Multitier mechanics control stromal adaptations in the swelling lymph node.

Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.

ABP1-TMK auxin perception for global phosphorylation and auxin canalization.

The phytohormone auxin triggers transcriptional reprogramming through a well-characterized perception machinery in the nucleus. By contrast, mechanisms that underlie fast effects of auxin, such as the regulation of ion fluxes, rapid phosphorylation of proteins or auxin feedback on its transport, remain unclear1-3. Whether auxin-binding protein 1 (ABP1) is an auxin receptor has been a source of debate for decades1,4. Here we show that a fraction of Arabidopsis thaliana ABP1 is secreted and binds auxin specifically at an acidic pH that is typical of the apoplast. ABP1 and its plasma-membrane-localized partner, transmembrane kinase 1 (TMK1), are required for the auxin-induced ultrafast global phospho-response and for downstream processes that include the activation of H+-ATPase and accelerated cytoplasmic streaming. abp1 and tmk mutants cannot establish auxin-transporting channels and show defective auxin-induced vasculature formation and regeneration. An ABP1(M2X) variant that lacks the capacity to bind auxin is unable to complement these defects in abp1 mutants. These data indicate that ABP1 is the auxin receptor for TMK1-based cell-surface signalling, which mediates the global phospho-response and auxin canalization.

Proteomic characterization of isolated Arabidopsis clathrin-coated vesicles reveals evolutionarily conserved and plant-specific components.

In eukaryotes, clathrin-coated vesicles (CCVs) facilitate the internalization of material from the cell surface as well as the movement of cargo in post-Golgi trafficking pathways. This diversity of functions is partially provided by multiple monomeric and multimeric clathrin adaptor complexes that provide compartment and cargo selectivity. The adaptor-protein assembly polypeptide-1 (AP-1) complex operates as part of the secretory pathway at the trans-Golgi network (TGN), while the AP-2 complex and the TPLATE complex jointly operate at the plasma membrane to execute clathrin-mediated endocytosis. Key to our further understanding of clathrin-mediated trafficking in plants will be the comprehensive identification and characterization of the network of evolutionarily conserved and plant-specific core and accessory machinery involved in the formation and targeting of CCVs. To facilitate these studies, we have analyzed the proteome of enriched TGN/early endosome-derived and endocytic CCVs isolated from dividing and expanding suspension-cultured Arabidopsis (Arabidopsis thaliana) cells. Tandem mass spectrometry analysis results were validated by differential chemical labeling experiments to identify proteins co-enriching with CCVs. Proteins enriched in CCVs included previously characterized CCV components and cargos such as the vacuolar sorting receptors in addition to conserved and plant-specific components whose function in clathrin-mediated trafficking has not been previously defined. Notably, in addition to AP-1 and AP-2, all subunits of the AP-4 complex, but not AP-3 or AP-5, were found to be in high abundance in the CCV proteome. The association of AP-4 with suspension-cultured Arabidopsis CCVs is further supported via additional biochemical data.

Tension-dependent stabilization of E-cadherin limits cell-cell contact expansion in zebrafish germ-layer progenitor cells.

Tension of the actomyosin cell cortex plays a key role in determining cell-cell contact growth and size. The level of cortical tension outside of the cell-cell contact, when pulling at the contact edge, scales with the total size to which a cell-cell contact can grow [J.-L. Maître et al., Science 338, 253-256 (2012)]. Here, we show in zebrafish primary germ-layer progenitor cells that this monotonic relationship only applies to a narrow range of cortical tension increase and that above a critical threshold, contact size inversely scales with cortical tension. This switch from cortical tension increasing to decreasing progenitor cell-cell contact size is caused by cortical tension promoting E-cadherin anchoring to the actomyosin cytoskeleton, thereby increasing clustering and stability of E-cadherin at the contact. After tension-mediated E-cadherin stabilization at the contact exceeds a critical threshold level, the rate by which the contact expands in response to pulling forces from the cortex sharply drops, leading to smaller contacts at physiologically relevant timescales of contact formation. Thus, the activity of cortical tension in expanding cell-cell contact size is limited by tension-stabilizing E-cadherin-actin complexes at the contact.

Somatic RIT1 delins in arteriovenous malformations hyperactivate RAS-MAPK signaling amenable to MEK inhibition.

