Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect.

Photoswitchable molecules exhibit light-dependent biological activity which allow us to control the therapeutic effect of drugs with high precision. Such molecules could solve some of the limitations of anticancer drugs by providing a localised effect in the tumour. Histone deacetylase inhibitors (HDACis) constitute a promising drug class for oncology whose application is often limited by a lack of selectivity. Herein, we developed photoswitchable HDACis based on a hemithioindigo scaffold. We established synthetic routes to access them and determined the optimal conditions for isomerisation and their thermal stability. We then optimised their enzyme activity through three rounds of re-design to identify examples that are up to 6-fold more active under illumination than in the dark. We also confirmed that our best derivative reduces the viability of HeLa cells only under illumination. All in all, we disclose a series of derivatives containing a hemithioindigo moiety, which display a light-dependent effect on both HDAC inhibition and cancer cell viability.

Structural genomic variation and behavioral interactions underpin a balanced sexual mimicry polymorphism.

How phenotypic diversity originates and persists within populations are classic puzzles in evolutionary biology. While balanced polymorphisms segregate within many species, it remains rare for both the genetic basis and the selective forces to be known, leading to an incomplete understanding of many classes of traits under balancing selection. Here, we uncover the genetic architecture of a balanced sexual mimicry polymorphism and identify behavioral mechanisms that may be involved in its maintenance in the swordtail fish Xiphophorus birchmanni. We find that ∼40% of X. birchmanni males develop a "false gravid spot," a melanic pigmentation pattern that mimics the "pregnancy spot" associated with sexual maturity in female live-bearing fish. Using genome-wide association mapping, we detect a single intergenic region associated with variation in the false gravid spot phenotype, which is upstream of kitlga, a melanophore patterning gene. By performing long-read sequencing within and across populations, we identify complex structural rearrangements between alternate alleles at this locus. The false gravid spot haplotype drives increased allele-specific expression of kitlga, which provides a mechanistic explanation for the increased melanophore abundance that causes the spot. By studying social interactions in the laboratory and in nature, we find that males with the false gravid spot experience less aggression; however, they also receive increased attention from other males and are disdained by females. These behavioral interactions may contribute to the maintenance of this phenotypic polymorphism in natural populations. We speculate that structural variants affecting gene regulation may be an underappreciated driver of balanced polymorphisms across diverse species.

Calibrating Observational Health Record Data Against a Randomized Trial.

Importance: The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this. Objective: To pilot an emulation of the KEYNOTE-189 RCT using a commercially available electronic health record (EHR) data source. Design, Setting, and Participants: This retrospective cohort study used an EHR database spanning from April 2007 to February 2023. Follow-up began on treatment initiation and proceeded until an outcome event, loss to follow-up, end of data, or end of study period (640 days). The population-based cohort was ascertained from EHRs provided by 52 health systems across the US. Eligibility criteria were defined as closely as possible to the benchmark RCT. Patients with non-small cell lung cancer initiating first-line treatment for metastatic disease were included. Patients with evidence of squamous non-small cell lung cancer, primary nonlung malignant neoplasms, or identified EGFR/ALK variations were excluded. Data were analyzed from June to October 2023. Exposures: Initiation of first-line pembrolizumab and chemotherapy and chemotherapy alone. Chemotherapy in both groups was defined as a combination of pemetrexed and platinum-based (carboplatin or cisplatin) therapy. Main Outcomes and Measures: Outcomes of interest were 12-month survival probability and mortality hazard ratio (HR). Results: A total of 1854 patients (mean [SD] age, 63.7 [9.6] years; 971 [52.4%] men) were eligible, including 589 patients who initiated pembrolizumab and chemotherapy and 1265 patients who initiated chemotherapy only. The cohort included 364 Black patients (19.6%) and 1445 White patients (77.9%). The 12-month survival probabilities were 0.60 (95% CI, 0.54-0.65) in the pembrolizumab group and 0.58 (95% CI, 0.55-0.62) in the chemotherapy-only group, compared with 0.69 (95% CI, 0.64-0.74) in the KEYNOTE-189 pembrolizumab group and 0.49 (95% CI, 0.42-0.56) in the KEYNOTE-189 chemotherapy-only group. The mortality HR was 0.95 (95% CI, 0.78-1.16), compared with 0.49 (95% CI, 0.38-0.64) in the KEYNOTE-189 RCT. Conclusions and Relevance: In this cohort study piloting an RCT emulation, results were incongruous with the benchmark trial. Differences in patient treatment and data capture between the RCT and EHR populations, confounding by indication, treatment crossover, and accuracy of captured diagnoses may explain these findings. Future feasibility assessments will require data sources to have important oncology-specific measures curated.

