Lifetime HIV testing among three samples of adults with histories of incarceration in Southern California.

ABSTRACTJustice-impacted persons may inconsistently access HIV testing. This cross-sectional secondary analysis investigates lifetime HIV testing prevalence among adults with prior histories of incarceration in Southern California, United States, participating in health-focused programming (n = 3 studies). Self-reported demographic and lifetime HIV testing data were collected between 2017-2023; descriptive analyses were conducted. Across the three samples, at least 74% of participants were male; Latino and African American individuals accounted for nearly two-thirds of participants. Lifetime HIV testing ranged from 72.8% to 84.2%. Males were significantly more likely than females to report never being tested in two samples and accounted for >95% of those never tested. No statistically significant differences in testing were observed by race/ethnicity. Single young adults (ages 18-26) were less likely than their partnered peers to report testing. HIV testing is critical for ensuring that individuals access prevention and treatment. HIV testing among justice-impacted adults in this study was higher than in the general population, potentially due to opt-out testing in correctional settings. Nevertheless, these findings underscore the importance of implementing targeted interventions to reduce structural (e.g., health insurance, access to self-testing kits) and social barriers (e.g., HIV stigma) to increase HIV testing among justice-impacted males and single young adults.

Knobloch syndrome in a patient from Chile.

Knobloch Syndrome (KS) is a rare autosomal recessive hereditary disease. Despite its clinical heterogeneity, it is characterized by vitreoretinal degeneration and high myopia, with or without occipital skull defects. It is caused by mutations in the COL18A1 gene, which codifies for collagen XVIII, present in retina and vascular endothelium. Since the first description of the disease by doctors Knobloch and Layer in 1972, over 100 cases and 20 pathogenic or likely pathogenic mutations have been reported. We present the case of a child born from a consanguineous couple in Chile with congenital high myopia and dysmorphisms without an occipital skull defect. Whole exome sequencing analysis revealed an inherited homozygous variant in COL18A1, c.4224_4225delinsC, p.Pro1411Leufs*35.

Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency.

The SERPINA1 gene is highly polymorphic, with more than 100 variants described in databases. SERPINA1 encodes the alpha-1 antitrypsin (AAT) protein, and severe deficiency of AAT is a major contributor to pulmonary emphysema and liver diseases. In Spanish patients with AAT deficiency, we identified seven new variants of the SERPINA1 gene involving amino acid substitutions in different exons: PiSDonosti (S+Ser14Phe), PiTijarafe (Ile50Asn), PiSevilla (Ala58Asp), PiCadiz (Glu151Lys), PiTarragona (Phe227Cys), PiPuerto Real (Thr249Ala), and PiValencia (Lys328Glu). We examined the characteristics of these variants and the putative association with the disease. Mutant proteins were overexpressed in HEK293T cells, and AAT expression, polymerization, degradation, and secretion, as well as antielastase activity, were analyzed by periodic acid-Schiff staining, Western blotting, pulse-chase, and elastase inhibition assays. When overexpressed, S+S14F, I50N, A58D, F227C, and T249A variants formed intracellular polymers and did not secrete AAT protein. Both the E151K and K328E variants secreted AAT protein and did not form polymers, although K328E showed intracellular retention and reduced antielastase activity. We conclude that deficient variants may be more frequent than previously thought and that their discovery is possible only by the complete sequencing of the gene and subsequent functional characterization. Better knowledge of SERPINA1 variants would improve diagnosis and management of individuals with AAT deficiency.

Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency.

Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2-18 years) diagnosed with AATD and 18 controls (aged 3-16 years).Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity, hTERT expression and AATD phenotypes; high-risk patients showed shorter telomeres, lower hTERT expression and decreased telomerase activity than intermediate-risk and low-risk patients.AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression.

Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors.

