From the Gut to the Brain: Is Microbiota a New Paradigm in Parkinson's Disease Treatment?

Parkinson's disease (PD) is recognized as the second most prevalent primary chronic neurodegenerative disorder of the central nervous system. Clinically, PD is characterized as a movement disorder, exhibiting an incidence and mortality rate that is increasing faster than any other neurological condition. In recent years, there has been a growing interest concerning the role of the gut microbiota in the etiology and pathophysiology of PD. The establishment of a brain-gut microbiota axis is now real, with evidence denoting a bidirectional communication between the brain and the gut microbiota through metabolic, immune, neuronal, and endocrine mechanisms and pathways. Among these, the vagus nerve represents the most direct form of communication between the brain and the gut. Given the potential interactions between bacteria and drugs, it has been observed that the therapies for PD can have an impact on the composition of the microbiota. Therefore, in the scope of the present review, we will discuss the current understanding of gut microbiota on PD and whether this may be a new paradigm for treating this devastating disease.

Syphilis in pregnancy and adverse birth outcomes: A nationwide longitudinal study in Brazil.

OBJECTIVE: The present study aimed to evaluate the association between syphilis in pregnancy and low birth weight, small for gestational age, and preterm birth. METHODS: This longitudinal study used Brazilian National Information System for livebirths (SINASC) linked to the gestational syphilis cases from Notifiable Diseases Information System (SINAN) from 2011 to 2017. Descriptive statistics and logistic regression were used to compare the birth outcomes of pregnant women with and without syphilis. The study protocol was approved by the Research Ethics Committee of the Institute of Collective Health of the Federal University of Bahia (CAAE: registration no. 18022319.4.0000.5030). RESULTS: A total of 17 930 817 live births were included in the study. Of these, 155 214 (8.7/1000) were exposed to syphilis during pregnancy. Maternal syphilis increased the odds of low birth weight (aOR 1.88, 95% CI: 1.85-1.91), small for gestational age (aOR 1.53, 95% CI: 1.51-1.56), and preterm birth (aOR 1.35, 95% CI: 1.33-1.37). Higher odds were observed for pregnant women with VDRL titer ≥64 and untreated maternal syphilis when compared to mothers without syphilis. Analysis stratified by prenatal care showed higher odds for all adverse birth outcomes for mothers attending ≤6 prenatal appointments. CONCLUSION: Our findings showed a strong association between gestational syphilis and adverse birth outcomes with increased odds observed among women with higher VDRL titers, lack of treatment, and fewer prenatal appointments. These results highlight the need for adequate screening and treatment for gestational syphilis during pregnancy to mitigate the risk of adverse birth outcomes.

Spiritual Distress, Hopelessness, and Depression in Palliative Care: Simultaneous Concept Analysis.

Spiritual distress, hopelessness, and depression are concepts that are often used in palliative care. A simultaneous concept analysis (SCA) of these concepts is needed to clarify the terminology used in palliative care. Therefore, the aim of this study is to conduct a SCA of spiritual distress, hopelessness, and depression in palliative care. A SCA was performed using the methodology of Haase's model. A literature search was conducted in March 2020 and updated in April 2022 and April 2024. The search was performed on the following online databases: CINAHL with Full-Text, MEDLINE with Full-Text, MedicLatina, LILACS, SciELO, and PubMed. The search was achieved without restrictions on the date of publication. A total of 84 articles were included in this study. The results highlight that the three concepts are different but also share some overlapping points. Spiritual distress is embedded in the rupture of their spiritual/religious belief systems, a lack of meaning in life, and existential issues. Hopelessness is a sense of giving up and an inability to control and fix the patient's situation. Finally, depression is a state of sadness with a multi-impaired situation. In conclusion, refining the three concepts in palliative care is essential since it promotes clarification and enhances knowledge development towards intervention.

Treatment modalities and outcomes in pediatric Cushing's disease - report of three cases and literature review.