Folate and cobalamin status, indicators, modulators, interactions, and reference ranges from early pregnancy until birth: the Reus-Tarragona birth cohort study.

BACKGROUND: Folate and cobalamin status, although essential for pregnancy, are not routinely monitored in prenatal care. OBJECTIVES: To investigate folate and cobalamin status and determinants throughout pregnancy, in the absence of mandatory folic acid (FA) fortification. METHODS: In a cohort study of 831 mothers recruited at <12 gestational weeks (GW), plasma folate, total homocysteine (tHcy), cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA), red blood cell folate (RBCF), and the combined cobalamin status indicator (cB12) were determined at ≤12, 15, 24-27, 34 GW, labor and in the cord. Single nucleotide polymorphisms affecting folate and cobalamin status were determined. FA, cobalamin, micronutrient supplement use, and dietary folate and cobalamin intake (food frequency questionnaire) were recorded. Folate and cobalamin status predictors were assessed by multiple linear regression analysis. RESULTS: Only 36.1% of the participants took FA preconceptionally and 47.4% and 7.3% had suboptimal RBCF (<906 nmol/L) and plasma cobalamin status (≤221 pmol/L), respectively, at ≤12 GW. RBCF determinants included planned pregnancy, FA supplementation, plasma cobalamin, and methylenetetrahydrofolate (MTHFR) 677C>T genotype. Cobalamin supplementation was positively associated with plasma cobalamin and early holoTC. Smoking and BMI were inversely associated with plasma cobalamin and early holoTC, but none were associated with MMA. Only participants with the MTHFR 677TT genotype, exceeding FA supplement recommendations, improved their folate status (interaction term: B (95% CI):0.15 (0.01, 0.29), P = 0.032). Smoking was inversely associated with plasma cobalamin status in participants with the methionine synthase reductase (MTRR) 524CC genotype only (interaction term:0.07 (0.01, 0.04), P = 0.014). Mothers with low early pregnancy cobalamin status and also those with bigger newborns, had lower cobalamin status at labor. CONCLUSIONS: Suboptimal early pregnancy folate or cobalamin status affected 47.4% and 7.3% of the participants, respectively. The MTHFR 677TT genotype predicted folate status throughout pregnancy. Smoking and BMI were negatively associated with cobalamin status throughout pregnancy. Clinical Trial Registry number and website where it was obtained: NCT01778205. www. CLINICALTRIALS: gov.

Swordtail fish hybrids reveal that genome evolution is surprisingly predictable after initial hybridization.

Over the past 2 decades, biologists have come to appreciate that hybridization, or genetic exchange between distinct lineages, is remarkably common-not just in particular lineages but in taxonomic groups across the tree of life. As a result, the genomes of many modern species harbor regions inherited from related species. This observation has raised fundamental questions about the degree to which the genomic outcomes of hybridization are repeatable and the degree to which natural selection drives such repeatability. However, a lack of appropriate systems to answer these questions has limited empirical progress in this area. Here, we leverage independently formed hybrid populations between the swordtail fish Xiphophorus birchmanni and X. cortezi to address this fundamental question. We find that local ancestry in one hybrid population is remarkably predictive of local ancestry in another, demographically independent hybrid population. Applying newly developed methods, we can attribute much of this repeatability to strong selection in the earliest generations after initial hybridization. We complement these analyses with time-series data that demonstrates that ancestry at regions under selection has remained stable over the past approximately 40 generations of evolution. Finally, we compare our results to the well-studied X. birchmanni × X. malinche hybrid populations and conclude that deeper evolutionary divergence has resulted in stronger selection and higher repeatability in patterns of local ancestry in hybrids between X. birchmanni and X. cortezi.

