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Friedreich ataxia (FRDA) is a multisystemic, autosomal recessive disorder caused by homozygous GAA expansion mutation in the first intron of frataxin (FXN) gene. FXN is a mitochondrial protein critical for iron-sulfur cluster biosynthesis and deficiency impairs mitochondrial electron transport chain functions and iron homeostasis within the organelle. Currently, there is no effective treatment for FRDA. We have previously demonstrated that single infusion of wild-type hematopoietic stem and progenitor cells (HSPCs) resulted in prevention of neurologic and cardiac complications of FRDA in YG8R mice, and rescue was mediated by FXN transfer from tissue engrafted, HSPC-derived microglia/macrophages to diseased neurons/myocytes. For a future clinical translation, we developed an autologous stem cell transplantation approach using CRISPR/Cas9 for the excision of the GAA repeats in FRDA patients CD34+ HSPCs; this strategy leading to increased FXN expression and improved mitochondrial functions. The aim of the current study is to validate the efficiency and safety of our gene editing approach in a disease-relevant model. We generated a cohort of FRDA patient-derived iPSCs and isogenic lines that were gene edited with our CRISPR/Cas9 approach. iPSC derived FRDA neurons displayed characteristic apoptotic and mitochondrial phenotype of the disease, such as non-homogenous microtubule staining in neurites, increased caspase-3 expression, mitochondrial superoxide levels, mitochondrial fragmentation, and partial degradation of the cristae compared to healthy controls. These defects were fully prevented in the gene edited neurons. RNASeq analysis of FRDA and gene edited neurons demonstrated striking improvement in gene clusters associated with endoplasmic reticulum (ER) stress in the isogenic lines. Gene edited neurons demonstrated improved ER-calcium release, normalization of ER stress response gene, XBP-1, and significantly increased ER-mitochondrial contacts that are critical for functional homeostasis of both organelles, as compared to FRDA neurons. Ultrastructural analysis for these contact sites displayed severe ER structural damage in FRDA neurons, that was undetected in gene edited neurons. Taken together, these results represent a novel finding for disease pathogenesis showing dramatic ER structural damage in FRDA, validate the efficacy profile of our FXN gene editing approach in a disease relevant model, and support our approach as an effective strategy for therapeutic intervention for Friedreichs ataxia.

Corynebacterium diphtheriae species complex (CdSC; also called cornyebacteria of the diphtheriae species complex) include Corynebacterium diphtheriae and C. ulcerans, 2 potentially toxigenic and highly pathogenic species for humans (1). Human [...]

Foundation: population aging represents a challenge for Emergency Services that have to face an increase in care pressure. Objective: to describe the epidemiological profile of the conditions in older adults treated in the Regional Emergency Service of the Cienfuegos municipality during the year 2022. Method: a descriptive and cross-sectional study was carried out. The universe was made up of 7748 patients, 51.0 % corresponded to the Cienfuegos municipality represented by 3917 patients. The variables analyzed were: age, sex, reason for call, response time to the request, final diagnosis, need for hospital admission and deaths during the journey. Absolute numbers and percentages were used from descriptive statistics and the standard deviation was used to know the variability of the variable. Results: older adults aged 60 to 64 years predominated, which represented 39.2 %; falls corresponded to 41.7 %; followed by calls made using vulgar language, which represented 28.7 %; 67.5 % were attended in less than 10 minutes; only 21.5 % of the elderly died during the journey; the need for hospital admission was represented by 76.5 %; the highest reports were due to high blood pressure and stroke. Depending on sex, women continue to make a difference. Conclusions: older adults aged 60 to 64 years and women predominated in the study. Falls and calls made due to abusive language were more prevalent. Patients were seen in less than 10 minutes. Only 21.5 % of the elderly died during the journey. The highest reports were due to high blood pressure and stroke.