OBJECTIVES: Cushing's disease (CD) is a diagnostic and therapeutic challenge, especially in pediatric patients. CD, primarily caused by adrenocorticotropic hormone-secreting pituitary adenomas, manifests typically with growth retardation and weight gain. There are no published guidelines for pediatric patients. CASE PRESENTATION: We report three pediatric patients diagnosed with CD in a Portuguese tertiary hospital. All patients presented with hypercortisolism features. All patients underwent transsphenoidal pituitary surgery (TSS) as a first-choice treatment; however, it was unsuccessful in one patient and the other patients experienced recurrence. Patients were submitted to different approaches so basal serum cortisol levels could be achieved. Two of three patients achieved remission. CONCLUSIONS: TSS remains the first-line treatment yet challenging due to microadenomas and technical complexities. Medical therapy with agents like metyrapone or ketoconazole, pituitary radiotherapy, or bilateral adrenalectomy are, usually, second-line interventions, unless there is a contraindication to surgery. Our findings support the finding that a shorter hypothalamic-pituitary-adrenal axis recovery time increases the risk of recurrence of CD. Our cases illustrate the intricate management and variable outcomes of pediatric CD, underscoring the importance of multidisciplinary care and continuous surveillance.

A Pediatric Gastric Dieulafoy Lesion: A Case Report and Literature Review.

This report presents a case of a 16-year-old male with severe upper gastrointestinal bleeding caused by a Dieulafoy lesion (DL). A DL is a rare but life-threatening condition characterized by sudden and massive bleeding from a small arterial vessel in the gastrointestinal (GI) tract. Diagnosis is often made through esophagogastroduodenoscopy (EGD), which reveals an enlarged submucosal blood vessel. The patient was successfully treated with adrenaline injection and hemoclipping during EGD. This case highlights the importance of considering a DL as a potential cause of severe upper GI bleeding in pediatric patients and emphasizes the significance of early recognition and intervention to achieve favorable outcomes. Additional investigation is required to enhance our comprehension of the occurrence, etiology, and most effective approaches to managing DLs in pediatric patients.

Recent changes in growth trajectories: a population-based cohort study of over 5 million Brazilian children born between 2001 and 2014.

Background: There is limited evidence on recent trends in childhood growth trajectories in Low-/middle-income countries. We investigated how age-trajectories for height and Body Mass Index (BMI) have changed among Brazilian children born in two different time periods after 2000. Methods: We used a population-based cohort (part of the "Cohort of 100-Million Brazilians") created by the linkage of three Brazilian administrative databases: the Cadastro Único of the Federal Government, the National System of Live Births and the National Nutritional and Food Surveillance System. We included longitudinal data on 5,750,214 children who were 3 to <10 years of age and born between 2001 and 2014 (20,209,133 observations). We applied fractional polynomial models with random-effects to estimate mean height and BMI trajectories for children. Findings: Compared to children born in 2001-2007, the cohort born in 2008-2014 were on average taller, by a z-score of 0.15 in boys and 0.12 in girls. Their height trajectories shifted upwards, by approximately 1 cm in both sexes. Levels of BMI increased little, by a z-score of 0.06 (boys) and 0.04 (girls). Mean BMI trajectories also changed little. However, the prevalence of overweight/obesity increased between cohorts, e.g., from 26.8% to 30% in boys and 23.9%-26.6% in girls aged between 5 and <10 years. Interpretation: An increase of 1 cm in mean height of Brazilian children during a short period indicates the improvement in maternal and child health, especially those from low-income families due to the new health and welfare policies in Brazil. Although mean BMI changed little, the prevalence of child overweight/obesity slightly increased and remained high. Funding: This work was supported by National Council for Scientific and Technological Development - CNPq; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES; National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre; Society for the Study of Human Biology; Fundação de Amparo à Pesquisa do Estado de Minas Gerais - FAPEMIG; Departamento de Ciência e Tecnologia da Secretaria de Ciência, Tecnologia, Inovação e Complexo da Saúde do Ministério da Saúde - Decit/SECTICS/MS. The study also used resources from the Centre for Data and Knowledge Integration for Health (CIDACS), which receives funding from the Bill & Melinda Gates Foundation, the Wellcome Trust, the Health Surveillance Secretariat of the Ministry of Health and the Secretariat of Science and Technology of the State of Bahia (SECTI-BA).

Evaluating the relationship between conditional cash transfer programme on preterm births: a retrospective longitudinal study using the 100 million Brazilian cohort.

