then weekly until 36 weeks postmenstrual age, death, or discharge. Using multilevel mixed-effect regression, we evaluated the influence of time since birth on diaphragm measurements, as well as bronchopulmonary dysplasia (BPD), birth weight (BW), and days of invasive mechanical ventilation (IMV). We included 107 infants, and we performed 519 DUs. All diaphragm thickness increased with time since birth, but the only additional variable that influenced this growth was BW: beta coefficients RIT = 0.00006; RET = 0.00005; LIT = 0.00005; and LET = 0.00004, p < 0.001. Right DTF values remained stable since birth but left DTF increased with time only in infants with BPD.   Conclusion: In our population we found that the higher the BW, the higher diaphragm thicknesses at birth and follow-up. Contrary to the previously published findings in adult and pediatric settings, we were unable to describe a relationship between days of IMV and diaphragm thickness in PT32. The final diagnosis of BPD does not influence this increase either, but it does increase left DTF. What is Known: • Diaphragm thickness and diaphragm thickening fraction have been related to the time on invasive mechanical ventilation in adults and pediatric patients, as well as with extubation failure. • Very few evidence is yet available on the use of diaphragmatic ultrasound in preterm infants. What is New: • Birth weight is the only variable related to diaphragm thickness in preterm infants born before 32 weeks postmenstrual age. • Days of invasive mechanical ventilation do not influence diaphragm increase in thickness in preterm infants.

Immediate Breast Reconstruction with Prosthesis and Titanized Mesh Using a Dual-Plane Approach: Complications and Risk Factors Analysis.

INTRODUCTION: The immediate breast reconstruction after mastectomy has gained prominence in recent years and is considered one of the main procedures in oncoplastic surgery. In the case of reconstruction with prostheses, the use of a mesh to extend the pectoralis major muscle is often required to partially cover the implant. The main objective of this study was to determine the percentage of complications in immediate breast reconstructions with a titanized mesh using a dual-plane approach and establish risk factors for prosthesis complications and extrusion. MATERIALS AND METHODS: A retrospective study that included women who received postmastectomy reconstructions from January 2012 to December 2019 in a secondary hospital in Spain. RESULTS: A total of 57 immediate reconstructions were performed in 47 women. There were complications in 16 mastectomies (28.1%), of which seven (12.3%) were Clavien-Dindo ≤ IIIa and nine (15.7%) were IIIb. A total of three patients presented prosthetic extrusion, and the prosthesis was removed in five. The degree of contracture according to the Baker scale was I-II in 50 mastectomies (87.7%) and III-IV in seven (12.3%). CONCLUSION: The immediate breast reconstruction with a titanized mesh using a dual-plane approach is a technique with an acceptable percentage of complications. The need for a Wise pattern and the necrosis of the nipple-areola complex in the postoperative period are risk factors for implant loss. Patients undergoing radiotherapy and/or chemotherapy and with a previous surgery are more likely to present capsular contracture. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors.

The Stress Response of the Holothurian Central Nervous System: A Transcriptomic Analysis.

Injury to the central nervous system (CNS) results in permanent damage and lack of function in most vertebrate animals, due to their limited regenerative capacities. In contrast, echinoderms can fully regenerate their radial nerve cord (RNC) following transection, with little to no scarring. Investigators have associated the regenerative capacity of some organisms to the stress response and inflammation produced by the injury. Here, we explore the gene activation profile of the stressed holothurian CNS. To do this, we performed RNA sequencing on isolated RNC explants submitted to the stress of transection and enzyme dissection and compared them with explants kept in culture for 3 days following dissection. We describe stress-associated genes, including members of heat-shock families, ubiquitin-related pathways, transposons, and apoptosis that were differentially expressed. Surprisingly, the stress response does not induce apoptosis in this system. Other genes associated with stress in other animal models, such as hero proteins and those associated with the integrated stress response, were not found to be differentially expressed either. Our results provide a new viewpoint on the stress response in the nervous system of an organism with amazing regenerative capacities. This is the first step in deciphering the molecular processes that allow echinoderms to undergo fully functional CNS regeneration, and also provides a comparative view of the stress response in other organisms.

COVID-19 impacts on household solid waste generation in six Latin American countries: a participatory approach.

