Independent transcriptional patterns reveal biological processes associated with disease-free survival in early colorectal cancer.

BACKGROUND: Bulk transcriptional profiles of early colorectal cancer (CRC) can fail to detect biological processes associated with disease-free survival (DFS) if the transcriptional patterns are subtle and/or obscured by other processes' patterns. Consensus-independent component analysis (c-ICA) can dissect such transcriptomes into statistically independent transcriptional components (TCs), capturing both pronounced and subtle biological processes. METHODS: In this study we (1) integrated transcriptomes (n = 4228) from multiple early CRC studies, (2) performed c-ICA to define the TC landscape within this integrated data set, 3) determined the biological processes captured by these TCs, (4) performed Cox regression to identify DFS-associated TCs, (5) performed random survival forest (RSF) analyses with activity of DFS-associated TCs as classifiers to identify subgroups of patients, and 6) performed a sensitivity analysis to determine the robustness of our results RESULTS: We identify 191 TCs, 43 of which are associated with DFS, revealing transcriptional diversity among DFS-associated biological processes. A prominent example is the epithelial-mesenchymal transition (EMT), for which we identify an association with nine independent DFS-associated TCs, each with coordinated upregulation or downregulation of various sets of genes. CONCLUSIONS: This finding indicates that early CRC may have nine distinct routes to achieve EMT, each requiring a specific peri-operative treatment strategy. Finally, we stratify patients into DFS patient subgroups with distinct transcriptional patterns associated with stage 2 and stage 3 CRC.

While treatments for patients with colorectal cancer have improved, many patients (around 30-50%) have cancers that will eventually relapse and these patients will die due to their disease. Researchers have been studying the genes involved in colorectal cancer to help us understand why some cancers might relapse. However, current methods to do this may miss subtle or hidden patterns in the gene activity related to cancer relapse. To deal with this, we used a special method called consensus-independent component analysis (c-ICA) to dig more deeply into the activity of genes. This helped us to uncover some potential biological processes underpinning colorectal cancer relapse, which ultimately could help researchers to identify better treatments for patients with colorectal cancer.

Positive Airway Pressure and Metabolic Markers in Children With Obstructive Sleep Apnea.

BACKGROUND: Increasing evidence suggests an association between childhood obstructive sleep apnea (OSA) and metabolic syndrome, with more research available on the potential impacts of positive airway pressure (PAP) on metabolic markers in children. The purpose of this systematic review is to provide a systematic synthesis of the evidence on the effect of PAP use on metabolic markers in children with OSA. METHODS: A search strategy with terms for "OSA" and metabolic markers in pediatrics was run to systematically assess 5 databases until August 26, 2022. Two reviewers independently screened eligible articles, extracted data, and conducted quality appraisal. Meta-analysis was done using random-effects models. Body mass index (BMI), glycemic, lipid, cardiovascular, and other metabolic and inflammatory markers were reported. RESULTS: Sixteen studies (N = 1,213) were included, 15 observational studies and 1 randomized controlled trial (RCT); most reported outcomes in children with obesity. Meta-analysis of 4 studies found no changes in BMI at median average follow-up of 12 months after PAP initiation. A reduction in heart rate and blood pressure parameters was demonstrated in several studies in children with OSA with and without obesity at a median average follow-up of 4.9 months after PAP initiation. Research in echocardiographic outcomes is limited, including one RCT in children with Down syndrome and OSA showing no changes in heart rate variability parameters. Evidence of improvements in glycemic and/or lipid control, liver enzymes, and inflammatory markers with PAP therapy is even more limited and of limited clinical importance. Risk of bias was moderate to critical and outcome evidence very low. CONCLUSIONS: Although evidence on effects of PAP on metabolic markers in children with OSA is encouraging, available literature is limited. Longitudinal studies are still required to further assess the long-term influence of PAP on metabolic and inflammatory markers, particularly in children with obesity.

Atraumatic Spontaneous Transvaginal Small Bowel Evisceration: A Rare Surgical Emergency.