BACKGROUND: Preterm births increase mortality and morbidity during childhood and later life, which is closely associated with poverty and the quality of prenatal care. Therefore, income redistribution and poverty reduction initiatives may be valuable in preventing this outcome. We assessed whether receipt of the Brazilian conditional cash transfer programme - Bolsa Familia Programme, the largest in the world - reduces the occurrence of preterm births, including their severity categories, and explored how this association differs according to prenatal care and the quality of Bolsa Familia Programme management. METHODS: A retrospective cohort study was performed involving the first live singleton births to mothersenrolled in the 100 Million Brazilian Cohort from 2004 to 2015, who had at least one child before cohort enrollment. Only the first birth during the cohort period was included, but born from 2012 onward. A deterministic linkage with the Bolsa Familia Programme payroll dataset and a similarity linkage with the Brazilian Live Birth Information System were performed. The exposed group consisted of newborns to mothers who received Bolsa Familia from conception to delivery. Our outcomes were infants born with a gestational age < 37 weeks: (i) all preterm births, (ii) moderate-to-late (32-36), (iii) severe (28-31), and (iv) extreme (< 28) preterm births compared to at-term newborns. We combined propensity score-based methods and weighted logistic regressions to compare newborns to mothers who did and did not receive Bolsa Familia, controlling for socioeconomic conditions. We also estimated these effects separately, according to the adequacy of prenatal care and the index of quality of Bolsa Familia Programme management. RESULTS: 1,031,053 infants were analyzed; 65.9% of the mothers were beneficiaries. Bolsa Familia Programme was not associated with all sets of preterm births, moderate-to-late, and severe preterm births, but was associated with a reduction in extreme preterm births (weighted OR: 0.69; 95%CI: 0.63-0.76). This reduction can also be observed among mothers receiving adequate prenatal care (weighted OR: 0.66; 95%CI: 0.59-0.74) and living in better Bolsa Familia management municipalities (weighted OR: 0.56; 95%CI: 0.43-0.74). CONCLUSIONS: An income transfer programme for pregnant women of low-socioeconomic status, conditional to attending prenatal care appointments, has been associated with a reduction in extremely preterm births. These programmes could be essential in achieving Sustainable Development Goals.

Impacts of mining disasters on the ambulatory care of the Brazilian national health system: the cases of Mariana and Brumadinho/Brazil.

BACKGROUND: Disasters are events that bring with them effects that contribute to the disruption of the normality of a population and thus highlight the vulnerabilities of the health system. In Mariana and Brumadinho, the collapse of the dam of ore tailings brought with it several impacts that were felt in the short term and will be felt in the medium and long term. And that by being intensely intertwined with issues of economic and productive nature, has as its meaning an uninterrupted result of its activities. METHODS: Through the DATASUS database, two specific variables were chosen to perform the analysis: the approved amount and the approved value. For this research, a methodological device, the segmented regression line, was used to observe the influences that the disasters that occurred in Mariana and Brumadinho had on the ambulatory health systems. RESULTS: The results of the segmented regression line show that, with Mariana, the amount approved continued to grow throughout the period, which shows that there was no change because of the disaster. There was a reduction in spending. In Brumadinho, regarding the amount approved, there was an upward trend in the disaster's month, which did not change immediately afterwards, and regarding expenditure, the growth pattern was maintained in all three periods. Corroborating this data, the relative and absolute base elements show an increase in the amount approved and in the number of services provided at various posts compared with Minas Gerais. CONCLUSIONS: Based on the findings, it was possible to understand that although disasters exert an influence that may have some effect on the health system, the lack of significance sometimes cannot be interpreted as a lack of impact on the disaster. The segmented regression line outlines some effects that are not conclusive but indicative of a numerical interpretation and a trend interpretation.

voyAGEr, a free web interface for the analysis of age-related gene expression alterations in human tissues.

We herein introduce voyAGEr, an online graphical interface to explore age-related gene expression alterations in 49 human tissues. voyAGEr offers a visualisation and statistical toolkit for the finding and functional exploration of sex- and tissue-specific transcriptomic changes with age. In its conception, we developed a novel bioinformatics pipeline leveraging RNA sequencing data, from the GTEx project, encompassing more than 900 individuals. voyAGEr reveals transcriptomic signatures of the known asynchronous ageing between tissues, allowing the observation of tissue-specific age periods of major transcriptional changes, associated with alterations in different biological pathways, cellular composition, and disease conditions. Notably, voyAGEr was created to assist researchers with no expertise in bioinformatics, providing a supportive framework for elaborating, testing and refining their hypotheses on the molecular nature of human ageing and its association with pathologies, thereby also aiding in the discovery of novel therapeutic targets. voyAGEr is freely available at https://compbio.imm.medicina.ulisboa.pt/app/voyAGEr.