Arteriovenous malformations (AVM) are benign vascular anomalies prone to pain, bleeding, and progressive growth. AVM are mainly caused by mosaic pathogenic variants of the RAS-MAPK pathway. However, a causative variant is not identified in all patients. Using ultra-deep sequencing, we identified novel somatic RIT1 delins variants in lesional tissue of three AVM patients. RIT1 encodes a RAS-like protein that can modulate RAS-MAPK signaling. We expressed RIT1 variants in HEK293T cells, which led to a strong increase in ERK1/2 phosphorylation. Endothelial-specific mosaic overexpression of RIT1 delins in zebrafish embryos induced AVM formation, highlighting their functional importance in vascular development. Both ERK1/2 hyperactivation in vitro and AVM formation in vivo could be suppressed by pharmacological MEK inhibition. Treatment with the MEK inhibitor trametinib led to a significant decrease in bleeding episodes and AVM size in one patient. Our findings implicate RIT1 in AVM formation and provide a rationale for clinical trials with targeted treatments.

Effectiveness of mRNA Covid-19 Vaccine among U.S. Health Care Personnel.

BACKGROUND: The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting. METHODS: We conducted a test-negative case-control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19-like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose). RESULTS: The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval [CI], 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer-BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (<50 years or ≥50 years), race and ethnic group, presence of underlying conditions, and level of patient contact. Estimates of vaccine effectiveness were lower during weeks 9 through 14 than during weeks 3 through 8 after receipt of the second dose, but confidence intervals overlapped widely. CONCLUSIONS: The BNT162b2 and mRNA-1273 vaccines were highly effective under real-world conditions in preventing symptomatic Covid-19 in health care personnel, including those at risk for severe Covid-19 and those in racial and ethnic groups that have been disproportionately affected by the pandemic. (Funded by the Centers for Disease Control and Prevention.).

Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.

BACKGROUND & AIMS: Intestinal fibrosis is a significant complication of Crohn's disease (CD). Gut microbiota reactive Th17 cells are crucial in the pathogenesis of CD; however, how Th17 cells induce intestinal fibrosis is still not completely understood. METHODS: In this study, T-cell transfer model with wild-type (WT) and Areg-/- Th17 cells and dextran sulfate sodium (DSS)-induced chronic colitis model in WT and Areg-/- mice were used. CD4+ T-cell expression of AREG was determined by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of AREG on proliferation/migration/collagen expression in human intestinal myofibroblasts was determined. AREG expression was assessed in healthy controls and patients with CD with or without intestinal fibrosis. RESULTS: Although Th1 and Th17 cells induced intestinal inflammation at similar levels when transferred into Tcrßxδ-/- mice, Th17 cells induced more severe intestinal fibrosis. Th17 cells expressed higher levels of AREG than Th1 cells. Areg-/- mice developed less severe intestinal fibrosis compared with WT mice on DSS insults. Transfer of Areg-/- Th17 cells induced less severe fibrosis in Tcrßxδ-/- mice compared with WT Th17 cells. Interleukin (IL)6 and IL21 promoted AREG expression in Th17 cells by activating Stat3. Stat3 inhibitor suppressed Th17-induced intestinal fibrosis. AREG promoted human intestinal myofibroblast proliferation, motility, and collagen I expression, which was mediated by activating mammalian target of rapamycin and MEK. AREG expression was increased in intestinal CD4+ T cells in fibrotic sites compared with nonfibrotic sites from patients with CD. CONCLUSIONS: These findings reveal that Th17-derived AREG promotes intestinal fibrotic responses in experimental colitis and human patients with CD. Thereby, AREG might serve as a potential therapeutic target for fibrosis in CD.

A Boolean algebra for genetic variants.

MOTIVATION: Beyond identifying genetic variants, we introduce a set of Boolean relations, which allows for a comprehensive classification of the relations of every pair of variants by taking all minimal alignments into account. We present an efficient algorithm to compute these relations, including a novel way of efficiently computing all minimal alignments within the best theoretical complexity bounds. RESULTS: We show that these relations are common, and many non-trivial, for variants of the CFTR gene in dbSNP. Ultimately, we present an approach for the storing and indexing of variants in the context of a database that enables efficient querying for all these relations. AVAILABILITY AND IMPLEMENTATION: A Python implementation is available at https://github.com/mutalyzer/algebra/tree/v0.2.0 as well as an interface at https://mutalyzer.nl/algebra.

Effect of Host-Switching on the Ecological and Evolutionary Patterns of Parasites.