Abdominal pain ranks as the predominant cause for emergency department consultations. Although rare, transvaginal evisceration of the small intestine necessitates immediate surgical intervention due to its potential to induce intestinal ischemia and peritonitis. Key risk factors include postmenopausal status, a history of gynecologic surgery, and heightened abdominal pressure. Clinical presentation typically involves pain and protrusion of intestinal contents or even abdominal viscera. Diagnosis relies on thorough clinical assessment, and treatment strategies should be tailored to each patient. Here, we describe the case of a 65-year-old female patient with a non-traumatic evisceration of the ileum, who had undergone total abdominal hysterectomy following anterior colpocele a year ago, subsequently necessitating exploratory laparotomy and repair of the vaginal ampulla.

Targeting Viral Transcription for HIV Cure Strategies.

Combination antiretroviral therapy (ART) suppresses viral replication to undetectable levels, reduces mortality and morbidity, and improves the quality of life of people living with HIV (PWH). However, ART cannot cure HIV infection because it is unable to eliminate latently infected cells. HIV latency may be regulated by different HIV transcription mechanisms, such as blocks to initiation, elongation, and post-transcriptional processes. Several latency-reversing (LRA) and -promoting agents (LPA) have been investigated in clinical trials aiming to eliminate or reduce the HIV reservoir. However, none of these trials has shown a conclusive impact on the HIV reservoir. Here, we review the cellular and viral factors that regulate HIV-1 transcription, the potential pharmacological targets and genetic and epigenetic editing techniques that have been or might be evaluated to disrupt HIV-1 latency, the role of miRNA in post-transcriptional regulation of HIV-1, and the differences between the mechanisms regulating HIV-1 and HIV-2 expression.

Ischemic Stroke as an Initial Manifestation of Antiphospholipid Syndrome in an Adolescent: A Case Report.

Cerebrovascular diseases in pediatric patients are relatively rare. Ischemic stroke in adolescents is associated with a poor prognosis. The most common causes include systemic diseases, such as heart disease and hypercoagulation disorders. It is important to mention that one of the most common acquired hypercoagulation states is the antiphospholipid syndrome (APS). Patients with this disease may present stroke as the first clinical manifestation, which not only increases morbidity in these patients but presents a diagnostic challenge. This case presents one example of how APS can present as a pediatric stroke. The diagnostic approach should always be through the presence of specific antibodies accompanied by the presence of a thromboembolic episode proven by catheterization or an imaging study. In the brain, the preferred imaging study is magnetic resonance imaging. Management is based on anticoagulation therapy and continuous monitoring in the intensive care unit.

Assessment of the impact of a personalised nutrition intervention in impaired glucose regulation over 26 weeks: a randomised controlled trial.

Dietary interventions can reduce progression to type 2 diabetes mellitus (T2DM) in people with non-diabetic hyperglycaemia. In this study we aimed to determine the impact of a DNA-personalised nutrition intervention in people with non-diabetic hyperglycaemia over 26 weeks. ASPIRE-DNA was a pilot study. Participants were randomised into three arms to receive either (i) Control arm: standard care (NICE guidelines) (n = 51), (ii) Intervention arm: DNA-personalised dietary advice (n = 50), or (iii) Exploratory arm: DNA-personalised dietary advice via a self-guided app and wearable device (n = 46). The primary outcome was the difference in fasting plasma glucose (FPG) between the Control and Intervention arms after 6 weeks. 180 people were recruited, of whom 148 people were randomised, mean age of 59 years (SD = 11), 69% of whom were female. There was no significant difference in the FPG change between the Control and Intervention arms at 6 weeks (- 0.13 mmol/L (95% CI [- 0.37, 0.11]), p = 0.29), however, we found that a DNA-personalised dietary intervention led to a significant reduction of FPG at 26 weeks in the Intervention arm when compared to standard care (- 0.019 (SD = 0.008), p = 0.01), as did the Exploratory arm (- 0.021 (SD = 0.008), p = 0.006). HbA1c at 26 weeks was significantly reduced in the Intervention arm when compared to standard care (- 0.038 (SD = 0.018), p = 0.04). There was some evidence suggesting prevention of progression to T2DM across the groups that received a DNA-based intervention (p = 0.06). Personalisation of dietary advice based on DNA did not result in glucose changes within the first 6 weeks but was associated with significant reduction of FPG and HbA1c at 26 weeks when compared to standard care. The DNA-based diet was effective regardless of intervention type, though results should be interpreted with caution due to the low sample size. These findings suggest that DNA-based dietary guidance is an effective intervention compared to standard care, but there is still a minimum timeframe of adherence to the intervention before changes in clinical outcomes become apparent.Trial Registration: www.clinicaltrials.gov.uk Ref: NCT03702465.