Indicators of Cobalamin Status During Pregnancy, Pregnancy Outcome and Long-Term Effects on Offspring Health.

BACKGROUND: Little attention has been given to prenatal cobalamin insufficiency in settings where dietary cobalamin intake is presumed adequate, such as populations with habitual intake of foods from animal sources. RESULTS: However, low cobalamin status in women of fertile age has been reported in Europe, United States, and Canada. In India, where cobalamin deficiency is highly prevalent, it has been associated with an increased risk of miscarriage, intrauterine growth retardation, as well as insulin resistance and lower neurodevelopment scores in the offspring. Low cobalamin status in pregnancy has been associated with similar outcomes as those reported in the Indian studies although the evidence is scant and conflicting. CONCLUSIONS: Consideration should be given to maternal cobalamin status in the context of prevention of adverse pregnancy outcomes as well as cobalamin insufficiency both in the mother and the offspring during lactation. Further attention is now justified with the increasing tendency toward plant-based diets. Reference intervals for cobalamin status during each trimester of pregnancy are needed and further investigation of the long-term conse-quences of low cobalamin status during pregnancy for health and development in the offspring is warranted.

Plain language titleInadequate cobalamin status during critical periods of growth and development can have negative consequences on maternal and childhood health.

Effect of Time-Varying Exposure to School-Based Health Promotion on Adiposity in Childhood.

BACKGROUND: The results of most school-based health promotion initiatives are inconclusive. OBJECTIVES: This trial assessed the effect of time-varying exposures to a multicomponent school-based health promotion intervention (SI! Program) on adiposity markers. METHODS: A total of 48 schools in Madrid (Spain) were cluster randomized to receive the SI! Program through elementary education grades 1 to 6 (E1-6, 12 schools, 459 children), 1 to 3 (E1-3, 12 schools, 513 children), or 4 to 6 (E4-6, 12 schools, 419 children) or to receive the standard curriculum (control, 12 schools, 379 children). The primary endpoint was the between-group difference at 3- and 6-year follow-up in the change from baseline in adiposity markers and the overall knowledge-attitudes-habits (KAH) score. RESULTS: At 3-year follow-up, children who had the intervention showed significantly lower increases than the control group in z-scores for body mass index (BMI), waist-to-height ratio (WHtR), and waist circumference (WC) (zBMI: -0.09; 95% CI: -0.16 to -0.03; P = 0.003; zWC and zWHtR: -0.19; 95% CI: -0.28 to -0.10; P < 0.001). At 6-year follow-up, the beneficial trend in zWC and zWHtR was maintained in the E1-6 and E1-3 groups: difference zWC control vs E1-6 (-0.19; 95% CI: -0.36 to -0.03; P = 0.020), control vs E1-3 (-0.22; 95% CI: -0.38 to -0.06; P = 0.009); difference zWHtR control vs E1-6 (-0.24; 95% CI: -0.41 to -0.06; P = 0.009), and control vs E1-3 (-0.29; 95% CI: -0.47 to -0.11; P = 0.001). No significant between-group differences were found in the change of overall KAH score. CONCLUSIONS: Early elementary school interventions may be more effective than later interventions on abdominal adiposity. Further research should assess the sustainability effects of school-based health promotion programs.

Can Microfluidics Improve Sperm Quality? A Prospective Functional Study.