INTRODUCTION: Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data from longitudinal studies of diastolic dysfunction (DD) in this group of patients are scarce. The objective of the present study was to assess the incidence, evolution, and predictors of DD in patients with breast cancer treated with anthracyclines. METHODS: This analytical, observational cohort study comprised 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) for breast cancer. All patients underwent clinical evaluation, echocardiogram, and measurement of cardiac biomarkers at baseline, end of anthracycline-based CHT, and at 3 months and 9 months after anthracycline-based CHT was completed. Fifteen patients receiving trastuzumab were followed with two additional visits at 6 and 12 months after the last dose of anthracycline-based CHT. A multivariate analysis was performed to find variables related to the development of DD. Fifteen of the 100 patients had baseline DD and were excluded from this analysis. RESULTS: At the end of follow-up (median: 12 months, interquartile range: 11.1-12.8), 49 patients (57.6%) developed DD. DD was persistent in 36 (73%) but reversible in the remaining 13 patients (27%). Four patients developed cardiotoxicity (three patients had left ventricular systolic dysfunction and one suffered a sudden cardiac death). None of the patients with normal diastolic function developed systolic dysfunction during follow-up. In the logistic regression model, body mass index (BMI) and age were independently related to the development of DD, with the following odds ratio values: BMI: 1.19 (95% confidence interval [CI]: 1.04-1.36), and age: 1.12 (95% CI: 1.03-1.19). Neither cardiac biomarkers nor remaining clinical variables were predictors of DD. CONCLUSION: Development of diastolic dysfunction after treatment with anthracycline or anthracycline- plus trastuzumab chemotherapy is common. BMI and age were independently associated with DD following anthracycline chemotherapy.

Decreased glutathione and low catalase activity contribute to oxidative stress in children with α-1 antitrypsin deficiency.

BACKGROUND: Recent investigations in animal models have revealed oxidative stress and oxidative damage in the pathogenesis of alpha-1 antitrypsin deficiency (AATD). However, no data are available on the oxidative stress status and antioxidant enzyme activity in these patients. This study was aimed to analyse the oxidative stress profile and enzymatic antioxidant defence mechanisms in children with AATD. METHODS: Oxidative stress parameters and the activity of the main antioxidant enzymes were prospectively measured in serum of fifty-one children diagnosed with AATD and thirty-eight control individuals. RESULTS: Oxidative stress was increased in the serum of children with intermediate- (MZ; SZ) and high-risk (ZZ) phenotypes for developing AATD-related emphysema and/or liver disease. When compared with the control group, intermediate- and high-risk groups showed significantly lower total glutathione and reduced glutathione levels, decreased catalase activity and increased glutathione peroxidase activity leading to an accumulation of hydrogen peroxide that would explain the significantly increased levels of oxidative stress biomarkers observed in these patients. No differences were observed between the control (MM) and the low-risk (MS; SS) groups. A gradation in oxidative stress parameters was observed when patients were compared among themselves, in that the expression of the Z allele produces a higher oxidative stress status in homozygous (ZZ) than in heterozygous (MZ; SZ) patients. CONCLUSIONS: Increased oxidative stress, together with reduced antioxidant defence are involved in the pathophysiology of AATD at early stages, opening up a new rationale for the use of antioxidant therapies in the treatment of the disease.

[Methylenetetrahydrofolate reductase polymorphisms as risk factors for myelomeningocele]. / Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile.

BACKGROUND: Mandatory fortification with folic acid (FA) was implemented in Chile in 2000. Thereafter, the rate of spina bifida decreased by 52 to 55%. Genetic abnormalities in folate metabolism may be involved in the etiology of spina bifida. AIM: To evaluate the association between myelomeningocele (MM) and c.A1298C and c.C677T polymorphisms within the coding gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) in the Chilean population. MATERIAL AND METHODS: These polymorphisms were genotyped in 105 patients showing isolated MM, born after the onset of FA fortification, and in their parents. The transmission disequilibrium test (TDT) was performed to evaluate alterations in the transmission of both alleles and haplotypes MTHFR polymorphism. We also evaluated the presence of parent-origin-effect (POE) of alleles using the Clayton's extension of the TDT. RESULTS: TDT analysis showed no significant distortions in the transmission of alleles or haplotypes. Moreover, although the POE showed increased risk for maternally derived allele, this risk was not statistically significant. CONCLUSIONS: The studied variants in the MTHFR gene (c.C677T and c.A1298C) do not constitute risk factors for MM in this sample of Chilean patients and their parents.

Early and late onset cardiotoxicity following anthracycline-based chemotherapy in breast cancer patients: Incidence and predictors.