Speciation via host-switching is a macroevolutionary process that emerges from a microevolutionary dynamic where individual parasites switch hosts, establish a new association, and reduce reproductive contact with the original parasite lineage. Phylogenetic distance and geographic distribution of the hosts have been shown to be determinants of the capacity and opportunity of the parasite to change hosts. Although speciation via host-switching has been reported in many host-parasite systems, its dynamic on the individual, population and community levels is poorly understood. Here we propose a theoretical model to simulate parasite evolution considering host-switching events on the microevolutionary scale, taking into account the macroevolutionary history of the hosts, to evaluate how host-switching can affect ecological and evolutionary patterns of parasites in empirical communities at regional and local scales. In the model, parasite individuals can switch hosts under variable intensity and have their evolution driven by mutation and genetic drift. Mating is sexual and only individuals that are sufficiently similar can produce offspring. We assumed that parasite evolution occurs at the same evolutionary time scale as their hosts, and that the intensity of host-switching decreases as the host species differentiate. Ecological and evolutionary patterns were characterized by the turnover of parasite species among host species, and parasite evolutionary tree imbalance respectively. We found a range of host-switching intensity that reproduces ecological and evolutionary patterns observed in empirical communities. Our results showed that turnover decreased as host-switching intensity increased, with low variation among the model replications. On the other hand, tree imbalance showed wide variation and non-monotonic tendency. We concluded that tree imbalance was sensitive to stochastic events, whereas turnover may be a good indicator of host-switching. We found that local communities corresponded to higher host-switching intensity when compared to regional communities, highlighting that spatial scale is a limitation for host-switching. [Dispersal of parasites, opportunity and capacity of interaction, phylogenetic conservatism, and community structure.].

Outcome of bleomycin electrosclerotherapy of slow-flow malformations in adults and children.

OBJECTIVES: To evaluate the safety and clinical outcome of bleomycin electrosclerotherapy (BEST) for treating extracranial slow-flow malformations. METHODS: In this retrospective investigation of a multicenter cohort presenting symptomatic slow-flow malformations, patient records were analyzed with respect to procedural details and complications. A treatment-specific, patient-reported questionnaire was additionally evaluated, obtained 3-12 months after the last treatment, to assess the subjective outcomes, including mobility, aesthetic aspects, and pain, as well as the occurrence of postprocedural skin hyperpigmentation. All outcome parameters were compared according to patients' age. RESULTS: Overall, 325 BEST treatments were performed in 233 patients after intralesional and/or intravenous bleomycin injection. The total complication rate was 10.2% (33/325), including 29/352 (8.9%) major complications. Patient-reported mobility decreased in 10/133 (8.8%), was stable in 30/113 (26.5%), improved in 48/113 (42.5%), and was rated symptom-free in 25/113 (22.1%) patients. Aesthetic aspects were rated impaired compared to baseline in 19/113 (16.8%), stable in 21/133 (18.6%), improved in 62/113 (54.9%), and perfect in 11/133 (9.7%) patients. Postprocedural skin hyperpigmentation occurred in 78/113 (69%) patients, remaining unchanged in 24/78 (30.8%), reduced in 51/78 (65.5%), and completely resolved in 3/78 (3.8%) patients. The median VAS pain scale was 4.0 (0-10) preprocedural and 2.0 (0-9) postprocedural. Children/adolescents performed significantly better in all parameters compared to adults (≥ 16 years) (mobility, p = 0.011; aesthetic aspects, p < 0.001; pain, p < 0.001). CONCLUSIONS: BEST is effective for treating slow-flow vascular malformations, with few but potentially significant major complications. Regarding patient-reported outcomes, children seem to benefit better compared to older patients, suggesting that BEST should not be restricted to adults. CLINICAL RELEVANCE STATEMENT: Bleomycin electrosclerotherapy is a safe and effective approach and therapy should not be restricted to adults due to good clinical outcomes in children.

Initial Hemorrhage Control Procedure for Splenic Injuries May Affect Risk of Venous Thromboembolism.