BACKGROUND: The COVID-19 pandemic necessitated rapid real-time surveillance of epidemiological data to advise governments and the public, but the accuracy of these data depends on myriad auxiliary assumptions, not least accurate reporting of cases by the public. Wastewater monitoring has emerged internationally as an accurate and objective means for assessing disease prevalence with reduced latency and less dependence on public vigilance, reliability, and engagement. How public interest aligns with COVID-19 personal testing data and wastewater monitoring is, however, very poorly characterized. OBJECTIVE: This study aims to assess the associations between internet search volume data relevant to COVID-19, public health care statistics, and national-scale wastewater monitoring of SARS-CoV-2 across South Wales, United Kingdom, over time to investigate how interest in the pandemic may reflect the prevalence of SARS-CoV-2, as detected by national testing and wastewater monitoring, and how these data could be used to predict case numbers. METHODS: Relative search volume data from Google Trends for search terms linked to the COVID-19 pandemic were extracted and compared against government-reported COVID-19 statistics and quantitative reverse transcription polymerase chain reaction (RT-qPCR) SARS-CoV-2 data generated from wastewater in South Wales, United Kingdom, using multivariate linear models, correlation analysis, and predictions from linear models. RESULTS: Wastewater monitoring, most infoveillance terms, and nationally reported cases significantly correlated, but these relationships changed over time. Wastewater surveillance data and some infoveillance search terms generated predictions of case numbers that correlated with reported case numbers, but the accuracy of these predictions was inconsistent and many of the relationships changed over time. CONCLUSIONS: Wastewater monitoring presents a valuable means for assessing population-level prevalence of SARS-CoV-2 and could be integrated with other data types such as infoveillance for increasingly accurate inference of virus prevalence. The importance of such monitoring is increasingly clear as a means of objectively assessing the prevalence of SARS-CoV-2 to circumvent the dynamic interest and participation of the public. Increased accessibility of wastewater monitoring data to the public, as is the case for other national data, may enhance public engagement with these forms of monitoring.

The incidence of diphtheria has been rising over the past decade, particularly in its cutaneous form. A clinical review of the case series was therefore required. We reviewed the epidemiological, clinical, microbiological and therapeutic data of cutaneous diphtheria cases, in adult patients living in metropolitan France with a skin sample positive for corynebacteria of the diphtheriae complex between 2018 and 2022. Of the 132 cases identified, 63 met the inclusion criteria. The mean age was 53.8 years, 68.3% were men and 56.7% had travelled outside mainland France. Immunization rate was 44%. Lesions involved the lower limbs (86.9%), corresponded to ulcerations in 82% of cases. Two species were identified in the study: C. diphtheriae (77%) and C. ulcerans (23%). 39% were toxigenic. Other bacteria were present in 88.9% of cases: Staphylococcus aureus (54.7%) and Streptococcus pyogenes (49.1%). 17.5% of clinicians ignored the presence of Corynebacteria of the diphtheriae species complex. Clinicians seem to be unfamiliar with this disease due to under-reporting and a lack of knowledge and awareness among clinicians, and rarely mention it, which explains the frequent failure to comply with French recommendations. Clinical data are consistent with the literature. Continued epidemiological surveillance, increased vaccination coverage in high-risk populations and better information of clinicians are essential to prevent and control this preventable disease.

Foundation: aging is a fact that affects the entire world population, and considerably, the most developed countries, in which life expectancy has been increasing as reflected in the United Nations report. Objective: to describe the social context and functional capacity in gerontos of clinic # 8 of Health Area I of the Cienfuegos municipality during the year 2022. Method: a descriptive cross-sectional study was carried out. A 30 % sample was randomly selected for a total of 131 elderly people. A structured interview was carried out, which included the general variables: age, sex, level of education, occupation, personal pathological history, support collaboration and to complete the social assessment, the Family Functioning Questionnaire was applied. Results: the age group of 60 to 65 years had the most prevalence, 45.5 % studied until they completed primary school, followed by those who completed secondary school with 29.0 %. Retirees were represented at 38.9 %, the main non-communicable diseases that prevailed were: high blood pressure, ischemic heart disease and type 2 diabetes mellitus, 40.4 % lived alone, 19.8 % had a caregiver, 14.5 % did not receive support and 9.9 % of the elderly who were in a probable state of social need. Conclusions: a well-nourished, loved, supported older adult, with all basic needs satisfied, as well as all associated diseases typical of this stage of life compensated, will have a better quality of life in any society.