Importance of genetic sequencing studies in managing chronic neonatal diarrhea: a case report of a novel variant in the glucose-galactose transporter SLC5A1.

Introduction: Congenital glucose-galactose malabsorption (CGGM) is a rare autosomal recessive disorder that primarily causes chronic intractable diarrhea. This study aims to describe the clinical history, laboratory profile, diagnostic workflow, and management of the first patient reported with CGGM in Mexico. Methods: The case involves a Mexican female infant with recurrent admissions to the emergency room since birth due to chronic diarrhea. Results: The infant was born at term by C-section with a birth weight of 3.120 kg and height of 48 cm for consanguineous parents. She had been breastfed until day 5 of her life when she presented lethargy, diarrhea, abdominal discomfort, and jaundice. During the first evaluation at the emergency room, the significant laboratory finding was blood tyrosine elevation; afterward, amino acid and succinylacetone determinations were obtained, discarding tyrosinemia. When admitted to the hospital, an abdominal ultrasound detected a duplex collecting system. At this time, rice formula was introduced to the patient. She was discharged with jaundice improvement, but diarrhea persisted. Several formula changes had been made from rice to extensively hydrolyzed casein protein to whey-based, with no clinical improvement; the patient still had 10-12 excretions daily. In the second hospitalization, the patient presented anemia, severe dehydration, hyperammonemia, and renal tubular acidosis. A next-generation sequencing panel for inborn errors of metabolism and congenital diarrhea was performed, identifying a homozygous variant in SLC5A1 (c.1667T > C). The diagnosis of CGGM was made at 3 months of age. The infant was initially treated with a modular galactose-glucose-free formula with oil, fructose, casein, minerals, and vitamins until a commercial fructose-based formula was introduced. This led to a complete resolution of diarrhea and improved nutritional status. Discussion: Diagnosing CGGM is challenging for clinicians, and next-generation sequencing is a valuable tool for providing appropriate treatment. More detailed information on patients with this condition might lead to possible phenotype-genotype correlations. This case's primary clinical and biochemical findings were chronic diarrhea, anemia, jaundice, renal tubular acidosis, hyperammonemia, and initial hypertyrosinemia. Symptoms were resolved entirely with the fructose-based formula.

Risk-Benefit Comparison Between Endoloop and Endostapler Devices for the Closure of Appendiceal Stumps in Laparoscopic Appendectomy.

Introduction Acute appendicitis is a common cause of acute abdomen and the most frequent surgical emergency in the world. Since the nineteenth century, surgical resolution has been the most accepted treatment worldwide, and laparoscopic appendectomy is currently preferred as the treatment of choice because it has several benefits. The closure of the appendiceal stump is the most crucial step during appendectomy since its inadequate management can cause post-surgical complications. Throughout recent years, several methods have been proposed to perform this closure. This study was performed to compare the post-surgical outcomes of the use of endoloop and endostapler devices. Methods This is a retrospective study of 290 patients aged 18 to 83 who underwent laparoscopic appendectomy between 2016 and 2020. Demographic data, clinical history, tomographic findings, and laboratory data were collected, as well as appendicular base management technique, severity degree of appendicitis at hospital admission, postoperative complications at 30 days, hospital readmission, and in-hospital stay. Statistical tests and binary logistic regression analyses were used to identify risk factors, with a significance level of p<0.05. Results Demographic data and clinical history did not show statistically significant differences. The presence of a pre-surgical abscess with tomography was 1.58 times higher in the endostapler group. Post-surgical results showed that the use of endostapler devices represented a 2.7 times higher risk of post-surgical abscess. The endostapler group was also found to have 1.87 times the risk of post-surgical sepsis. Conclusion Our study shows that the use of an endoloop reduces the risk of postoperative abscess by 16.5% and protects against the development of post-surgical sepsis by 30%.