INTRODUCTION: Venous thromboembolism (VTE) continues to be a major cause of morbidity in trauma. It is unclear whether the type of hemorrhage control procedure (i.e., splenectomy versus angioembolization) is associated with an increased risk of VTE. We hypothesize that hemodynamically stable patients undergoing angioembolization for blunt high-grade splenic injuries have lower rates of VTE compared to those undergoing splenectomy. METHODS: The American College of Surgeons Trauma Quality Program dataset from 2017 to 2019 was queried to identify all patients with American Association for the Surgery of Trauma grade 3-5 blunt splenic injuries. Outcomes including VTE rates were compared between those who were managed with splenectomy versus angioembolization. Propensity score matching (1:1) was performed adjusting for age, sex, initial vital signs, Injury Severity Score, and splenic injury grade. RESULTS: The analysis included 4698 matched patients (splenectomy [n = 2349] and angioembolization [n = 2349]). The median (interquartile range) age was 41 (27-58) years and 69% were male. Patients were well matched between groups. Angioembolization was associated with significantly lower VTE than splenectomy (2.2% versus 3.4%, P = 0.010) despite less use of VTE chemoprophylaxis (70% versus 80%, P < 0.001), as well as a relative delay in initiation of chemoprophylaxis (44 h versus 33 h, P < 0.001). Hospital and intensive care unit length of stay and mortality were also significantly lower in the angioembolization group. CONCLUSIONS: Angioembolization is associated with a significantly lower incidence of VTE than splenectomy. Thus, angioembolization should be considered for initial management of hemodynamically stable patients with high-grade blunt splenic injuries in whom laparotomy is not otherwise indicated.

Nationwide Analysis of Firearm Injury Versus Other Penetrating Trauma: It's Not All the Same Caliber.

INTRODUCTION: Ballistic injuries cause both a temporary and permanent cavitation event, making them far more destructive and complex than other penetrating trauma. We hypothesized that global injury scoring and physiologic parameters would fail to capture the lethality of gunshot wounds (GSW) compared to other penetrating mechanisms. METHODS: The 2019 American College of Surgeons Trauma Quality Programs participant use file was queried for the mortality rate for GSW and other penetrating mechanisms. A binomial logistic regression model ascertained the effects of sex, age, hypotension, tachycardia, mechanism, Glasgow Coma Scale, ISS, and volume of blood transfusion on the likelihood of mortality. Subgroup analyses examined isolated injuries by body regions. RESULTS: Among 95,458 cases (82% male), GSW comprised 46.4% of penetrating traumas. GSW was associated with longer hospital length of stay (4 [2-9] versus 3 [2-5] days), longer intensive care unit length of stay (3 [2-6] versus 2 [2-4] days), and more ventilator days (2 [1-4] versus 2 [1-3]) compared to stab wounds, all P < 0.001. The model determined that GSW was linked to increased odds of mortality compared to stab wounds (odds ratio 4.19, 95% confidence interval 3.55-4.93). GSW was an independent risk factor for acute kidney injury, acute respiratory distress syndrome, venous thromboembolism, sepsis, and surgical site infection. CONCLUSIONS: Injury scoring systems based on anatomical or physiological derangements fail to capture the lethality of GSW compared to other mechanisms of penetrating injury. Adjustments in risk stratification and reporting are necessary to reflect the proportion of GSW seen at each trauma center. Improved classification may help providers develop quality processes of care. This information may also help shape public discourse on this highly lethal mechanism.

Survival of In-Hospital Cardiopulmonary Arrest in Trauma Patients.

INTRODUCTION: Relative to other hospitalized patients, trauma patients are younger with fewer comorbidities, but the incidence and outcomes of in-hospital cardiopulmonary arrest (IHCA) with cardiopulmonary resuscitation (CPR) in this population is unknown. Therefore, we aimed to investigate factors associated with survival in trauma patients after IHCA to test the hypothesis that compared to other hospitalized patients, trauma patients with IHCA have improved survival. METHODS: Retrospective review of the Trauma Quality Improvement Program database 2017 to 2019 for patients who had IHCA with CPR. Primary outcome was survival to hospital discharge. Secondary outcomes were in-hospital complications, hospital length of stay, intensive care unit length of stay, and ventilator days. Data were compared with univariate and multivariate analyses at P < 0.05. RESULTS: In 22,346,677 admitted trauma patients, 14,056 (0.6%) received CPR. Four thousand three hundred seventy-seven (31.1%) survived to discharge versus 26.4% in a national sample of all hospitalized patients (P < 0.001). In trauma patients, median age was 55 y, the majority were male (72.2%). Mortality was higher for females versus males (70.3% versus 68.3%, P = 0.026). Multivariate regression showed that older age 1.01 (95% confidence interval (CI) 1.01-1.02), Hispanic ethnicity 1.21 (95% CI 1.04-1.40), and penetrating trauma 1.51 (95% CI 1.32-1.72) were risk factors for mortality, while White race was a protective factor 0.36 (95% CI 0.14-0.89). CONCLUSIONS: This is the first study to show that the incidence of IHCA with CPR is approximately six in 1000 trauma admissions and 31% survive to hospital discharge, which is higher than other hospitalized patients. Age, gender, racial, and ethnic disparities also influence survival.