Mitochondrial Dysfunction in Advanced Maternal Aged Cumulus Cells: A Possible Link to ATP Synthase Impairment?

Age-related changes in the mitochondrial status of human cumulus cells (hCCs) impact oocyte quality; however, the relationship between hCC mitochondrial (dys)function and reproductive aging remains poorly understood. This study aimed to establish the interplay between hCC mitochondrial dysfunction and women's reproductive potential. In this investigation, 266 women were enrolled and categorized into two groups based on their age: a young group (<35 years old) and an advanced maternal age (AMA) group (≥35 years old). Comprehensive analysis of reproductive outcomes was conducted in our population. Various mitochondrial-related parameters were analyzed across distinct subsets. Specifically, mitochondrial membrane potential (∆Ψm) and mitochondrial mass were examined in 53 samples, mtDNA content in 25 samples, protein levels in 23 samples, bioenergetic profiles using an XF24 Extracellular Flux Analyzer in 6 samples, and levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) in 39 and 43 samples, respectively. In our study, the reproductive potential of AMA women sharply decreased, as expected. Additionally, an impairment in the mitochondrial function of hCCs in older women was observed; however, no differences were found in terms of mitochondrial content. Regarding oxidative phosphorylation, metabolic profiling of hCCs from AMA women indicated a decrease in respiratory capacity, which was correlated with an age-dependent decrease in the ATP synthase (ATP5A1) protein level. However, intracellular ROS and ATP levels did not differ between groups. In conclusion, our study indicates that age-related dysfunction in hCCs is associated with impaired mitochondrial function, and, although further studies are required, ATP synthase could be relevant in this impairment.

Vasodilation and Blood Pressure-Lowering Effect of 3-Demethyl-2-Geranyl-4-Prenylbellidifoline, a Xanthone Obtained from Garcinia achachairu, in Hypertensive Rats.

3-demethyl-2-geranyl-4-prenylbellidifoline (DGP), a natural xanthone isolated from Garcinia achachairu, has previously demonstrated remarkable diuretic and renal protective actions. The present study expands its actions on the cardiovascular system by evaluating its vasorelaxant and blood pressure-lowering effects in spontaneously hypertensive rats (SHRs). Aortic endothelium-intact (E+) preparations of SHRs pre-contracted by phenylephrine and exposed to cumulative concentrations of G. achachairu extract, fractions, and DGP exhibited a significant relaxation compared to vehicle-only exposed rings. The non-selective muscarinic receptor antagonist (atropine), the non-selective inhibitor of nitric oxide synthase (L-NAME), as well as the inhibitor of soluble guanylate cyclase (ODQ) altogether avoided DGP-induced relaxation. Tetraethylammonium (small conductance Ca2+-activated K+ channel blocker), 4-aminopyridine (a voltage-dependent K+ channel blocker), and barium chloride (an influx-rectifying K+ channel blocker) significantly reduced DGP capacity to induce relaxation without the interference of glibenclamide (an ATP-sensitive inward rectifier 6.1 and 6.2 K+ channel blocker). Additionally, administration of DGP, 1 mg/kg i.v., decreased the mean, systolic, and diastolic arterial pressures, and the heart rate of SHRs. The natural xanthone DGP showed promising potential as an endothelium-dependent vasorelaxant, operating through the nitric oxide pathway and potassium channels, ultimately significantly reducing blood pressure in hypertensive rats.

Characterization of Diclofenac-induced Renal Damage in Normotensive and Hypertensive Rats: A Comparative Analysis.