The same sperm selection techniques in assisted reproduction clinics have remained largely unchanged despite their weaknesses. Recently, microfluidic devices have emerged as a novel methodology that facilitates the sperm selection process with promising results. A prospective case-control study was conducted in two phases: 100 samples were used to compare the microfluidic device with Density Gradient, and another 100 samples were used to compare the device with the Swim-up. In the initial phase, a significant enhancement in progressive motility, total progressive motile sperm count, vitality, morphology, and sperm DNA fragmentation were obtained for the microfluidic group compared to Density Gradient. Nevertheless, no statistically significant differences were observed in sperm concentration and chromatin structure stability. In the subsequent phase, the microfluidic group exhibited significant increases in sperm concentration, total progressive motile sperm count, and vitality compared to Swim-up. However, non-significant differences were seen for progressive motility, morphology, DNA structure stability, and DNA fragmentation. Similar trends were observed when results were stratified into quartiles. In conclusion, in a comparison of microfluidics with standard techniques, an improvement in sperm quality parameters was observed for the microfluidic group. However, this improvement was not significant for all parameters.

Pervasive gene flow despite strong and varied reproductive barriers in swordtails.

One of the mechanisms that can lead to the formation of new species occurs through the evolution of reproductive barriers. However, recent research has demonstrated that hybridization has been pervasive across the tree of life even in the presence of strong barriers. Swordtail fishes (genus Xiphophorus) are an emerging model system for studying the interface between these barriers and hybridization. We document overlapping mechanisms that act as barriers between closely related species, X. birchmanni and X. cortezi, by combining genomic sequencing from natural hybrid populations, artificial crosses, behavioral assays, sperm performance, and developmental studies. We show that strong assortative mating plays a key role in maintaining subpopulations with distinct ancestry in natural hybrid populations. Lab experiments demonstrate that artificial F1 crosses experience dysfunction: crosses with X. birchmanni females were largely inviable and crosses with X. cortezi females had a heavily skewed sex ratio. Using F2 hybrids we identify several genomic regions that strongly impact hybrid viability. Strikingly, two of these regions underlie genetic incompatibilities in hybrids between X. birchmanni and its sister species X. malinche. Our results demonstrate that ancient hybridization has played a role in the origin of this shared genetic incompatibility. Moreover, ancestry mismatch at these incompatible regions has remarkably similar consequences for phenotypes and hybrid survival in X. cortezi × X. birchmanni hybrids as in X. malinche × X. birchmanni hybrids. Our findings identify varied reproductive barriers that shape genetic exchange between naturally hybridizing species and highlight the complex evolutionary outcomes of hybridization.

High-Risk Congenital Heart Disease in Pregnancy.

High-risk congenital heart disease (CHD) in pregnancy presents a complex clinical challenge. With improved medical care and increased survival rates, a growing population of adults with complex CHD are surviving to adulthood, including women of reproductive age. This chapter focuses on risk stratification and management of pregnant women with high-risk CHD, emphasizing the importance of considering both anatomical and physiological complexity. Maternal physiological changes, such as blood volume increase, cardiac output changes, and alterations in vascular resistance, can significantly impact high-risk CHD patients. Management of high-risk CHD in pregnancy necessitates a multidisciplinary approach and individualized care.

2-iodohexadecanal induces autophagy during goiter involution.

BACKGROUND: Iodine plays an important role in thyroid physiology and biochemistry. The thyroid is capable of producing different iodolipids such as 2-iodohexadecanal (2-IHDA). Data from different laboratories have shown that 2-IHDA inhibits several thyroid parameters and it has been postulated as intermediary on the action of iodide function. OBJECTIVE: To explore different mechanisms involved during the involution of the hyperplastic thyroid gland of Wistar rats towards normality induced by 2-IHDA. METHODS: Goiter was induced by the administration of MMI for 10 days, then the treatment was discontinued and Wistar rats were injected with 2-IHDA or KI. RESULTS: During involution, 2-IHDA treatment reduced PCNA expression compared to spontaneous involution. KI treatment caused an increase of Caspase-3 activity and TUNEL-positive cells. In contrast, 2-IHDA failed to alter this value but induced an increase of LC3B expression. KI but not 2-IHDA led to an increase in peroxides levels, catalase and glutathione peroxidase activity. CONCLUSIONS: We demonstrated that 2-IHDA, in contrast to iodide, did not lead to an increase in oxidative stress or apoptosis induction, indicating that the involution triggered by 2-IHDA in Wistar rats, is primarily due to the inhibition of cell proliferation and the induction of autophagy.