Timing of Pediatric Incarcerated Inguinal Hernia Repair: A Review of Nationwide Readmissions Data.

INTRODUCTION: In pediatric patients, incarcerated inguinal hernias are often repaired on presentation. We hypothesize that in appropriate patients, repair may be safely deferred. METHODS: The Nationwide Readmissions Database was used to identify pediatric patients (aged < 18 y) with incarcerated inguinal hernia from 2010 to 2014. Patients were stratified by management approach (Early Repair versus Deferral). Overall frequencies of these operative strategies were calculated. Propensity score matching was then performed to control for patient age, comorbidities, perinatal conditions, and congenital anomalies. Outcomes including complications, surgical procedures, and readmissions were compared. Outpatient surgeries were not assessed. RESULTS: Among 6148 total patients with incarcerated inguinal hernia, the most common strategy was to perform Early Repair (88% versus 12% Deferral). Following propensity score matching, the cohort included 1288 patients (86% male, average age 1.7 ± 4.1 years). Deferral was associated with equivalent rates of readmission within one year (13% versus 15%, P = 0.143), but higher readmissions within the first 30 days (7% versus 3%, P = 0.002) than Early Repair. Deferral patients had lower rates of orchiectomy (2% versus 5%, P = 0.001), wound infections (< 2% versus 2%, P = 0.020), and other infections (7% versus 15%, P < 0.001). The frequency of other complications including bowel resection, oophorectomy, testicular atrophy, sepsis, and pneumonia were equivalent between groups. Three percent of Deferrals had a diagnosis of incarceration on readmission. CONCLUSIONS: Deferral of incarcerated inguinal hernia repair at index admission is associated with higher rates of hospital readmissions within the first 30 days but equivalent readmission within the entire calendar year. These patients are at risk of repeat incarceration but have significantly lower rates of orchiectomy than their counterparts who undergo inguinal hernia repair at the index admission. We propose that prospective studies be performed to identify good candidates for Elective Deferral following manual reduction and overnight observation. Such studies must capture outpatient surgical outcomes.

International Perspective on Extremity Vascular Trauma in Children: A Scoping Review.

OBJECTIVE: Extremity vascular trauma in children can result in significant morbidity and mortality. Most published studies have focused on supracondylar humeral fracture related injuries, with little focus on other injuries. This scoping review describes the current state of knowledge on paediatric vascular injuries in the upper and lower limbs, excluding injuries related to supracondylar humeral fractures. METHODS: MEDLINE, PubMed, Web of Science, and Cochrane databases were searched for relevant studies evaluating the epidemiology, diagnosis, management, and outcomes of upper and lower limb vascular trauma in those aged under 18 years. Studies related to supracondylar humeral fractures were excluded. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for Scoping Reviews was used. RESULTS: A total of 39 studies was included, all of which were retrospective, and 74% of which were based in North America or Europe. Extremity vascular trauma was reported to cause 0.6 - 4.4% of all paediatric trauma admissions, with penetrating mechanisms and upper limb injuries being the most common. Operative intervention was reported in 80 - 100% of children in the included studies. Primary repair was the most commonly reported operative intervention, followed by interposition graft and bypass graft. Synthetic graft use was less commonly reported (incidence range 0.5 - 33%). Lower limb fasciotomies and amputations were not commonly reported (incidence range 0 - 23% and 0 - 13%, respectively). The mortality rate appeared low, with 23 studies reporting no deaths (incidence range 0 - 4%). Complications were reported inconsistently, with no uniform outcome or follow up measures used. CONCLUSION: The incidence of extremity vascular trauma appears low in children, with penetrating mechanisms and upper extremity injuries appearing to dominate. Most studies are from high income countries, with probable selection bias towards those treated by operative intervention. Prospective studies are required focusing on patterns of injury, rates of operative and endovascular intervention, and long term outcomes.

Epoxiconazole degradation in water samples: a comparative study of Fenton, photo-Fenton, solar photo-Fenton, and solar photolysis processes.