The COVID-19 pandemic has greatly impacted the Americas, the continent with the highest number of COVID-related deaths according to WHO statistics. In Latin America, strict confinement conditions at the beginning of the pandemic put recycling activity to a halt and augmented the consumption of plastic as a barrier to stop the spread of the virus. The lack of data to understand waste management dynamics complicates waste management strategy adjustments aimed at coping with COVID-19. As a novel contribution to the waste management data gap for Latin America, this study uses a virtual and participatory methodology that collects and generates information on household solid waste generation and composition. Data was collected between June and November 2021 in six countries in Latin America, with a total of 503 participants. Participants indicated that the pandemic motivated them to initiate or increase waste reduction (41%), waste separation (40%), and waste recovery (33%) activities. Forty-three percent of participants perceived an increase in total volume of their waste; however, the quantitative data showed a decrease in household waste generation in Peru (-31%), Honduras (-25%), and Venezuela (-82%). No changes in waste composition were observed. Despite the limited sample size, this data provides a much-needed approximation of household waste generation and composition in the pandemic situation during 2021.

Can inflammatory biomarkers help in the diagnosis and prognosis of gangrenous acute cholecystitis? A prospective study.

The diagnosis of gangrenous acute cholecystitis represents a diagnostic challenge for the physician and is rarely identified preoperatively. We report a longitudinal prospective study in 180 patients who underwent cholecystectomy for acute cholecystitis. A ROC curve was obtained to determine the preoperative cut-off for various biomarkers (neutrophil to lymphocyte ratio [NLR], C-reactive protein [CRP], platelet to lymphocyte ratio [PLR], lactate and procalcitonin) and their association with both preoperative and postoperative findings. The area under the curve (AUC) for NLR, CRP, PLR, lactate and procalcitonin was 0.75, 0.8, 0.65 and 0.6, respectively. NLR > 5 and CRP > 100 are still independent factors for gangrene (adjusted odds ratio [OR], 2 and 2.1, respectively).

Filaria specific antibody response profiling in plasma from anti-retroviral naïve Loa loa microfilaraemic HIV-1 infected people.

BACKGROUND: In West and Central Africa areas of endemic Loa loa infections overlap with regions of high prevalence of human immunodeficiency virus type 1 (HIV-1) infections. Because individuals in this region are exposed to filarial parasites from birth, most HIV-1 infected individuals invariably also have a history of filarial parasite infection. Since HIV-1 infection both depletes immune system and maintains it in perpetual inflammation, this can hamper Loa loa filarial parasite mediated immune modulation, leading to enhanced loaisis. METHODS: In this study we have assessed in plasma from asymptomatic anti-retroviral (ARV) naïve Loa loa microfilaraemic HIV-1 infected people the filarial antibody responses specific to a filariasis composite antigen consisting of Wbgp29-BmR1-BmM14-WbSXP. The antibody responses specific to the filariasis composite antigen was determined by enzyme linked immunosorbent assay (ELISA) in plasma from ARV naïve Loa loa microfilaraemic HIV-1 infected participants. In addition the filarial antigen specific IgG antibody subclass profiles were also determined for both HIV-1 positive and negative people. RESULTS: Both Loa loa microfilaraemic HIV-1 positive and negative individuals showed significantly higher plasma levels of IgG1 (P < 0.0001), IgG2 (P < 0.0001) and IgM (P < 0.0001) relative to amicrofilaraemic participants. A significant increase in IgE (P < 0.0001) was observed exclusively in Loa loa microfilaraemic HIV-1 infected people. In contrast there was a significant reduction in the level of IgG4 (p < 0.0001) and IgG3 (P < 0.0001) in Loa loa microfilaraemic HIV-1 infected individuals. CONCLUSIONS: Loa loa microfilaraemia in ARV naïve HIV-1 infected people through differential reduction of plasma levels of filarial antigen specific IgG3, IgG4 and a significant increase in plasma levels of filarial antigen specific IgE could diminish Loa loa mediated immune-regulation. This in effect can result to increase loaisis mediated immunopathology in antiretroviral naive HIV-1 infected people.

In vitro evaluation of a novel system for monitoring surgical hemoglobin loss.