Age-friendly initiatives: Mexico.

While the implementation of these initiatives varies globally and continues to face low uptake in the global south, it is crucial to underscore key ongoing efforts, particularly in developing nations. This allows us to have knowledge about progress and identify areas that require more effective strategies to advance the cause of global healthy aging. The aim of this mini-review was to describe some of the key age-friendly initiatives made in Mexico through Governmental and Non-Governmental entities to promote healthy aging, at different levels of health and social institutions, covering the healthcare systems, community, and education.

Single-center study on features of immune mediated diseases in JAK2 (V617F)-positive myeloproliferative neoplasms and the potential therapeutic role of JAK inhibitors.

OBJECTIVE: The Janus Kinase (JAK) 2 (V617F) mutation is the most frequently detected in myeloproliferative neoplasms (MPN). JAK2(V617F) mutation displays a pro-inflammatory phenotype that may be associated to a higher risk of immune mediated diseases (IMIDs), thromboembolic complications or other cancers. We aimed to evaluate the prevalence and main features of both rheumatic and non-rheumatic IMIDs in a cohort of MPNs patients with JAK2 (V617F) mutation. METHODS: Study of all patients diagnosed with MPNs and JAK2 (V617F) mutation at a tertiary hospital in Northern Spain from 2004 to 2022. We focused on patients with rheumatic IMIDs to assess the time from IMIDs diagnosis to the detection of JAK2V617F mutation, the clinical course and severity of the disease, potential thrombotic complications, malignancies and therapeutic response. RESULTS: 130 patients (73 men/57 women; mean age, 70.1 ± 14.5 years) were identified. Fifty-four (41.5 %) patients were diagnosed with at least one IMID. The prevalence of rheumatic IMIDs was 7.7 % (n = 10), including rheumatoid arthritis (n = 4), polymyalgia rheumatica (n = 3), Sjögren syndrome (n = 1), antiphospholipid syndrome (n = 1) and autoinflammatory syndrome with WDR1 mutation (n = 1). Thrombotic complications were observed in 4 of these 10 patients. The clinical course of the rheumatic IMID was mild in most cases and responded to conventional immunosuppressive therapy. One patient was successfully treated with Baricitinib, a JAK1/JAK2 inhibitor. CONCLUSIONS: A high prevalence of rheumatic IMIDs is observed in patients with MPNs and JAK2 (V617F) mutation. JAK inhibitors might be a targeted therapy option in these patients.

In Silico Structural Protein Evaluation of the Phenylalanine Hydroxylase p.(Tyr77His) Variant Associated with Benign Hyperphenylalaninemia as Identified through Mexican Newborn Screening.

