Description of lymphocyte and cytokine profiles in individuals with acute myeloid leukemia associated with FLT3-ITD and NPM1 mutation status.

The pathogenesis of acute myeloid leukemia (AML) involves mutations in genes such as FLT3 and NPM1, which are also associated with the prognosis of the disease. The immune system influences disease progression, but the mechanisms underlying the interaction between the immune system and AML are not clear. In this study, the profiles of lymphocytes and cytokines were described in individuals with AML stratified by molecular changes associated with prognosis. The participants included in this study were newly diagnosed AML patients (n = 43) who were about to undergo chemotherapy. Subtypes of lymphocytes in peripheral blood, including B cells, T cells, and natural killer cells, and serum concentrations of cytokines, including Th1, Th2, and Th17, were studied by flow cytometry assays (BD FACSCanto II). The correlations between lymphocyte subsets, cytokines, and genetic/prognostic risk stratification (based on the FLT3 and NPM1 genes) were analyzed. The differences in B lymphocytes (%), T lymphocytes (%), plasmablasts (%), leukocytes (cells/µl), and tumor necrosis factor (pg/ml) were determined between groups with FLT3-ITD+ and FLT3-ITD- mutations. The presence of mutations in NPM1 and FLT3-ITD and age suggested changes in the lymphocyte and cytokine profile in individuals with AML.

Subcellular imaging of lipids and sugars using genetically encoded proximity sensors.

Live cell imaging of lipids and other metabolites is a long-standing challenge in cell biology. Bioorthogonal labeling tools allow for the conjugation of fluorophores to several phospholipid classes, but cannot discern their trafficking between adjacent organelles or asymmetry across individual membrane leaflets. Here we present fluorogen-activating coincidence sensing (FACES), a chemogenetic tool capable of quantitatively imaging subcellular lipid pools and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of conjugated molecules. We first validate this approach for quantifying discrete phosphatidylcholine pools in the ER and mitochondria that are trafficked by lipid transfer proteins. We then show that transmembrane domain-containing FAPs can be used to reveal the membrane asymmetry of multiple lipid classes that are generated in the trans-Golgi network. Lastly, we demonstrate that FACES is a generalizable tool for subcellular bioorthogonal imaging by measuring changes in mitochondrial N -acetylhexosamine levels. These results demonstrate the use of fluorogenic tags for spatially-defined molecular imaging.

Obturator to Femoral Nerve Transfer: 2-Dimensional Operative Video.

Injury to the femoral nerve can cause femoral nerve palsy,1 resulting in severe ambulation difficulties and loss of sensory function in the anteromedial thigh and medial calf.2,3 Treatment options focus on nerve repair by direct coaptation, nerve grafting, or nerve transfer.3 If the proximal nerve stump is inaccessible, the location of nerve injury is at a distance from the site of muscle innervation, and/or there is a large nerve gap, nerve transfer may be a promising alternative treatment option.4-6 Nerve transfer uses only one coaptation site and allows for a faster recovery time due to a shorter nerve regeneration distance.2,3 A 32-year-old woman presented with persistent and severe proximal right lower extremity weakness after a right retroperitoneal femoral nerve schwannoma resection at an outside institution. After surgery, she reported that she could not flex her right hip or extend her right knee. MRI demonstrated a right femoral nerve gap defect (7.5 cm) at the schwannoma resection site. A right obturator to femoral nerve transfer was performed (see Video). 1.5-year follow-up visit showed that she had begun to have evidence of active recruitment of the right quadriceps muscle and started walking without a knee brace. 2.5-year follow-up visit showed improving strength (4-) in her right quadriceps muscle, independent walking for longer distances, and participation in sporting activities. The patient consented to the procedure, and the patients and any identifiable individuals consented to publication of his/her image. Institutional Review Board approval was not required for this single case observational surgical video.

Ventricular Pseudoaneurysm and Free Wall Rupture After Acute Myocardial Infarction: JACC Focus Seminar 4/5.

