Transcription of HIV-1 at sites of intact latent provirus integration.

HIV-1 anti-retroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 10010,000X less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir thereby influencing cytopathic effects and proviral immune evasion.

Subacute cadmium exposure changes different metabolic functions, leading to type 1 and 2 diabetes mellitus features in female rats.

Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd-exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd-exposed rats had increased liver cholesterol levels, insulin receptor beta (IRß) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats.

Prevalence of resistance-associated viral variants to the HIV-specific broadly neutralising antibody 10-1074 in a UK bNAb-naïve population.

Broadly neutralising antibodies (bNAbs) targeting HIV show promise for both prevention of infection and treatment. Among these, 10-1074 has shown potential in neutralising a wide range of HIV strains. However, resistant viruses may limit the clinical efficacy of 10-1074. The prevalence of both de novo and emergent 10-1074 resistance will determine its use at a population level both to protect against HIV transmission and as an option for treatment. To help understand this further, we report the prevalence of pre-existing mutations associated with 10-1074 resistance in a bNAb-naive population of 157 individuals presenting to UK HIV centres with primary HIV infection, predominantly B clade, receiving antiretroviral treatment. Single genome analysis of HIV proviral envelope sequences showed that 29% of participants' viruses tested had at least one sequence with 10-1074 resistance-associated mutations. Mutations interfering with the glycan binding site at HIV Env position 332 accounted for 95% of all observed mutations. Subsequent analysis of a larger historic dataset of 2425 B-clade envelope sequences sampled from 1983 to 2019 revealed an increase of these mutations within the population over time. Clinical studies have shown that the presence of pre-existing bNAb mutations may predict diminished therapeutic effectiveness of 10-1074. Therefore, we emphasise the importance of screening for these mutations before initiating 10-1074 therapy, and to consider the implications of pre-existing resistance when designing prevention strategies.

Seroprevalence of antibodies against SARS-CoV-2 in the school community in Campo Grande, state of Mato Grosso do Sul, Brazil, October 2021-November 2022.

Introduction: With the reopening of schools during the coronavirus disease 2019 (COVID-19) pandemic, it was imperative to understand the role of students and education professionals in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this paper, we determined the seroprevalence of the SARS-CoV-2 anti-nucleocapsid antibodies in the school community in Campo Grande, the capital and most populous city of the state of Mato Grosso do Sul (Brazil) and evaluated its association with sex, school level, and school type. Materials and methods: The survey was carried out in 20 public and private schools in the urban region of Campo Grande using the TR DPP® COVID-19 immunoglobulin M/immunoglobulin G (IgM/IgG) kit from the Immunobiological Technology Institute (Bio-Manguinhos, Rio de Janeiro, Brazil). Testing was carried out in three periods: from October to December 2021; from March to July 2022; and from August to November 2022. The participants were students aged 6-17 years enrolled in primary or secondary schools and professionals of different ages and roles. Results: During the first testing period, 162 participants were seropositive for the IgM and/or IgG anti-nucleocapsid SARS-CoV-2 antibodies, with an estimated seroprevalence of 19.6% using Bayesian multilevel regression. In the second period, 251 participants were seropositive (estimated seroprevalence, 34.6%), while in the third period, 393 participants were seroconverted (estimated seroprevalence, 56.7%). In 2022, there was an increase in the seroconversion rate compared to that in 2021. The most frequently described acute manifestations in the three periods were fever, headache, sore throat, and runny nose. In terms of the demographic profile, there was no predominance of seropositivity between the sexes, although women represented approximately 70% of the study population. There were also no differences between students and school staff. Discussion: The results made it possible to evaluate the extent of SARS-CoV-2 transmission in the school community through immunity developed against the virus, in addition to providing information about COVID-19 symptoms in children, adolescents, and adults.

Estrone-mediated lowering of ROS and NOX4 improves endothelial function in ovariectomized wistar rats.

Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms - i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions.

Latin American Consensus on the Treatment of Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is well known as a serious health problem worldwide, especially in low-income countries or those with limited resources, such as most countries in Latin America. International guidelines cannot always be applied to a population from a large region with specific conditions. This study established a Latin American guideline for care of patients with head and neck cancer and presented evidence of HNSCC management considering availability and oncologic benefit. A panel composed of 41 head and neck cancer experts systematically worked according to a modified Delphi process on (1) document compilation of evidence-based answers to different questions contextualized by resource availability and oncologic benefit regarding Latin America (region of limited resources and/or without access to all necessary health care system infrastructure), (2) revision of the answers and the classification of levels of evidence and degrees of recommendations of all recommendations, (3) validation of the consensus through two rounds of online surveys, and (4) manuscript composition. The consensus consists of 12 sections: Head and neck cancer staging, Histopathologic evaluation of head and neck cancer, Head and neck surgery-oral cavity, Clinical oncology-oral cavity, Head and neck surgery-oropharynx, Clinical oncology-oropharynx, Head and neck surgery-larynx, Head and neck surgery-larynx/hypopharynx, Clinical oncology-larynx/hypopharynx, Clinical oncology-recurrent and metastatic head and neck cancer, Head and neck surgery-reconstruction and rehabilitation, and Radiation therapy. The present consensus established 48 recommendations on HNSCC patient care considering the availability of resources and focusing on oncologic benefit. These recommendations could also be used to formulate strategies in other regions like Latin America countries.

Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update.

PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.

Essential data variables for a minimum dataset for head and neck cancer trials and clinical research: HNCIG consensus recommendations and database.

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website.

Differentiated thyroid carcinoma: what the nonspecialists needs to know.

Differentiated thyroid carcinoma (DTC) accounts for most cases of thyroid cancer, and the heterogeneity of DTC requires that management decisions be taken by a multidisciplinary team involving endocrinologists, head and neck surgeons, nuclear medicine physicians, pathologists, radiologists, radiation oncologists, and medical oncologists. It is important for nonspecialists to recognize and refer patients with DTC who will benefit from a specialized approach. Recent advances in knowledge and changes in management of DTC call for the need to raise awareness on the part of these nonspecialist physicians, including general endocrinologists and medical oncologists at large. We provide an overview of diagnostic and therapeutic principles in DTC, especially those that bear direct implication on day-to-day management of these patients by generalists. Patients with DTC may be broadly categorized as having localized, locally persistent/recurrent, or metastatic disease. Current recommendations for DTC include a three-tiered system that classifies patients with localized disease into low, intermediate, or high risk of persistent or recurrent disease. Risk stratification should be performed at baseline and repeated on an ongoing basis, depending on clinical evolution. One of the overarching goals in the management of DTC is the need to personalize treatment by tailoring its modality and intensity according to ongoing prognostic stratification, evolving knowledge about the disease, and patient characteristics and preference. In metastatic disease that is refractory to radioactive iodine, thyroid tumors are being reclassified into molecular subtypes that better reflect their biological properties and for which molecular alterations can be targeted with specific agents.

The impact of colonialism on head and neck cancer in Brazil: a historical essay focussing on tobacco, alcohol and slavery.

Colonialism's enduring impact on Brazil has had significant implications for health and oncology outcomes. This historical essay delves into the profound changes brought about by the transatlantic slave trade from Africa to the Americas, particularly in terms of its influence on the economy, sociocultural habits, and health outcomes. This essay explores the enduring connections between the colonial period's operational dynamics in Brazil and the current epidemiological panorama of head and neck cancer (HNC). The examination provides original insights on the role of tobacco and alcohol production and consumption, alongside the investigation of structural racism, which contributes to disparities in access to diagnosis, treatment, and prognosis for patients with HNC. This article presents novel visions and an analysis of evidence-based strategies to disrupt the adverse impact of colonialism's legacy on the epidemiology of HNC in Brazil.

A hierarchical approach for evaluating athlete performance with an application in elite basketball.

In this paper, we present the ON score for evaluating the performance of athletes and teams that includes a season-long evaluation system, a single-game evaluation, and an evaluation of an athlete's overall contribution to their team. The approach used to calculate the ON score is based on mixed-effects regression models that take into account the hierarchical structure of the data and a principal component analysis to calculate athlete rating. We apply our methodology to a large dataset of National Basketball Association (NBA) games spanning four seasons from 2015-2016 to 2018-2019. Our model is validated using two systematic approaches, and our results demonstrate the reliability of our approach to calculate an athlete's performance. This provides coaches, General Managers and player agents with a powerful tool to gain deeper insights into their players' performance, make more informed decisions and ultimately improve team performance. Our methodology has several key advantages. First, by incorporating the hierarchical structure of the data, we can obtain valuable information about an athlete's contribution within their team. Second, the use of principal component analysis allows us to calculate a single score, the ON score, that captures the overall performance of an athlete. Third, our approach is based on classical restricted likelihood methods, which makes the calculation faster than Bayesian methods typically requiring 1000 posterior samples. With our approach, coaches and managers can evaluate athletes' performance throughout the season, compare athletes and teams over a year, and assess an athlete's performance during a single game. Our methodology can also complement other ratings and box score metrics to provide a more comprehensive assessment of an athlete's performance as our method uses the hierarchical nature of performance data (i.e. player nested within team over season) which is typically ignored in player rating systems. In summary, our methodology represents a significant contribution to the field of sports analytics and provides the foundation for future developments.