Hyperphenylalaninemia (HPA), which includes phenylketonuria (PKU), is a genetic autosomal recessive disorder arising from a deficiency in the enzyme named phenylalanine hydroxylase (PAH). Affected patients can experience severe and irreversible neurological impairments when phenylalanine (Phe) blood concentration exceeds 360 µmol/L (6 mg/dL). Here, we describe a female HPA patient who was born in Mexico to Cuban non-consanguineous parents and identified by newborn screening, and who bears the previously unreported PAH NM_000277.3(PAH):c.[229T>C];[1222C>T] or p.[Tyr77His];[Arg408Trp] genotype. At diagnosis, the patient showed a Phe blood level of 321 µmol/L (5.3 mg/dL), indicative of mild HPA. Neither of the PAH variants found in this patient had been previously reported in the mutational PAH spectrum of the Mexican population. The c.229T>C or p.(Tyr77His) PAH variant was previously related to mild HPA in the Swedish population. Our in silico structural analysis and molecular docking showed that mutated His 77 residue is located in the allosteric site of PAH at the interface of the two monomers. The PDBsum in silico tool predicted that this variant would cause minimal structural disturbance of the protein interface in the presence of Phe at the allosteric site. Docking studies revealed that these structural changes might be attenuated by the allosteric effect of Phe. Given the classic PKU phenotype conditioned by the "Celtic" or c.[1222C>T] or p.(Arg408Trp) PAH variant, which is the second variant in this patient, we propose that p.(Tyr77His) has a hypomorphic feature that could explain her mild HPA phenotype. Our results show the importance of following up on cases detected by NBS and the value of genetic studies and in silico tools that aid in the establishment of correct therapeutic strategies.

Estudio observacional de pacientes de una Unidad de Lípidos en tratamiento hipolipemiante para prevención primaria y secundaria: Estudio ULFI / Observational study of patients from a Lipid Unit on lipid-modifying therapy for primary and secondary prevention: ULFI Study

Objetivos: Evaluar la consecución de los objetivos de colesterol unido a lipoproteínas de baja densidad (cLDL) establecidos por las guías europeas de manejo de las dislipemias de 2019 y de prevención cardiovascular de 2021, describir el tratamiento hipolipemiante realizado, analizar el logro de los objetivos según el tratamiento hipolipemiante recibido y estudiar los factores asociados al éxito terapéutico. Diseño: Estudio observacional con 185 pacientes de ambos sexos de 18 años o más en tratamiento hipolipemiante para prevención primaria o secundaria, atendidos en la Unidad de Lípidos. Resultados: El 62,1% de los pacientes presentó un riesgo cardiovascular (RCV) muy alto según la guía de 2019, y el 60,5% según la de 2021. Del total de casos, el 22,7% logró un control adecuado del cLDL según la guía de 2019 y el 20% lo hizo de acuerdo con la de 2021. El 47,6% de los pacientes recibió tratamiento hipolipemiante de muy alta intensidad y el 14,1% lo recibió de extremadamente alta intensidad. El 76% de los sujetos con muy alto RCV en tratamiento hipolipemiante de extremadamente alta intensidad logró los objetivos terapéuticos de ambas guías. En el análisis multivariante, los factores asociados al éxito terapéutico fueron la presencia de enfermedad cardiovascular arteriosclerótica, la intensidad del tratamiento hipolipemiante, la diabetes mellitus y el consumo bajo o moderado de alcohol. Conclusiones: El control de la dislipemia es mejorable. Los tratamientos hipolipemiantes de alta o extremadamente alta intensidad pueden contribuir a optimizar el control de los pacientes con mayor RCV. (AU)

Objectives: To evaluate the achievement of low-density lipoprotein cholesterol (LDLc) goals established by the 2019 European Guidelines for the Management of Dyslipidemias and 2021 Cardiovascular Disease Prevention Guidelines, describe the lipid-lowering treatment received, analyze the achievement of goals according to the lipid-lowering treatment received and study the factors associated with therapeutic success. Design: Observational study that included 185 patients of both sexes aged 18 or over undergoing lipid-lowering treatment for primary or secondary prevention, attended at the Lipid Unit. Results: 62.1% of the patients had a very high cardiovascular risk (CVR) according to the 2019 guidelines, and 60.5% according to the 2021 guidelines. Of the total cases, 22.7% achieved adequate control of LDLc according to the 2019 guidelines and 20% according to the 2021 guidelines. 47.6% of the patients received very high intensity lipid-lowering treatment, and 14.1% received extremely high intensity lipid-lowering treatment. 76% of subjects with very high CVR on extremely high intensity lipid-lowering treatment achieved the therapeutic objectives of both guides. In the multivariate analysis, factors associated with therapeutic success were the presence of arteriosclerotic cardiovascular disease, the intensity of lipid-lowering treatment, diabetes mellitus, and low to moderate alcohol consumption. Conclusions: Dyslipidemia control is improvable. High or extremely high intensity lipid-lowering treatments can contribute to optimizing control of patients with higher CVR. (AU)

A Review of Disparities and Unmet Newborn Screening Needs over 33 Years in a Cohort of Mexican Patients with Inborn Errors of Intermediary Metabolism.