Epoxiconazole (EPO) is classified as a persistent organic pollutant due to its ability to persist in the environment for prolonged periods. Its degradation is pivotal in mitigating its environmental impact. This investigation focuses on assessing the degradation of EPO using various methodologies, namely Fenton, photo-Fenton, solar photo-Fenton, and solar photolysis, conducted in both Milli-Q water and groundwater. These experiments encompassed evaluations at both the standard pH typically used in photo-Fenton reactions and the natural pH levels inherent to the respective aqueous environments. Additionally, EPO degradation products were analyzed after a 60-min reaction. Notably, in systems utilizing groundwater, the inclusion of additional iron was unnecessary, as the naturally occurring iron content in the groundwater facilitated the intended processes. Specifically, in Milli-Q water, solar photo-Fenton demonstrated an EPO degradation efficiency of 97%. Furthermore, the substitution of Milli-Q water with groundwater in Fenton-like processes did not significantly affect the efficacy of EPO degradation. These findings underscore the potential of solar photo-Fenton as an economically viable and environmentally sustainable strategy for EPO degradation.

Risk of Neuropsychiatric Symptoms Among People Who Develop Cognitive Impairment With and Without a History of Post-traumatic Stress Disorder.

We aimed to prospectively assess the change in neuropsychiatric symptoms among people who develop cognitive impairment and have a history of post-traumatic stress disorder (PTSD). We analyzed longitudinal data from the National Alzheimer's Coordinating Center Unified Data Set (March 2015 to December 2021). Analyses included individuals who were cognitively normal and who had nonmissing assessment of PTSD at the initial visit and had at least 1 follow-up visit with cognitive impairment. We compared the difference in the mean neuropsychiatric symptom score at the first Unified Data Set visit versus the first visit with a Clinical Dementia Rating of 0.5 between those with and without a history of PTSD. The mean neuropsychiatric symptom score change did not differ between those with and without a history of PTSD (1.06 vs. 0.77, respectively; P =0.79). The null results found in this study warrant future research. Several methodological limitations might explain these results.

Reevaluating the FDA's warning against the use of probiotics in preterm neonates: A societal statement by ESPGHAN and EFCNI.

The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks.

Single-cell analysis of early progenitor cells that build coronary arteries.

Arteries and veins are specified by antagonistic transcriptional programs. However, during development and regeneration, new arteries can arise from pre-existing veins through a poorly understood process of cell fate conversion. Here, using single-cell RNA sequencing and mouse genetics, we show that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Before the onset of coronary blood flow, pre-artery cells appeared in the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein-specifying transcription factor COUP-TF2 (also known as NR2F2) prevented plexus cells from overcoming the pre-artery threshold by inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independently of blood flow upon the release of inhibition mediated by COUP-TF2 and cell cycle factors.

Long-term weight loss of distal gastric bypass is moderately superior compared to proximal gastric bypass in patients with a BMI of 37-44 Kg/m2.

PURPOSE: The laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the standard procedures in metabolic surgery. Different limb lengths have been proposed in the past to maximize weight loss (WL) and reduce metabolic complications. Distal gastric bypass surgery with a very short common channel (CC) (up to 100 cm) has been often criticized due to frequent side effects such as malnutrition, bone weakening and short-bowel syndrome. We introduced a modified version of a distal LRYGB with a 50-70 cm long biliopancreatic limb (BPL) and an intermediate short CC (120-150 cm). Our primary goal was to compare the long-term WL between distal and proximal LRYGB in two cohorts of patients. Secondary outcomes were weight regain (WR), insufficient weight loss (IWL), postoperative complications and metabolic changes 5 years after surgery. METHODS: In this retrospective study we collected data from 160 patients operated between 2014 and 2015, with a BMI of 37-44 Kg/m2. 101 patients underwent a distal and 59 patients a proximal LRYGB in two bariatric centers. WL was calculated as percent of excess of BMI loss (%EBMIL), loss of body mass index (Delta-BMI), percent of excess weight loss (%EWL) and percent of total weight loss (%TWL). Data were collected 3, 6, 9, 12, 24, 48 and 60 months after surgery. RESULTS: The distal LRYGB resulted in significantly better 5-year-WL compared to the proximal bypass in terms of %EBMIL (median at 5 years: 83% vs. 65%, p = 0.001), %TWL (median at 5 years: 32% vs. 26%, p = 0.017) and %EWL (median at 5 years: 65% vs. 51%, p = 0.029), with equal major complications and metabolic alterations. In addition, WR was significantly lower in patients with distal bypass (18% vs. 35%, p = 0.032). CONCLUSIONS: Distal LYRGB with a 120-150 long CC results in better WL and WL-maintenance compared to proximal LRYGB without major side effects after five years.