Postinfarction ventricular free-wall rupture is a rare mechanical complication, accounting for <0.01% to 0.02% of cases. As an often-catastrophic event, death typically ensues within minutes due to sudden massive hemopericardium resulting in cardiac tamponade. Early recognition is pivotal, and may allow for pericardial drainage and open surgical repair as the only emergent life-saving procedure. In cases of contained rupture with pseudo-aneurysm (PSA) formation, hospitalization with subsequent early surgical intervention is warranted. Not uncommonly, PSA may go unrecognized in asymptomatic patients and diagnosed late during subsequent cardiac imaging. In these patients, the unsettling risk of complete rupture demands early surgical repair. Novel developments, in the field of transcatheter-based therapies and multimodality imaging, have enabled percutaneous PSA repair as a feasible alternate strategy for patients at high or prohibitive surgical risk. Contemporary advancements in the diagnosis and treatment of postmyocardial infarction ventricular free-wall rupture and PSA are provided in this review.

Improving access to cancer clinical research in Brazil: recent advances and new opportunities. Expert opinions from the 4th CURA meeting, São Paulo, 2023.

Clinical research is the cornerstone of improvements in cancer care. However, it has been conducted predominantly in high-income countries with few clinical trials available in Brazil and other low-and-middle-income countries (LMIC). Of note, less than one-third of registered clinical trials addressing some of the most commonly diagnosed cancers (breast, lung and cervical) recruited patients from LMIC in the last years. The Institute Project CURA promoted the fourth CURA meeting, discussing barriers to cancer clinical research and proposing potential solutions. A meeting was held in São Paulo, Brazil, in June 2023 with representatives from different sectors: Brazilian Health Regulatory Agency (Anvisa), National Commission of Ethics in Research (CONEP), non-governmental organisations, such as the Latin American Cooperative Oncology Group, the Brazilian Society of Clinical Oncology (SBOC), Contract Research Organisations, pharmaceutical companies and investigators. A total of 16 experts pointed out achievements as shortening the time of regulatory processes involving Anvisa and CONEP, development of staff training programs, maintenance of the National Program of Oncological Attention (PRONON), and the foundation of qualified centres in North and Northeast Brazilian regions. Participants also highlighted the need to be more competitive in the field, which requires optimising ongoing policies and implementing new strategies as decentralisation of clinical research centres, public awareness campaigns, community-centered approaches, collaborations and partnerships, expansion of physicians-directed policies, exploring the role of the steering committee. Active and consistent reporting of the initiatives might help to propagate ongoing advances, increasing Brazilian participation in clinical cancer research. Engagement of all players is crucial to maintain continuous progress with further improvements in critical points including regulatory timelines and increments in qualified human resources which aligned with new educational initiatives focused on physicians and the general population will expand access to cancer clinical trials in Brazil.

Ventricular Septal Rupture After Myocardial Infarction: JACC Focus Seminar 3/5.

Ventricular septal rupture remains a dreadful complication of acute myocardial infarction. Although less commonly observed than during the prethrombolytic era, the condition remains complex and is often associated with refractory cardiogenic shock and death. Corrective surgery, although superior to medical treatment, has been associated with high perioperative morbidity and mortality. Transcatheter closure techniques are less invasive to surgery and offer a valuable alternative, particularly in patients with cardiogenic shock. In these patients, percutaneous mechanical circulatory support represents a novel opportunity for immediate stabilization and preserved end-organ function. Multimodality imaging can identify favorable septal anatomy for the most appropriate type of repair. The heart team approach will define optimal timing for surgery vs percutaneous repair. Emerging concepts are proposed for a deferred treatment approach, including orthotropic heart transplantation in ideal candidates. Finally, for futile situations, palliative care experts and a medical ethics team will provide the best options for end-of-life clinical decision making.

Shorter communications: Exploring the impact of a brief smartphone-based alcohol intervention app (DrinksRation) on the quality of life of UK military veterans.

Alcohol misuse - defined as consuming more than 14 units of alcohol per week - is a well-established problem among veterans. This study investigated the change in quality of life among help-seeking UK veterans who completed a 28-day brief alcohol intervention delivered via a digital smartphone application (called DrinksRation) and have previously sought clinical help for a mental health disorder. This study was a secondary outcome analysis of data collected during a randomised control trial. In total, 123 UK veterans participated in the study and were randomly allocated to either the intervention or control arm. Participants completed self-report questionnaires regarding their alcohol use and quality of life (WHOQOL-BREF) at baseline, day 28 (end of intervention), day 84, and day 168. At the primary endpoint (day 84), we found significantly greater improvements in the intervention arm compared to the control arm for psychological quality of life (Cohen's d = 0.47), and environmental quality of life (d = 0.34). However, we observed no statistically significant differences between the intervention and control arm for social relationships and physical quality of life. Further, for day 168 we found no significant differences. Findings suggest that DrinksRation can increase quality of life among help-seeking veterans who have previously sought help for a mental health disorder, but the increases were modest and restricted to certain domains. Additional treatment may be needed for long-term and sustained improvements in quality of life.