Selenium bioavailability modulates the sensitivity of thyroid cells to iodide excess.

INTRODUCTION: Iodide is an essential micronutrient for the synthesis of thyroid hormones and its imbalance is involved in the origin of different thyroid pathological processes. Selenium (Se) is another essential trace element that contributes to thyroid preservation through the control of the redox homeostasis. Different studies have demonstrated that sodium-iodide-symporter (NIS) is downregulated in the presence of iodide excess and Se supplementation reverses this effect. We also demonstrated that NOX4-derived ROS are involved in NIS repression induced by iodide excess. The aim of this study was to investigate how Se bioavailability is decisive in the sensitivity to iodide excess on a differentiated rat thyroid cell line (FRTL-5). RESULTS: We demonstrated that siRNA-mediated silencing of Nox4 suppressed AKT phosphorylation induced by iodide excess. Iodide increases TGF-ß1 mRNA expression, AKT phosphorylation, ROS levels and decreases GPX1 and TXRND1 mRNAs expression while Se reversed these effects. Furthermore, iodide induced Nrf2 transcriptional activity only in Se-supplemented cultures, suggesting that Se positively influences Nrf2 activation and selenoenzyme response in FRTL-5. Se, also inhibited NF-κB phosphorylation induced by iodide excess. In addition, we found that iodide excess decreased total phosphatase activity and PTP1B and PTEN mRNA expression. Se supply restored only PTEN mRNA expression. Finally, we studied the 2-α-iodohexadecanal (2-IHD) effects since it has been proposed as intermediary of iodide action on thyroid autoregulation. 2-IHD stimulated PI3K/AKT activity and reduced NIS expression by a ROS-independent mechanism. Also, we found that 2-IHD increased TGF-ß1 mRNA and TGF-ß inhibitor (SB431542) reverses the 2-IHD inhibitory effect on NIS mRNA expression, suggesting that TGF-ß1 signaling pathway could be involved. Although Se reduced 2-IHD-induced TGFB1 levels, it could not reverse its inhibitory effect on NIS expression. CONCLUSION: Our study suggests that Se bioavailability may improve the expression of antioxidant genes through the activation of Nrf2, interfere in PI3K/AKT signaling and NIS expression by redox modulation.

Assisted reproductive technology: what are the cardiovascular risks for women?

INTRODUCTION: Infertility affects 15% of women of reproductive age in the United States. The use of assisted reproductive technology (ART) has been rising globally, as well as a growing recognition of reproductive factors that increase risk for cardiovascular disease (CVD). AREAS COVERED: Women with infertility who use ART are more likely to have established CVD risk factors, such as obesity, dyslipidemia, hypertension, and diabetes. They are also more likely to experience adverse pregnancy outcomes, which are associated with both peripartum and long-term cardiovascular complications. ART may lead to increased cardiometabolic demands due to ovarian stimulation, pregnancy itself, and higher rates of multifetal gestation. Preeclampsia risk appears greater with frozen rather than fresh embryo transfers. EXPERT OPINION: The use of ART and its association with long term CVD has not been well-studied. Future prospective and mechanistic studies investigating the association of ART and CVD risk may help determine causality. Nevertheless, CVD risk screening is critical pre-pregnancy and during pregnancy to reduce pregnancy complications that elevate future CVD risk. This also offers a window of opportunity to connect patients to longitudinal care for early management of cardiometabolic risk profile and initiation of preventive lifestyle and pharmacotherapy interventions tailored toward patient-specific risk factors.