BACKGROUND: Diclofenac is the non-steroidal anti-inflammatory drug (NSAID) mostly prescribed worldwide, but it is highly associated with hypertension and acute kidney injury. Despite that, little information is available about the renal effects of diclofenac in hypertensive individuals, which led us to carry out this comparative study between the renal effects of this NSAID in normotensive (NTR) and spontaneously hypertensive rats (SHR). METHODS: Male Wistar NTR and SHR were orally treated with vehicle (V: 10 mL/kg) or diclofenac sodium (D: 100 mg/kg) once a day for 3 days. Urine volume, electrolytes excretion (Na+, K+, Cl-, and Ca2+), urea, creatinine, pH, and osmolarity were evaluated. Furthermore, blood samples and renal tissue were collected to perform biochemical and histological analysis. RESULTS: Diclofenac increased the renal corpuscle and bowman's space in the SHR, while no microscopic changes were observed in the renal tissue of NTR. Regarding the urinary parameters, diclofenac reduced urine volume, pH, osmolarity, and all electrolytes excretion, followed by decreased urea and creatinine levels in both lineages. Moreover, it also induced hyponatremia, hypokalemia, and hypocalcemia in SHR, while reduced glutathione-S-transferase activity, lipid hydroperoxides, and nitrite levels in renal tissue. CONCLUSIONS: The data presented herein demonstrated that diclofenac induces renal damage and impaired renal function in both NTR and SHR, but those effects are exacerbated in SHR, as seen by the histological changes and electrolytes balance disturbance, therefore, reinforcing that diclofenac may increase the risks of cardiovascular events in hypertensive patients.

Challenges in Extubation: A Case of a Non-removable Tracheal Tube Following Surgery.

This report details a challenging case of difficult extubation due to a lodged tracheal tube following surgery, presenting an unexpected and complex clinical situation. An inspection of the airway using videolaryngoscopy revealed an over-inflated cuff beneath the vocal cords. Initial efforts to deflate the cuff with various methods were unsuccessful. The situation was ultimately resolved through the intervention of an otolaryngology surgeon. This case not only reviews various mechanisms of difficult endotracheal tube removal reported in the literature, but also underscores the potential for serious complications and highlights the critical role of multidisciplinary collaboration in managing extubation challenges. Additionally, our manuscript discusses alternative strategies that can be employed in scenarios where an otolaryngology surgeon is not available, offering practical guidance for anesthesiologists confronted with similar situations.

Identifying biologically implausible values in big longitudinal data: an example applied to child growth data from the Brazilian food and nutrition surveillance system.

BACKGROUND: Several strategies for identifying biologically implausible values in longitudinal anthropometric data have recently been proposed, but the suitability of these strategies for large population datasets needs to be better understood. This study evaluated the impact of removing population outliers and the additional value of identifying and removing longitudinal outliers on the trajectories of length/height and weight and on the prevalence of child growth indicators in a large longitudinal dataset of child growth data. METHODS: Length/height and weight measurements of children aged 0 to 59 months from the Brazilian Food and Nutrition Surveillance System were analyzed. Population outliers were identified using z-scores from the World Health Organization (WHO) growth charts. After identifying and removing population outliers, residuals from linear mixed-effects models were used to flag longitudinal outliers. The following cutoffs for residuals were tested to flag those: -3/+3, -4/+4, -5/+5, -6/+6. The selected child growth indicators included length/height-for-age z-scores and weight-for-age z-scores, classified according to the WHO charts. RESULTS: The dataset included 50,154,738 records from 10,775,496 children. Boys and girls had 5.74% and 5.31% of length/height and 5.19% and 4.74% of weight values flagged as population outliers, respectively. After removing those, the percentage of longitudinal outliers varied from 0.02% (<-6/>+6) to 1.47% (<-3/>+3) for length/height and from 0.07 to 1.44% for weight in boys. In girls, the percentage of longitudinal outliers varied from 0.01 to 1.50% for length/height and from 0.08 to 1.45% for weight. The initial removal of population outliers played the most substantial role in the growth trajectories as it was the first step in the cleaning process, while the additional removal of longitudinal outliers had lower influence on those, regardless of the cutoff adopted. The prevalence of the selected indicators were also affected by both population and longitudinal (to a lesser extent) outliers. CONCLUSIONS: Although both population and longitudinal outliers can detect biologically implausible values in child growth data, removing population outliers seemed more relevant in this large administrative dataset, especially in calculating summary statistics. However, both types of outliers need to be identified and removed for the proper evaluation of trajectories.

Naringen's Effects on Diuresis and Prevention of Urolithiasis in Hypertensive Rats.

This research demonstrates the diuretic effect of naringenin, a flavanone aglycone found in citrus, on spontaneously hypertensive female and male rats (SHR). The data reinforces existing literature findings that male SHR exhibits higher systolic blood pressure than age-matched females. Urine volume assessed over 8 hours was lower when obtained from SHR males than females. When these animals were orally treated with different doses of naringenin (0.1-1 mg/kg), this increased urinary volume in both genders at the highest dose tested. In contrast, the lowest dose promoted a significant natriuretic effect. The other electrolytes analyzed in urine were not significantly altered, except potassium excretion, which was shown to be increased in the urine of SHR males. Furthermore, naringenin showed promise in reducing calcium oxalate (CaOx) crystal formation in an in vitro model, presenting potential advantages in lithiasis prevention.