BACKGROUND: Accurate measurement of intraoperative blood loss is an important clinical variable in managing fluid resuscitation and avoiding unnecessary transfusion of blood products. In this study, we measured surgical blood loss using a tablet computer programmed with a unique algorithm modeled after facial recognition technology. The aim of the study was to assess the accuracy and performance of the system on surgical laparotomy sponges in vitro. METHODS: Whole blood samples of premeasured hemoglobin (Hb) and volume were reconstituted from units of human packed red blood cells and plasma and distributed across surgical laparotomy sponges. Normal saline was added to simulate the presence of varying levels of hemodilution and/or irrigation use. Soaked sponges from 4 different manufacturers were scanned using the Triton System with Feature Extraction Technology (Gauss Surgical, Inc., Palo Alto, CA) under 3 different ambient light conditions in an operating room. Accuracy of Hb loss measurement was evaluated relative to the premeasured values using linear regression and Bland-Altman analysis. Correlations between studied variables and measurement bias were analyzed using nonparametric tests. RESULTS: The overall mean percent error for measure of Hb loss for the Triton System was 12.3% (95% confidence interval [CI], 8.2%-16.4%). A strong positive linear correlation between the premeasured and actual Hb masses was noted across the full range of intraoperative lighting conditions, including (A) high (r = 0.95 [95% CI, 0.93-0.96]), (B) medium (r = 0.94 [95% CI, 0.93-0.96]), and (C) low (r = 0.90 [95% CI, 0.87-0.93]) mean ambient light intensity. Bland-Altman analysis revealed a bias of 0.01 g [95% CI, -0.03 to 0.06 g] of Hb per sponge between the 2 measures. The corresponding lower and upper limits of agreement were -1.16 g (95% CI, -1.21 to -1.12 g) per sponge and 1.19 g (95% CI, 1.15-1.24 g) per sponge, respectively. Measurement bias of estimated blood loss and Hb mass using the new system were not associated with the volume of saline used to reconstitute the samples (P = 0.506 and P = 0.469, respectively), suggesting that the system is robust under a wide range of sponge saturation conditions. CONCLUSIONS: Mobile blood loss monitoring using the Triton system is accurate in assessing Hb mass on surgical sponges across a range of ambient light conditions, sponge saturation, saline contamination, and initial blood Hb. Utilization of this tool could significantly improve the accuracy of blood loss estimates.

The Gender Minority Stress and Resilience Measure: Psychometric Validity for Use in Spanish.

Purpose: Stigma is a fundamental driver of HIV disparities among transgender women (TW). The gender minority stress and resilience (GMSR) measure has not been validated in Spanish-speaking, resource-limited settings. We examined the psychometric properties of a translated and abbreviated GMSR among TW in Tijuana, Mexico. Methods: From 2020 to 2021, 152 participants were recruited through social media and venue-based sampling. We collected information on the abbreviated GMSR, psychosocial factors (e.g., depressive symptoms), and sociodemographics. The abbreviated GMSR assessed 7 factors (Discrimination, Rejection, Internalized Transphobia, Negative Expectations, Nondisclosure, Pride, and Community Connectedness). Confirmatory factor analysis, Cronbach's alphas, and McDonald's omegas assessed structural validity. Pearson's partial correlations assessed criterion, convergent, and discriminant validities. Results: The 7-factor structure solution had acceptable fit (root mean square error of approximation [95% confidence interval]=0.05 [0.05-0.06]; comparative fit index/Tucker-Lewis index=0.92/0.91); and internal reliability (α=0.62-0.89; ω=0.62-0.89). Depressive (r=0.22-0.43; p<0.001-0.007), post-traumatic stress disorder (PTSD; r=0.20-0.34; p<0.001-0.017) symptoms, and perceived stress (r=0.19-0.41; p≤0.001-0.030) were all positively associated with all stress factors (e.g., Discrimination, Rejection, Internalized Transphobia, Negative Expectations, and Nondisclosure). The resilience factor Pride was associated with fewer PTSD symptoms (r=-0.18; p=0.027), lower perceived life stress (r=-0.21; p=0.012), and greater general resilience (r=0.26; p=0.002). The Community Connectedness resilience factor was associated with fewer depressive symptoms (r=-0.22; p=0.007). Constructs were conceptually distinct with factor correlations below 0.60. Conclusion: Findings suggest that the Spanish-translated, abbreviated GMSR is a reliable and valid measure. These data expand the usability of the GMSR to TW in a Latin American, Spanish-speaking context.

The acceptability and feasibility of an intercultural birth center in the highlands of Chiapas, Mexico.

BACKGROUND: An intercultural birthing house was established in the Highlands of Chiapas, Mexico, as an intervention to reduce maternal mortality among indigenous women. This birth center, known locally as the Casa Materna, is a place where women can come to give birth with their traditional birth attendant. However, three months after opening, no woman had used the birthing house. METHODS: This study reports on the knowledge, attitudes and practices related to childbirth and use of the Casa Materna from the perspective of the health workers, traditional birth attendants and the program's target population. Structured interviews, in-depth interviews and focus group discussions were conducted with participants from each of these groups. Data was searched for emerging themes and coded. RESULTS AND CONCLUSIONS: Findings show that the potential success of this program is jeopardized by lack of transport and a strong cultural preference for home births. The paper highlights the importance of community participation in planning and implementing such an intervention and of establishing trust and mutual respect among key actors. Recommendations are provided for moving forward the maternal health agenda of indigenous women in Chiapas.

[Laparoscopic treatment of acute gastric volvulus]. / Tratamiento del vólvulo gástrico agudo mediante abordaje laparoscópico.