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.

IntroductionCeliac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals. The haplotypes HLA-DQ2 and DQ8, transglutaminase (TGA) antibodies, and biopsy findings are the main tests performed in the evaluation and CD diagnosis. The objective was to establish possible correlations between transglutaminase levels, genetic markers tests, and qualitative intestinal biopsy findings (modified Marsh classification) at the diagnosis.MethodsA retrospective cohort study. The selection criteria were confirmed CD cases with genetic tests performed. Statistical analysis was done mainly through One-way ANOVA, Kendall's correlation coefficient (T), and linear regression.ResultsThe study included 112 patients, with a mean age of 6 ± 4 years. All cases were tested to HLA-DQ2, and it was positive in 93%. HLA-DQ8 was tested in 73% of cases and it was positive in 61%. The percentage of negative genetic markers (DQ2/DQ8) was 4.5% for patients tested to both haplotypes. A comparison of DQ2/DQ8 (positive and negative) with clinical findings and tests performed did not identify any differences for most of the parameters analyzed. Cases of type I diabetes presented significant negative expression for DQ2(−); p = 0.05 and positive expression for DQ8(+); p = 0.023. The TGA antibody levels ranged from 18 to 36,745 U/ml. An inverse correlation was found between age and TGA-L level (p = 0.043). In 23% of the cases, the TGA levels were greater than 1,000 U/ml and presented a moderate positive correlation with the atrophy biopsy profile (T = 0.245). Patients with an atrophic biopsy profile (Marsh III) had a moderate positive correlation with growth failure (T = 0.218) but a negative correlation with constipation (T = −0.277).ConclusionIn terms of diagnosis tests for CD, transglutaminase levels and age presented an inverse correlation, with the level decreasing as age increased. A moderately positive correlation was found between mean transglutaminase with intestinal atrophy and growth retardation. The genetic test DQ2 was positive for 93% and negative genetic markers (DQ2/DQ8) represented 4.5% of cases studied.

Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.

BackgroundThis study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples.SettingA nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children.MethodsIntensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons.ResultsA total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0-24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0-24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 μg/mL (0.16-0.28) in the second trimester, 0.21 μg/mL (0.11-0.56) in the third trimester, and 0.61 μg/mL (0.42-1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited.ConclusionsStandard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.

CNDOL is an a priori, approximate Fockian for molecular wave functions. In this study, we employ several modes of singly excited configuration interaction (CIS) to model molecular excitation properties by using four combinations of the one electron operator terms. Those options are compared to the experimental and theoretical data for a carefully selected set of molecules. The resulting excitons are represented by CIS wave functions that encompass all valence electrons in the system for each excited state energy. The Coulomb–exchange term associated to the calculated excitation energies is rationalized to evaluate theoretical exciton binding energies. This property is shown to be useful for discriminating the charge donation ability of molecular and supermolecular systems. Multielectronic 3D maps of exciton formal charges are showcased, demonstrating the applicability of these approximate wave functions for modeling properties of large molecules and clusters at nanoscales. This modeling proves useful in designing molecular photovoltaic devices. Our methodology holds potential applications in systematic evaluations of such systems and the development of fundamental artificial intelligence databases for predicting related properties. [ABSTRACT FROM AUTHOR]