INTRODUCTION: Cardiotoxicity represents a major limitation for the use of anthracyclines or trastuzumab in breast cancer patients. Data on longitudinal studies about early and late onset cardiotoxicity in this group of patients is scarce. The objective of the present study was to assess predictors of early and late onset cardiotoxicity in patients with breast cancer treated with A. METHODS: 100 consecutive patients receiving anthracycline-based chemotherapy (CHT) to treat breast cancer were included in this prospective study. All patients underwent evaluation at baseline, at the end of CHT, 3 months after the end of CHT and 1 and 4 years after the beginning of CHT. Clinical data, systolic and diastolic echo parameters and cardiac biomarkers including high sensitivity Troponin T (TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP) and Heart-type fatty acid binding protein (H-FABP) were assessed. RESULTS: Mean doxorubicin dose was 243 mg/m2. Mean follow-up was 51.8 ± 8.2 months. At one-year incidence of anthracycline related-cardiotoxicity (AR-CT) was 4% and at the end of follow-up was 18% (15 patients asymptomatic left ventricular systolic dysfunction, 1 patients heart failure and 2 patients a sudden cardiac death). Forty-nine patients developed diastolic dysfunction (DD) during first year. In the univariate analysis DD during first year was the only parameter associated with AR-CT (Table 1). In the logistic regression model DD was independently related with the development of AR-CT, with an odds ratio value of 7.5 (95% CI 1.59-35.3). CONCLUSIONS: Incidence of late-onset cardiotoxicity is high but mostly subclinical. Diastolic dysfunction early after chemotherapy is a strong predictor of anthracycline cardiotoxicity.

Correction: Magallon et al. Oxidative Stress and Endoplasmic Reticulum Stress in Rare Respiratory Diseases. J. Clin. Med. 2021, 10, 1268.

Sara Pastor was not included as an author in the original publication [...].

Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals.

Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.

An in vitro evaluation of two dentine adhesive systems to seal the pulp chamber using a glucose penetration model.

OBJECTIVES: To evaluate the sealing capability of Cavit™ G with or without Clearfil™ S3 Bond and Prime & Bond NT placed in the pulp chamber. STUDY DESIGN: Forty single rooted premolars, extracted for orthodontic and periodontal reasons, with intact coronal surface and mature apices, were standardized to a length of 15 mm. The teeth were instrumented, filled with a gutta-percha master cone and divided into three groups to obturate the pulp chambers: Cavit™ G; Clearfil™ S3 Bond plus Cavit™ G and Prime & Bond® NT plus Cavit™ G. A glucose leakage model was used for evaluating the coronal microleakage. The Mann-Whitney test was used to evaluate the differences in the means of the glucose leakage. RESULTS: An increase in glucose penetration was observed during the first week in groups Cavit™ G and Cavit™ G+PBNT. The glucose penetration values of all groups were similar at 30 and 45 days, and there were no significant differences among them in both time periods (p=0.736 and p=0.581, respectively). CONCLUSIONS: The adhesive systems did not improve the capability of Cavit™ G to seal the pulp chamber over time.

Intraorifice sealing ability of different materials in endodontically treated teeth.

OBJECTIVES: To evaluate Cavit TM G, ProRoot TM MTA and Tetric® EvoFlow as intraorifice barriers to prevent coronal microleakage in root canal treatment. STUDY DESIGN: Forty-two human single rooted teeth were divided randomly in three experimental groups of 10 specimens each and two control groups. The experimental groups were prepared with hand instrumentation and cold lateral condensed technique of the gutta-percha. Four millimetres of coronal gutta-percha were removed and replaced by one of the following filling materials: Cavit TM G, Tetric® EvoFlow or ProRoot TM MTA. In the experimental groups, leakage was measured by the concentration of leaked glucose in the apical reservoir at 1, 7, 30, and 45 days, using the enzymatic glucose oxidase method. Data were analyzed by means of Mann-Whitney U and Kruskal-Wallis tests at α=0.05. RESULTS: The glucose penetration results of three experimental groups increased gradually over time. No significant differences were found among groups at 24 hours and 1 week. At thirty and forty-five days, Cavit TM and Tetric® EvoFlow values were significantly different (p=0.007 and p=0.023, respectively). CONCLUSIONS: The sealing ability of the Cavit TM G, ProRoot TM MTA and Tetric® EvoFlow used as intraorifice materials tends to be similar over time.

Special Issue: Rare Respiratory Diseases: A Personal and Public Health Issue.

In the 1970s, the term "rare disease" was coined to describe a category of inherited metabolic diseases with low prevalence and a wide range of symptoms [...].

New Laboratory Protocol to Determine the Oxidative Stress Profile of Human Nasal Epithelial Cells Using Flow Cytometry.