Advances in an early diagnosis by expanded newborn screening (NBS) have been achieved mainly in developed countries, while populations of middle- and low-income countries have poor access, leading to disparities. Expanded NBS in Mexico is not mandatory. Herein, we present an overview of the differences and unmet NBS needs of a group of Mexican patients with inborn errors of intermediary metabolism (IEiM), emphasizing the odyssey experienced to reach a diagnosis. We conducted a retrospective observational study of a historical cohort of patients with IEiM from a national reference center. A total of 924 patients with IEiM were included. Although 72.5% of the diseases identified are detectable by expanded NBS, only 35.4% of the patients were screened. The mortality in the unscreened group was almost two-fold higher than that in the screened group. Patients experienced a median diagnostic delay of 4 months, which is unacceptably long considering that to prevent disability and death, these disorders must be treated in the first days of life. Patients had to travel long distances to our reference center, contributing to their unacceptable diagnostic odyssey. This study highlights the urgent need to have an updated, expanded NBS program with adequate follow up in Mexico and promote the creation of regional medical care centers. We also provide compelling evidence that could prove valuable to decision makers overseeing public health initiatives for individuals impacted by IEiM from middle- and low-income countries.

Chirality-Induced Spin Selectivity in Supramolecular Chirally Functionalized Graphene.

Chiral graphene hybrid materials have attracted significant attention in recent years due to their various applications in the areas of chiral catalysis, chiral separation and recognition, enantioselective sensing, etc. On the other hand, chiral materials are also known to exhibit chirality-dependent spin transmission, commonly dubbed "chirality induced spin selectivity" or CISS. However, CISS properties of chiral graphene materials are largely unexplored. As such, it is not clear whether graphene is even a promising material for the CISS effect given its weak spin-orbit interaction. Here, we report the CISS effect in chiral graphene sheets, in which a graphene derivative (reduced graphene oxide or rGO) is noncovalently functionalized with chiral Fmoc-FF (Fmoc-diphenylalanine) supramolecular fibers. The graphene flakes acquire a "conformational chirality" postfunctionalization, which, combined with other factors, is presumably responsible for the CISS signal. The CISS signal correlates with the supramolecular chirality of the medium, which depends on the thickness of graphene used. Quite interestingly, the noncovalent supramolecular chiral functionalization of conductive materials offers a simple and straightforward methodology to induce chirality and CISS properties in a multitude of easily accessible advanced conductive materials.

Postoperative pain management in the elderly. Literature review

Timely post-operative pain management in elderly patients is critically important. Given their physiological changes and comorbidities, management in this group of patients is different from the rest of the population. Knowledge of potentially inappropriate medications (Beers criteria) is relevant because of the presence of comorbidities in this population. Although acetaminophen continues to be safe, non-steroidal anti-inflammatory agents produce several adverse effects which need to be considered before they are used. On the other hand, opioids continue to be one of the pillars in analgesia, with due consideration of their adverse affects and interactions, and the need for dose adjustments. Adequate postoperative pain management prevents adverse effects and the risk of developing chronic pain.

El manejo oportuno del dolor en la población anciana durante el periodo posoperatorio es de vital importancia. Este grupo de pacientes, dado sus cambios fisiológicos y comorbilidades, requieren un manejo diferente al resto de la población. Es relevante conocer cuáles medicamentos son potencialmente inapropiados para su uso (criterios de Beers) ante las comorbilidades de esta población. Si bien el acetaminofén continúa siendo seguro, los antiinflamatorios no esteroideos causan varios efectos adversos que ameritan consideración antes de su uso; por su parte, los opioides siguen siendo uno de los pilares analgésicos, teniendo en cuenta sus efectos adversos y valorando la necesidad de ajuste de dosis e interacciones. El adecuado manejo del dolor posoperatorio previene desenlaces adversos y el riesgo de cronificación.