A geospatial analysis of cardiometabolic diseases and their risk factors considering environmental features in a midsized city in Argentina.

New approaches to the study of cardiometabolic disease (CMD) distribution include analysis of built environment (BE), with spatial tools as suitable instruments. We aimed to characterize the spatial dissemination of CMD and the associated risk factors considering the BE for people attending the Non-Invasive Cardiology Service of Hospital Nacional de Clinicas in Córdoba City, Argentina during the period 2015-2020. We carried out an observational, descriptive, cross-sectional study performing non-probabilistic convenience sampling. The final sample included 345 people of both sexes older than 35 years. The CMD data were collected from medical records and validated techniques and BE information was extracted from Landsat-8 satellite products. A geographic information system (GIS) was constructed to assess the distribution of CMD and its risk factors in the area. Out of the people sampled, 41% showed the full metabolic syndrome and 22.6% only type-2 diabetes mellitus (DM2), a cluster of which was evidenced in north-western Córdoba. The risk of DM2 showed an association with high values of the normalized difference vegetation index (NDVI) (OR= 0.81; 95% CI: - 0.30 to 1.66; p=0.05) and low normalized difference built index (NDBI) values that reduced the probability of occurrence of DM2 (OR= -1.39; 95% CI: -2.62 to -0.17; p=0.03). Considering that the results were found to be linked to the environmental indexes, the study of BE should include investigation of physical space as a fundamental part of the context in which people develop medically within society. The novel collection of satellite-generated information on BE proved efficient.

Female-specific risk factors of parity and menopause age and risk of carotid plaque: the multi-ethnic study of atherosclerosis.

BACKGROUND: Female-specific factors of grand multiparity (≥5 births) and early menopause age are associated with an increased risk of cardiovascular disease (CVD). However, mechanisms are incompletely understood. Carotid plaque is a marker of subclinical atherosclerosis and associated with increased CVD risk. We evaluated the association of female-specific factors with plaque burden. METHODS: We included 2,313 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis, free of clinical CVD, whose parity and menopause age were ascertained by questionnaires and carotid plaque measured by ultrasound at baseline and 10 years later. Parity was categorized as nulliparity (reference), 1-2, 3-4 and ≥5 live births. Menopause age was categorized as <45, 45-49, 50-54 (reference) and ≥55 years. Multivariable regression was performed to evaluate the association of parity and menopause age with carotid plaque presence (yes/no) and extent [carotid plaque score (CPS)]. RESULTS: The mean age was 64±9 years; 52.3% had prevalent carotid plaque at baseline. Compared to nulliparity, grand multiparity was significantly associated with prevalent carotid plaque after adjustment for CVD risk factors (prevalence ratio 1.17 (95% CI 1.03-1.35)) and progression of CPS over 10 years [percent difference 13% (95% CI 3-23)]. There was not any significant association of menopause age with carotid plaque presence or progression in fully-adjusted models. CONCLUSION: In a multiethnic cohort, grand multiparity was independently associated with carotid plaque presence and progression. Early menopause, a known risk factor for CVD, was not captured by carotid plaque in this study. These findings may have implications for refining CVD risk assessment in women.

School-Based Cardiovascular Health Promotion in Adolescents: A Cluster Randomized Clinical Trial.