Several studies have shown the importance of oxidative stress (OS) in respiratory disease pathogenesis. It has been reported that the nasal epithelium may act as a surrogate for the bronchial epithelium in several respiratory diseases involving OS. However, the sample yields obtained from nasal biopsies are modest, limiting the number of parameters that can be determined. Flow cytometry has been widely used to evaluate cellular OS profiles. It has the advantage that analyses can be performed using a small amount of sample. Therefore, we aimed to set up a new method based on flow cytometry to assess the oxidative profile of human nasal epithelial cells which could be used in research on respiratory diseases. Levels of total nitric oxide, superoxide anion, peroxynitrite, and intracellular peroxides were measured. Reduced thiol levels, such as antioxidant-reduced glutathione and oxidative damaged lipids and proteins, were also analysed. The intracellular calcium levels, plasma membrane potential, apoptosis, and percentage of live cells were also studied. Finally, a strategy to evaluate the mitochondrial function, including mitochondrial hydrogen peroxide, superoxide anion, mitochondrial mass, and membrane potential, was set up. Using small amounts of sample and a non-invasive sampling technique, the described method enables the measurement of a comprehensive set of OS parameters in nasal epithelial cells, which could be useful in research on respiratory diseases.

Oxidative Stress and Endoplasmic Reticulum Stress in Rare Respiratory Diseases.

Several studies have shown that some rare respiratory diseases, such as alpha-1 antitrypsin deficiency (AATD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and primary ciliary dyskinesia (PCD) present oxidative stress (OS) and endoplasmic reticulum (ER) stress. Their involvement in these pathologies and the use of antioxidants as therapeutic agents to minimize the effects of OS are discussed in this review.

miR-320c Regulates SERPINA1 Expression and Is Induced in Patients With Pulmonary Disease.

INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting in lung and liver disease with a great clinical variability. MicroRNAs have been identified as disease modifiers; therefore miRNA deregulation could play an important role in disease heterogeneity. Members of miR-320 family are involved in regulating of multiple processes including inflammation, and have potential specific binding sites in the 3'UTR region of SERPINA1 gene. In this study we explore the involvement of miR-320c, a member of this family, in this disease. METHODS: Firstly in vitro studies were carried out to demonstrate regulation of SERPINA1 gene by miR-320. Furthermore, the expression of miR-320c was analyzed in the blood of 98 individuals with different AAT serum levels by using quantitative PCR and expression was correlated to clinical parameters of the patients. Finally, HL60 cells were used to analyze induction of miR-320c in inflammatory conditions. RESULTS: Overexpression of miR-320 members in human HepG2 cells led to inhibition of SERPINA1 expression. Analysis of miR-320c expression in patient's samples revealed significantly increased expression of miR-320c in individuals with pulmonary disease. Additionally, HL60 cells treated with the pro-inflammatory factor lipopolysaccharide (LPS) showed increase in miR-320c expression, suggesting that miR-320c responds to inflammation. CONCLUSION: Our findings demonstrate that miR-320c inhibits SERPINA1 expression in a hepatic cell line and its levels in blood are associated with lung disease in a cohort of patients with different AAT serum levels. These results suggest that miR-320c can play a role in AAT regulation and could be a biomarker of inflammatory processes in pulmonary diseases.

Cardiac anatomy for the interventional arrhythmologist: I.terminology and fluoroscopic projections.

Cardiac anatomy is complex and its understanding is essential for the interventional arrhythmologist. The first difficulty is the terminology used to describe the location of sites of mapping and ablation. For many years, electrophysiologists have named these positions following the conventional electrocardiographical vocabulary, or the terminology used by surgeons performing arrhythmic surgery. This traditional nomenclature, however, failed to take note of the crucial principle of considering the location of the heart in the human body as viewed in its erect position. In other words, it had failed to use an attitudinally appropriate terminology. Almost 10 years ago, a new attitudinal nomenclature was proposed for the right and left atrioventricular junctions. In this first of a series of reviews of cardiac anatomy as seen by the interventional arrhythmologist, we discuss the role of attitudinally appropriate terminology, and relate this to the projections used for cardiac fluoroscopy, fluorography, and angiography. Throughout our series of reviews, we will illustrate the value of The Visible Human Slice and Surface Server in facilitating the understanding of the fluoroscopic anatomy. (PACE 2010; 497-507).