SARS-CoV-2 accessory proteins involvement in inflammatory and profibrotic processes through IL11 signaling.

SARS-CoV-2, the cause of the COVID-19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. In this study, transcriptomics analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 is a member of the IL6 family of cytokines. IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease and functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID-19, evidenced altered profibrotic gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID-19 disease.

Impact of Obefazimod on Viral Persistence, Inflammation, and Immune Activation in People With Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy.

BACKGROUND: Persistence of viral reservoirs has been observed in people with human immunodeficiency virus (HIV), despite long-term antiretroviral therapy (ART), and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits human immunodeficiency virus type 1 (HIV-1) replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed people with HIV. METHODS: We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viremia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed people with HIV who received daily doses of 50 mg obefazimod for 12 weeks (n = 13) or 150 mg for 4 weeks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4 weeks. RESULTS: The 50- and 150-mg doses of obefazimod were safe, although the 150-mg dose showed inferior tolerability. The 150-mg dose reduced HIV-1 DNA (P = .008, median fold change = 0.6) and residual viremia in all individuals with detectable viremia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants and reduced the activation markers CD38, HLA-DR, and PD-1 and several inflammation biomarkers. CONCLUSIONS: The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents.

Chirality-induced spin selectivity in functionalized carbon nanotube networks: The role of spin-orbit coupling.

Spin-orbit coupling in a chiral medium is generally assumed to be a necessary ingredient for the observation of the chirality-induced spin selectivity (CISS) effect. However, some recent studies have suggested that CISS may manifest even when the chiral medium has zero spin-orbit coupling. In such systems, CISS may arise due to an orbital polarization effect, which generates an electromagnetochiral anisotropy in two-terminal conductance. Here, we examine these concepts using a chirally functionalized carbon nanotube network as the chiral medium. A transverse measurement geometry is used, which nullifies any electromagnetochiral contribution but still exhibits the tell-tale signs of the CISS effect. This suggests that CISS may not be explained solely by electromagnetochiral effects. The role of nanotube spin-orbit coupling on the observed pure CISS signal is studied by systematically varying nanotube diameter. We find that the magnitude of the CISS signal scales proportionately with the spin-orbit coupling strength of the nanotubes. We also find that nanotube diameter dictates the supramolecular chirality of the medium, which in turn determines the sign of the CISS signal.

25OHVitamin D Levels in a Canarian Pediatric Population with and without Type 1 Diabetes: The Role of Acidosis.

The role of Vitamin D in the development of type 1 diabetes (T1D) is controversial. The Canary Islands have the highest incidence of childhood-onset T1D in Spain and one of the highest in Europe. We aimed to evaluate 25OHVitamin D concentrations in a Canarian pediatric population, to assess the existence of seasonal variation, to study their association with T1D, and to evaluate the role of acidosis in its levels. In a retrospective, case-control study, we obtained data from 146 T1D patients (<15 years of age) and 346 control children; 25OHVitamin D concentrations were assessed in serum by automatic ChemiLuminescence ImmunoAssay technology. We found significantly higher 25OHVitamin D levels in the summer and autumn months and an inverse correlation between T1D and age; 25OHVitamin D sufficiency was similar in both groups (44.5% vs. 45.1%), with significant differences in the percentage of patients presenting vitamin D deficiency (11.6% (T1D) vs. 16.4% (controls)). When stratified according to the presence of ketoacidosis at sampling, only patients with acidosis showed lower 25OHVitamin D concentrations than controls. Despite its subtropical geographic location, Vitamin D deficiency is frequent in children in Gran Canaria, and 25OHVitamin D concentrations show seasonal variation. After adjusting for acidosis, no differences were found between children with and without T1D.