Importance: School-based interventions offer an opportunity for health promotion in adolescence. Objective: To assess the effect of 2 multicomponent educational health promotion strategies of differing duration and intensity on adolescents' cardiovascular health (CVH). Design, Setting, and Participants: The SI! Program for Secondary Schools is a 4-year cluster randomized clinical intervention trial conducted in 24 secondary schools from Barcelona and Madrid, Spain, from September 7, 2017, to July 31, 2021. Eligible participants were adolescents enrolled in the first grade of secondary school. Interventions: Schools and their participants were randomized to receive a health promotion intervention (SI! Program) over 4 school years (long-term intervention [LTI], 8 schools, 412 adolescents) or 2 school years (short-term intervention [STI], 8 schools, 504 adolescents) or to receive the standard curriculum (control, 8 schools, 441 adolescents). Main outcome and Measures: The primary end point was the between-group difference at 2 and 4 years in the change from baseline of the overall CVH score, as defined by the American Heart Association (range, 0-14 points, with a higher score indicating a healthier CVH profile). Intervention effects were tested with multilevel mixed-effects models. A complete-case intention-to-treat analysis was performed as the primary analysis. Results: Of the randomized students, the study enrolled 1326 adolescents (684 [51.6%] boys, mean [SD] age, 12.5 [0.4] years at recruitment) with a study completion rate of 86.0%. Baseline overall CVH scores were 10.3 points in the LTI group, 10.6 points in the STI group, and 10.5 points in the control group. After 2 years, at halfway through the LTI and at the end of the STI, the difference in the CVH score change was 0.44 points (95% CI, 0.01-0.87; P = .04) between the LTI group and the control group and 0.18 points (95% CI, -0.25 to 0.61; P = .39) between the STI group and the control group. At 4 years, differences for the LTI and STI groups vs control were 0.12 points (LTI: 95% CI, -0.19 to 0.43; P = .42) and 0.13 points (STI: 95% CI, -0.17 to 0.44; P = .38). No adverse events were reported. Conclusions and Relevance: Overall, the tested school-based health promotion strategies in this randomized clinical trial had a neutral effect on the CVH of the adolescents. Although there was evidence of a marginal beneficial effect at a point halfway through implementation in the LTI group, such a benefit was not noted at 4 years. Further research is warranted into the efficacy of school-based health promotion programs. Trial Registration: ClinicalTrials.gov Identifier: NCT03504059.

Rediscovery of Rubuspendulus Rusby (Rosaceae) and a new record for the flora of Ecuador and Peru.

We report the rediscovery of Rubuspendulus Rusby, "Mora India", described in 1933 from Colombia and not mentioned again until the present study. We also update its distribution with eight new localities in Colombia, seven in Ecuador and one in Peru, being a new record for the flora of the latter two countries. This is the first time that R.pendulus' stipules and flowers are found and detailed through a botanical description, illustrations and photographs. Rubuspendulus is morphologically differentiated from R.bogotensis Benth., R.mollifrons Focke, R.porphyromallos Focke and R.urticifolius Poir., with whom it was previously confused and we give a brief explanation on the type specimen status of R.mollifrons and R.porphyromallos.

Neuroimaging Correlates of Post-Traumatic Stress Disorder in Traumatic Brain Injury: A Systematic Review of the Literature.

Neuroimaging is widely utilized in studying traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). The risk for PTSD is greater after TBI than after non-TBI trauma, and PTSD is associated with worse outcomes after TBI. Studying the neuroimaging correlates of TBI-related PTSD may provide insights into the etiology of both conditions and help identify those TBI patients most at risk of developing persistent symptoms. The objectives of this systematic review were to examine the current literature on neuroimaging in TBI-related PTSD, summarize key findings, and highlight strengths and limitations to guide future research. A Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) compliant literature search was conducted in PubMed (MEDLINE®), PsycINFO, Embase, and Scopus databases prior to January 2022. The database query yielded 4486 articles, which were narrowed based on specified inclusion criteria to a final cohort of 16 studies, composed of 854 participants with TBI. There was no consensus regarding neuroimaging correlates of TBI-related PTSD among the included articles. A small number of studies suggest that TBI-related PTSD is associated with white matter tract changes, particularly in frontotemporal regions, as well as changes in whole-brain networks of resting-state connectivity. Future studies hoping to identify reliable neuroimaging correlates of TBI-related PTSD would benefit from ensuring consistent case definition, preferably with clinician-diagnosed TBI and PTSD, selection of comparable control groups, and attention to imaging timing post-injury. Prospective studies are needed and should aim to further differentiate predisposing factors from sequelae of TBI-related PTSD.