Foundation: sexually transmitted infections are a problem that can harm human beings, especially adolescents.Objective: to describe the adolescents’ knowledge about sexually transmitted infections from the Naiguatá Parish. La Guaira. Methods: descriptive, cross-sectional study carried out from June to December 2021. The universe of 471 adolescents and a sample of 142 (30.0%) was selected, using the simple random method. A structured survey of eight questions was applied. The analyzed variables were: age, sex, beginning of sexual relations, knowledge about sexually transmitted infections: diseases considered to be sexually transmitted, routes of transmission, clinical manifestations, risk of acquiring them, measures to prevent them, and their complications.Results: the prevailing age was 16 years old and the female sex; 41.5% started sexual relations at 14 years of age. Ignorance of sexually transmitted infections, their transmission routes and their clinical manifestations prevailed. AIDS, syphilis and gonorrhea were identified as sexually transmitted infections; recognized the use of condoms as a form of prevention and death (66.9%) and pelvic inflammation (53.5%) as the main complications of these diseases.Conclusions: the adolescents’ knowledge about sexually transmitted infections continues to be insufficient.

Clinical, epidemiologic, and microbiologic analyses revealed emergence of 26 cases of Corynebacterium diphtheriae species complex infections on Réunion Island, France, during 2015–2020. Isolates were genetically diverse, indicating circulation and local transmission of several diphtheria sublineages. Clinicians should remain aware of the risk for diphtheria and improve diagnostic methods and patient management.

Foundation: according to the World Health Organization, diabetes causes 300,000 deaths a year in Latin America and the Caribbean and in the Cienfuegos province since 2020 it ranks as the seventh cause of death. Objective: to characterize mortality from diabetes mellitus in the Cienfuegos province in the first nine months of 2020. Methods: a descriptive investigation was carried out on health systems and services based on a series of cases to characterize mortality from diabetes mellitus in Cienfuegos in the first nine months of 2020. The deceased were compiled taking into account: sex, age, skin color, educational level, place of residence, territorial stratum, disease, associated risk factors and direct causes of death. The arithmetic mean and standard deviation were used. The results are presented in the form of tables and graphs. Results: the greatest affectation was in the last decades of life for the female gender, as well as residence in an urban territory, among the first direct causes of death are pulmonary thromboembolism, as well as acute chronic renal failure; hydroelectrolytic imbalance stands out in a considerable number of deaths. Conclusions: the last decades of life were the most affected and the female sex, the main causes of death were: pulmonary thromboembolism and acute chronic renal failure. The hydroelectrolytic imbalance stands out in a considerable number of the deceased.

Background: infection by the human immunodeficiency virus is one of the most important sexually transmitted infections for health worldwide and one of the most frightening of this century.Objective: to characterize the infection by the human immunodeficiency virus in people aged 50 years and older.Methods: a cross-sectional descriptive observational research was carried out, which included all the people diagnosed with the human immunodeficiency virus, in Cienfuegos, from 1986 to 2021. The analyzed variables were: age, sex, sexual orientation, research group, diagnoses by year and residence municipality.Results: people in the age group of 50 to 59 years contributed the highest incidence with 75.21%; the predominant sexual orientation was homosexual (58,9 %). According to the research groups, in the three age groups the captured group stands out with 41.88%. A sustained increase was observed in the province, mainly in the male sex, rising in recent years.Conclusions: the increase in patients aged 50 and older diagnosed with human immunodeficiency virus indicates that it is necessary to address the problem with a different clinical-epidemiological approach. These characteristics increase the risk of HIV infection, they must be monitored with the application of the MINSAP 50 and + Work Line. It is necessary to carry out activities aimed at reducing the risk.

Epidemiological evidence shows that life habits, particularly dietary ones, have a direct influence on quality and life expectancy. Nutrition is one of the key factors to develop any physical activity or simply to feel well-being. The nutritional evaluation in a patient has a direct effect on the physiotherapy treatment, therefore, in order to really optimize the repair and the recovery process, the physiotherapist provides the required nutritional guidance. Only an additional intake of natural nutrients is not enough, it is necessary to complement it with other therapeutic tools within physiotherapy. People suffering from chronic diseases have transformations in eating practices, created by the underlying disease, so it is important to vary dietary habits in order to regain health. The role of the physiotherapist is decisive, to promote adherence to nutritional treatment of patients with non-communicable diseases.