Role of affinity in plasma cell development in the germinal center light zone.

Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined precisely. Here, we use a fate-mapping approach to examine the relationship between GC B cells selected to undergo additional rounds of affinity maturation, GC pre-PC, and PC. The data show that initial PC selection overlaps with GC B cell selection, but that the PC compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-PC selection sieves the GC to enable the accumulation of a more restricted group of high-affinity antibody-secreting PC.

Comparison of markerless and marker-based motion capture systems using 95% functional limits of agreement in a linear mixed-effects modelling framework.

Biomechanics analysis of human movement has been proven useful for maintenance of health, injury prevention, and rehabilitation in both sports and clinical populations. A marker-based motion capture system is considered the gold standard method of measurement for three dimensional kinematics measurements. However, the application of markers to anatomical bony points is a time consuming process and constrained by inter-, intra-tester and session reliability issues. The emergence of novel markerless motion capture systems without the use of reflective markers is a rapidly growing field in motion analysis. However an assessment of the level of agreement of a markerless system with an established gold standard marker-based system is needed to ensure the applicability of a markerless system. An extra layer of complexity is involved as the kinematics measurements are functional responses. In this paper a new approach is proposed to generate 95% functional limits of agreement (fLoA) using the linear mixed-effects modelling framework for hierarchical study designs. This approach is attractive as it will allow practitioners to extend their use of linear mixed models to assess agreement in method comparison studies in all domains where functional responses are recorded.

Continually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers.

Follicular helper T cells (TFH) mediate B cell selection and clonal expansion in germinal centers (GCs), and follicular regulatory T cells (TFR) prevent the emergence of self-reactive B cells and help to extinguish the reaction. Here we show that GC reactions continually recruit T cells from both the naïve conventional and naive thymic regulatory T cell (Treg) repertoires. In the early GC, newly recruited T cells develop into TFH, whereas cells entering during the contraction phase develop into TFR cells that contribute to GC dissolution. The TFR fate decision is associated with decreased antigen availability and is modulated by slow antigen delivery or mRNA vaccination. Thus, invasion of ongoing GCs by newly developing TFH and TFR helps remodel the GC based on antigen availability.

Differences in Prevalence of Transfusion Protocols between Critically Ill Neurologic and Non-Neurologic Patient Populations.

This study describes the prevalence of blood transfusion protocols in ICUs caring for neurologically vs. non-neurologically injured patients across a sample of US ICUs. This prospective, observational multi-center cohort study is a subgroup analysis of the USCIITG-CIOS, comprising 69 ICUs across the US (25 medical, 24 surgical, 20 mixed ICUs). Sixty-four ICUs were in teaching hospitals. A total of 6179 patients were enrolled, with 1266 (20.4%) having central nervous system (CNS) primary diagnoses. We evaluated whether CNS versus non-CNS diagnosis was associated with care in ICUs with restrictive transfusion protocols (RTPs) or massive transfusion protocols (MTPs) and whether CNS versus non-CNS diagnosis was associated with receiving blood products or colloids during the initial 24 h of care. Protocol utilization in CNS vs. non-CNS patients was as follows: RTPs-36.9% vs. 42.9% (p < 0.001); MTPs-48.3% vs. 47.4% (p = 0.57). Blood product transfusions in the first 24 h of ICU care (comparing CNS vs. non-CNS patients) were as follows: packed red blood cells-4.3% vs. 14.6% (p < 0.001); fresh frozen plasma-2.9% vs. 5.1% (p < 0.001); colloid blood products-3.2% vs. 9.2% (p < 0.001). In this cohort, we found differences in ICU utilization of RTPs, but not MTPs, when comparing where critically ill patients with neurologic versus non-neurologic primary diagnoses received ICU care.

BioIn-Tacto: A compliant multi-modal tactile sensing module for robotic tasks.

We present the open-source design and fabrication of a compliant multimodal tactile sensing module. The sensing module design presented here enables robotic end-effectors to sense contact properties like pressure and vibration and estimate a quaternion that represents the deformation due to contact. We elaborated the module's compliant structure fabrication process to use only 3D printed molds and a vacuum chamber, making it accessible to a broad range of roboticists. The process also allows production batches of up to five modules and easy deployment to robotic hands. The repository associated contains packages that support the Robot Operating System (ROS) to perform data collection and visualization. All hardware Computer-Aided Design (CAD) files and software source codes have been released and can be easily assembled and modified. The sensing module proposed in this paper uses off-the-shelf Microelectromechanical (MEMs) barometers and Magnetic, Angular Rate and Gravity (MARG) systems. Those components may be replaced by alternatives depending on the sensor's availability, constraints related to the module's size, or robotic application without prejudice to sensor functionality.