Predictive factors for the outcome of noninvasive ventilation in pediatric acute respiratory failure.

OBJECTIVES: To identify success and failure prognostic signs of noninvasive ventilation in pediatric acute respiratory failure. Noninvasive ventilation constitutes an alternative treatment for pediatric acute respiratory failure. However, tracheal intubation should not be delayed when considered necessary. DESIGN: Prospective, noncontrolled, clinical study. SETTING: Pediatric intensive care unit in a university hospital. PATIENTS: Children (age range, 1 month-16 yrs) with moderate-to-severe acute respiratory failure who received noninvasive ventilation during a 4-year period. Failure was defined as the need for tracheal intubation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nine (19.1%) of 47 patients needed tracheal intubation between the third and 87th hour after the start of treatment (33.6 ± 29.6 hrs). Failure was associated with the younger age group (4 ± 3.3 yrs vs. 7.7 ± 5 yrs, p < .04), acute respiratory distress syndrome (failure/acute respiratory distress syndrome: 5 of 10 vs. failure/non acute respiratory distress syndrome: 4 of 37, p = .013), and worsening radiographic images taken at 24 hrs and/or 48-72 hrs (p = .001 and p < .001, respectively). A significant reduction in heart rate was observed between the second and fourth hour after starting noninvasive ventilation (130 ± 25.8 bpm vs. 116 ± 27.7 bpm, p < .001) and Pco2 (54.1 ± 19.5 torr vs. 48.6 ± 14.3 torr; 7.21 ± 2.6 vs. 6.48 ± 1.91 kPa, p < .007) in the success group. The failure group had a higher rate of breathing assistance, both initial and maximal. In the multivariant analysis, only maximum mean airway pressure and Fio2 formed part of the success/failure discriminant function with a cutoff point of 11.5 and 0.57, respectively. CONCLUSIONS: Modifications in a patient's respiratory assistance were made depending on the clinical, blood gas, and radiologic evolution of the patient. Mean airway pressure and Fio2 values of >11.5 and 0.6, respectively, predict failure and possibly set the limit above the patient's risk of delayed intubation increases.

Gene Therapy in Rare Respiratory Diseases: What Have We Learned So Far?

Gene therapy is an alternative therapy in many respiratory diseases with genetic origin and currently without curative treatment. After five decades of progress, many different vectors and gene editing tools for genetic engineering are now available. However, we are still a long way from achieving a safe and efficient approach to gene therapy application in clinical practice. Here, we review three of the most common rare respiratory conditions-cystic fibrosis (CF), alpha-1 antitrypsin deficiency (AATD), and primary ciliary dyskinesia (PCD)-alongside attempts to develop genetic treatment for these diseases. Since the 1990s, gene augmentation therapy has been applied in multiple clinical trials targeting CF and AATD, especially using adeno-associated viral vectors, resulting in a good safety profile but with low efficacy in protein expression. Other strategies, such as non-viral vectors and more recently gene editing tools, have also been used to address these diseases in pre-clinical studies. The first gene therapy approach in PCD was in 2009 when a lentiviral transduction was performed to restore gene expression in vitro; since then, transcription activator-like effector nucleases (TALEN) technology has also been applied in primary cell culture. Gene therapy is an encouraging alternative treatment for these respiratory diseases; however, more research is needed to ensure treatment safety and efficacy.

Knowledge of Rare Respiratory Diseases among Paediatricians and Medical School Students.

Alpha-1-antitrypsin deficiency (AATD) and primary ciliary dyskinesia (PCD) are underdiagnosed rare diseases showing a median diagnostic delay of five to ten years, which has negative effects on patient prognosis. Lack of awareness and education among healthcare professionals involved in the management of these patients have been suggested as possible causes. Our aim was to assess knowledge of these diseases among paediatricians and medical school students to determine which knowledge areas are most deficient. A survey was designed with questions testing fundamental aspects of the diagnosis and treatment of AATD and PCD. A score equal to or greater than 50% of the maximum score was set as the level necessary to ensure a good knowledge of both diseases. Our results indicate a profound lack of knowledge of rare respiratory diseases among paediatric professionals and medical students, suggesting that it is necessary to increase rare respiratory diseases training among all physicians responsible for suspecting and diagnosing them; this will allow early diagnosis and the setup of preventive measures and appropriate early-stage treatment. The first step in closing this knowledge gap could be to include relevant material in the medical syllabus.