INTRODUCTION: Gastric volvulus is an uncommon clinical condition and is associated with type ii-iii hiatal hernias. Its acute presentation constitutes a surgical emergency. Despite its low frequency, results of laparoscopic treatment have already been published. MATERIAL AND METHODS: A retrospective study was performed on all cases diagnosed with gastric volvulus undergoing laparoscopic surgery between 1998 and 2010. The surgical technique, the post-operative outcome, and the clinical follow-up are described. RESULTS: A total of 10 cases were identified, one was a primary gastric volvulus, and the remainder were secondary. A laparoscopic anterior gastropexy as the sole procedure was performed on 7 patients. A Nissen fundoplication with mesh reinforcement of the crural closure was performed on the 3 remaining cases. Postoperative outcome was uneventful in 9 patients, with an early start of the diet, and hospital discharge between 48-72 h. After a mean follow-up period of 18 months, radiological hernia recurrence occurred in one case but recurrence of the volvulus was not observed. CONCLUSION: Laparoscopic anterior gastropexy is, in our experience, an effective and safe procedure with a low morbidity, for the treatment of acute gastric volvulus in patients with high surgical risk.

[Accessible science outreach] / Etiología del maltrato a residentes de medicina desde la teoría de la violencia simbólica.

The organization in hospital medicine services is characterized by its hierarchy, where the difference in knowledge and status between medical directors, heads of service, specialist doctors and residents implicitly entail a power dynamic that generates abuse. According to Bourdieu's symbolic theory, the framework that underlies abuse is formed by symbolic violence that materializes in complex relationships in which each person knows their hierarchical position and does not question it. But this symbolic violence is experienced unconsciously, where abuse is perceived as an attitude that is part of an established order where the abuser and the abused act without questioning the abuse and perpetuating the historically inherited model. To eradicate abuse of residents, it is necessary to become aware of the symbolic foundation of abuse that legitimizes and perpetuates it to unmask the relationship between the abuser and the abused, proposing a new relational framework based on respect and dialogue.

La organización en los servicios de medicina hospitalaria se caracteriza por su jerarquización, donde la diferencia de conocimientos y de estatus entre directores médicos, jefes de servicio, médicos especialistas y residentes conlleva implícitamente una dinámica de poder generadora de maltrato. Según la teoría simbólica de Bourdieu el entramado que subyace al maltrato está formado por la violencia simbólica que se materializa en unas relaciones complejas en las que cada uno conoce su posición jerárquica y no la cuestiona. Pero está violencia simbólica es experimentada de forma inconsciente, donde el maltrato se percibe como una actitud que forma parte de un orden establecido donde el maltratador y el maltratado actúan sin cuestionar el maltrato y perpetuando el modelo heredado históricamente. Para erradicar el maltrato a los residentes es preciso tomar conciencia de la fundamentación simbólica del maltrato que lo legitima y perpetua para desenmascarar la relación entre el maltratador y el maltratado, proponiendo un nuevo marco relacional basado en el respeto y el diálogo.

A three-dimensional Oral health-related quality of life framework for temporomandibular joint disorders: A structural analysis of the Oral Health Impact Profile-14.

OBJECTIVES: the objective is to analyze the structure and relationship between the components of the Oral health-related quality of life using the Oral Health Impact Profile-14 (OHIP-14) for patients with temporomandibular joint disorders (TMJD). METHODS: two studies were examinated by means of factor analysis, multidimensional scaling and their spatial display in a cross-sectional design (n = 153). RESULTS: three-dimensional solutions with an adequate fit were found: residual distribution, root mean square of residuals (RMSR) = 0.04, Goodness of Fit Index (GFI) = 0.96, and Adjusted Goodness of Fit Index (AGFI) = 0.93; and Stress I = 0.023, respectively. The overall ordinal alpha coefficient was 0.92 (CI=0.90 to 0.94). The ordinal alpha coefficients for functional impact, psychosocial impact and psychological impact factors were 0.87 (CI=0.84 to 0.90), 0.88 (CI=0.84 to 0.91) and 0.78 (CI= 0.72 to 0.83), respectively. Item 9 was the most central, followed by 7 and 11. Items 1 and 2 had minor associations. There was no evidence of differences between centers: edge weight differences (M = 0.226, p = 0.94), global strength invariance test (S = 1.88, p = 0.1), centrality invariance test (p >0.05), edge invariance test (p >0.05). CONCLUSIONS: the links between the dimensions and the items seem to involve psychological components. Oral health-related quality of life emerged as a three-dimensional structure (Functional Impact, Psychosocial Impact and Psychological Impact) of functional and psychosocial elements in which physical, psychological, and social disability were essential, while theoretical functional limitation was least important. CLINICAL SIGNIFICANCE: the three-dimensional OHRQoL system for temporomandibular disorders (TMD) is a worthwhile alternative to interpret psychological and psychosocial aspects.

Oncogenic signaling is coupled to colorectal cancer cell differentiation state.

Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.