Ethnoracial disparities in childhood growth trajectories in Brazil: a longitudinal nationwide study of four million children.

BACKGROUND: The literature contains scarce data on inequalities in growth trajectories among children born to mothers of diverse ethnoracial background in the first 5 years of life. OBJECTIVE: We aimed to investigate child growth according to maternal ethnoracial group using a nationwide Brazilian database. METHODS: A population-based retrospective cohort study employed linked data from the CIDACS Birth Cohort and the Brazilian Food and Nutrition Surveillance System (SISVAN). Children born at term, aged 5 years or younger who presented two or more measurements of length/height (cm) and weight (kg) were followed up between 2008 and 2017. Prevalence of stunting, underweight, wasting, and thinness were estimated. Nonlinear mixed effect models were used to estimate childhood growth trajectories, among different maternal ethnoracial groups (White, Asian descent, Black, Pardo, and Indigenous), using the raw measures of weight (kg) and height (cm) and the length/height-for-age (L/HAZ) and weight-for-age z-scores (WAZ). The analyses were also adjusted for mother's age, educational level, and marital status. RESULTS: A total of 4,090,271 children were included in the study. Children of Indigenous mothers exhibited higher rates of stunting (26.74%) and underweight (5.90%). Wasting and thinness were more prevalent among children of Pardo, Asian, Black, and Indigenous mothers than those of White mothers. Regarding children's weight (kg) and length/height (cm), those of Indigenous, Pardo, Black, and Asian descent mothers were on average shorter and weighted less than White ones. Regarding WAZ and L/HAZ growth trajectories, a sharp decline in average z-scores was evidenced in the first weeks of life, followed by a period of recovery. Over time, z-scores for most of the subgroups analyzed trended below zero. Children of mother in greater social vulnerability showed less favorable growth. CONCLUSION: We observed racial disparities in nutritional status and childhood growth trajectories, with children of Indigenous mothers presenting less favorable outcomes compared to their White counterparts. The strengthening of policies aimed at protecting Indigenous children should be urgently undertaken to address systematic ethnoracial health inequalities.

Successful management of bilateral orbital metastases from invasive lobular breast cancer with abemaciclib and letrozole: a case report and literature review.

Breast cancer is a significant global health concern, contributing to substantial morbidity and mortality among women. Hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer constitutes a considerable proportion of cases, and significant advancements have been made in its management. CDK4/6 inhibitors (CDK4/6is) are a new targeted therapy that has demonstrated efficacy in adjuvant, advanced and metastatic settings. The propensity of lobular breast carcinomas for estrogen-rich sites, such as periocular tissues and orbital fat, may explain their tendency for orbital metastases. Current treatment strategies for these cases are predominantly palliative, and the prognosis remains poor. This article presents a unique case of a 51-year-old female with progressive right periorbital edema, pain, and limited ocular motility. An imaging work-up showed bilateral intra and extraconal orbital infiltration, which was biopsied. The histopathologic analysis disclosed mild chronic inflammatory infiltrate with thickened fibrous tissue and moderately differentiated lobular carcinoma cells, positive for GATA3 and CK7 markers, with 100% of tumor nuclei expressing estrogen receptors (ER+). A systemic evaluation showed a multicentric nodular formation in both breasts. Further diagnostic assessments unveiled an HR+/HER2- bilateral lobular breast carcinoma with synchronous bilateral orbital metastases. Systemic treatment was initiated with abemaciclib 150mg twice daily and letrozole 2.5mg once a day. However, this regimen was interrupted due to toxicity. After two weeks, treatment was resumed with a reduced abemaciclib dose (100mg twice daily) alongside letrozole, with a reasonable tolerance. Nearly two years after the initial diagnosis of inoperable metastatic cancer, the patient remains on the same systemic treatment regimen with no signs of invasive disease. This case report is the first of a patient presenting with bilateral orbital metastases from bilateral lobular breast cancer, showing an impressive and sustained response to a first-line treatment regimen combining abemaciclib and letrozole. A literature review on bilateral orbital metastases from breast cancer is also presented.