Friedreich ataxia (FRDA) is a multisystemic, autosomal recessive disorder caused by homozygous GAA expansion mutation in the first intron of frataxin (FXN) gene. FXN is a mitochondrial protein critical for iron-sulfur cluster biosynthesis and deficiency impairs mitochondrial electron transport chain functions and iron homeostasis within the organelle. Currently, there is no effective treatment for FRDA. We have previously demonstrated that single infusion of wild-type hematopoietic stem and progenitor cells (HSPCs) resulted in prevention of neurologic and cardiac complications of FRDA in YG8R mice, and rescue was mediated by FXN transfer from tissue engrafted, HSPC-derived microglia/macrophages to diseased neurons/myocytes. For a future clinical translation, we developed an autologous stem cell transplantation approach using CRISPR/Cas9 for the excision of the GAA repeats in FRDA patients’ CD34+ HSPCs; this strategy leading to increased FXN expression and improved mitochondrial functions. The aim of the current study is to validate the efficiency and safety of our gene editing approach in a disease-relevant model. We generated a cohort of FRDA patient-derived iPSCs and isogenic lines that were gene edited with our CRISPR/Cas9 approach. iPSC derived FRDA neurons displayed characteristic apoptotic and mitochondrial phenotype of the disease, such as non-homogenous microtubule staining in neurites, increased caspase-3 expression, mitochondrial superoxide levels, mitochondrial fragmentation, and partial degradation of the cristae compared to healthy controls. These defects were fully prevented in the gene edited neurons. RNASeq analysis of FRDA and gene edited neurons demonstrated striking improvement in gene clusters associated with endoplasmic reticulum (ER) stress in the isogenic lines. Gene edited neurons demonstrated improved ER-calcium release, normalization of ER stress response gene, XBP-1, and significantly increased ER-mitochondrial contacts that are critical for functional homeostasis of both organelles, as compared to FRDA neurons. Ultrastructural analysis for these contact sites displayed severe ER structural damage in FRDA neurons, that was undetected in gene edited neurons. Taken together, these results represent a novel finding for disease pathogenesis showing dramatic ER structural damage in FRDA, validate the efficacy profile of our FXN gene editing approach in a disease relevant model, and support our approach as an effective strategy for therapeutic intervention for Friedreich’s ataxia.

BackgroundAlthough mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission.MethodsA Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis.ResultsForty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1-6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding.ConclusionsSubcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.

Background: epidemics of unknown emerging diseases test not only the technical and human capacity of health professionals, but also of all those who make up the scientific community in society.Objective: to describe the organization of health care services in the fight against COVID-19 at the Héroes de Paya Girón Specialized Outpatient Center, in Cienfuegos.Methods: a research was carried out on health systems and services that describe the stages of hospital reconversion for the care of suspected and confirmed patients, the number of admitted patients, the extension to a nearby school center and the maintenance of other vital services. Human resources and availability of beds for patient care were also taken into account. The After Action Review method was applied to study lessons learned. The information was obtained from interviews with ten key informants and from the statistics and human resources departments’ reports.Results: the organization of medical care during the year 2020 was related to the evolution of the pandemic in the province. 569 adults and 91 pediatric patients were admitted. On January the 5th, 2021, the second stage of confronting the disease began and the mission of the center was transformed towards the care of positive cases of COVID-19, the number of intensive care beds was increased, a sign of the progressive worsening of patients especially from the end of June, July and August 2021.Conclusions: it can be affirmed that there is a center in the Cienfuegos Province with the capacity to rearrange itself in less than 24 hours to take care of patients with emerging infectious diseases. This shows the need to increase the training of Graduates in Intensive Nursing, as well as to create an Organization and Procedures Manual in each service, adjusted to the care protocols and asepsis, antisepsis and biosafety measures.