Association of interpregnancy interval with adverse pregnancy outcomes according to the outcomes of the preceding pregnancy: a longitudinal study with 4.7 million live births from Brazil.

Background: Earlier studies have proposed a link between the Interpregnancy Interval (IPI) and unfavorable birth outcomes. However, it remains unclear if the outcomes of previous births could affect this relationship. We aimed to investigate whether the occurrence of adverse outcomes-small for gestational age (SGA), preterm birth (PTB), and low birth weight (LBW)-at the immediately preceding pregnancy could alter the association between IPI and the same outcomes at the subsequent pregnancy. Methods: We used a population-based linked cohort from Brazil (2001-2015). IPI was measured as the difference, in months, between the preceding birth and subsequent conception. Outcomes included SGA (<10th birthweight percentile for gestational age and sex), LBW (<2500 g), and PTB (gestational age <37 weeks). We calculated risk ratios (RRs), using the IPI of 18-22 months as the reference IPI category, we also stratified by the number of adverse birth outcomes at the preceding pregnancy. Findings: Among 4,788,279 births from 3,804,152 mothers, absolute risks for subsequent SGA, PTB, and LBW were higher for women with more adverse outcomes in the preceding delivery. The RR of SGA and LBW for IPIs <6 months were greater for women without previous adverse outcomes (SGA: 1.44 [95% Confidence Interval (CI): 1.41-1.46]; LBW: 1.49 [1.45-1.52]) compared to those with three previous adverse outcomes (SGA: 1.20 [1.10-1.29]; LBW: 1.24 [1.15-1.33]). IPIs ≥120 months were associated with greater increases in risk for LBW and PTB among women without previous birth outcomes (LBW: 1.59; [1.53-1.65]; PTB: 2.45 [2.39-2.52]) compared to women with three adverse outcomes at the index birth (LBW: 0.92 [0.78-1.06]; PTB: 1.66 [1.44-1.88]). Interpretation: Our study suggests that women with prior adverse outcomes may have higher risks for adverse birth outcomes in subsequent pregnancies. However, risk changes due to differences in IPI length seem to have a lesser impact compared to women without a prior event. Considering maternal obstetric history is essential in birth spacing counseling. Funding: Wellcome Trust225925/Z/22/Z.

Adipose tissue derived stem cell secretome induces motor and histological gains after complete spinal cord injury in Xenopus laevis and mice.

Mesenchymal stem cell-based therapies have been studied for spinal cord injury (SCI) treatment due to their paracrine action upon damaged tissues. MSCs neuroregenerative role may relate to the contents of their secretome in anti-inflammatory cytokines and growth-permissive factors. We propose using the secretome of MSCs isolated from the adipose tissue-adipose tissue-derived stem cells (ASCs) as a cell-free based therapy for SCI. In vivo studies were conducted in two SCI models, Xenopus laevis and mice, after complete spinal cord transection. Our results on both models demonstrated positive impacts of ASC secretome on their functional recovery which were correlated with histopathological markers of regeneration. Furthermore, in our mice study, secretome induced white matter preservation together with modulation of the local and peripheral inflammatory response. Altogether, these results demonstrate the neuroregenerative and potential for inflammatory modulation of ASC secretome suggesting it as a good candidate for cell-free therapeutic strategies for SCI.

betAS: intuitive analysis and visualization of differential alternative splicing using beta distributions.

Next-generation RNA sequencing allows alternative splicing (AS) quantification with unprecedented resolution, with the relative inclusion of an alternative sequence in transcripts being commonly quantified by the proportion of reads supporting it as percent spliced-in (PSI). However, PSI values do not incorporate information about precision, proportional to the respective AS events' read coverage. Beta distributions are suitable to quantify inclusion levels of alternative sequences, using reads supporting their inclusion and exclusion as surrogates for the two distribution shape parameters. Each such beta distribution has the PSI as its mean value and is narrower when the read coverage is higher, facilitating the interpretability of its precision when plotted. We herein introduce a computational pipeline, based on beta distributions accurately modeling PSI values and their precision, to quantitatively and visually compare AS between groups of samples. Our methodology includes a differential splicing significance metric that compromises the magnitude of intergroup differences, the estimation uncertainty in individual samples, and the intragroup variability, being therefore suitable for multiple-group comparisons. To make our approach accessible and clear to both noncomputational and computational biologists, we developed betAS, an interactive web app and user-friendly R package for visual and intuitive differential splicing analysis from read count data.