Fermentation of whey-derived matrices by Kluyveromyces marxianus: alcoholic beverage development from whey and fruit juice mixes.

This research paper addresses the hypotheses that Kluyveromyces marxianus can be cultured with good alcohol production on different whey-derived matrices, and that the fermented product can be used in order to develop alcoholic beverages with acceptable sensory characteristics by mixtures with yeast-fermented fruit-based matrices. Growth and fermentative characteristics of Kluyveromyces marxianus LFIQK1 in different whey-derived matrices were explored by culturing (24 h, 30°C) on reconstituted whey, demineralized whey, heat-treated whey and milk permeate media. High lactose consumption, ethanol production and yield were observed. Reconstituted whey matrix was selected for mixing with orange or strawberry juices fermented using Saccharomyces cerevisiae to obtain alcoholic beverages (W-OR and W-ST, respectively). Consumer evaluation of beverages was performed using acceptability and Check-All-That-Apply (CATA) questions. Good acceptance was observed, significantly higher for W-ST than for W-OR. CATA questions gave information about organoleptic characteristics of beverages. Penalty analysis showed W-R and W-ST were positively associated with smooth/refreshing and fruity/natural, respectively. Liking was represented, accordingly with penalty analysis, by natural/refreshing. A novel alternative for utilization of whey and whey-related matrices by alcoholic beverages production with natural ingredients is presented.

Pathologic features of brain hemorrhage after radiation treatment: case series with somatic mutation analysis.

BACKGROUND: Radiation treatment for diseases of the brain can result in hemorrhagic adverse radiation effects. The underlying pathologic substrate of brain bleeding after irradiation has not been elucidated, nor potential associations with induced somatic mutations. METHODS: We retrospectively reviewed our department's pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl's Prussian Blue, and Masson's Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies. RESULTS: One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes. CONCLUSIONS: Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.

Forgotten Goiter Presenting As Acute Respiratory Distress Following a Thyroidectomy: A Case Report.

Airway complications account for a significant amount of post-thyroidectomy complications. Forgotten goiter is a residual thyroid mass left after total thyroidectomy, an event already depicted in the literature. Clinical presentation is diverse, ranging from asymptomatic tracheal deviation to symptoms caused by hormonally active thyroid tissue or airway obstruction due to mass effect. However, it has never been documented as the cause of acute respiratory distress following thyroid surgery. We report the case of a 65-year-old female undergoing left hemithyroidectomy due to long-standing substernal goiter. Anesthesia induction and surgery were uneventful. On extubation, the patient presented with acute respiratory distress requiring prompt airway management. A computed tomography scan revealed residual intrathoracic goiter resulting in significant airway compression. Therefore, although a rare event, a forgotten goiter should be considered by a multidisciplinary team when patients undergoing surgery for substernal goiter develop acute postoperative airway obstruction after common post-thyroidectomy complications have been excluded.

Survival of the Hmong population diagnosed with colon and rectal cancers in the United States.

BACKGROUND: The Hmong population constitutes an independent ethnic group historically dispersed throughout Southeast Asia; fallout from the Vietnam War led to their forced migration to the United States as refugees. This study seeks to investigate characteristics of the Hmong population diagnosed with in colorectal cancer (CRC) as well as survival within this population. METHODS: Cases of colon and rectal adenocarcinoma diagnosed between 2004 and 2017 were identified from the National Cancer Database (NCDB). Summary statistics of demographic, clinical, socioeconomic, and treatment variables were generated with emphasis on age and stage at the time of diagnosis. Cox-proportional hazard models were constructed for survival analysis. RESULTS: Of 881,243 total CRC cases within the NCDB, 120 were classified as Hmong. The average age of Hmong individuals at diagnosis was 58.9 years compared 68.7 years for Non-Hispanic White (NHW) individuals (p < 0.01). The distribution of analytic stage differed between the Hmong population and the reference NHW population, with 61.8% of Hmong individuals compared to 45.8% of NHW individuals with known stage being diagnosed at stage III or IV CRC compared to 0, I, or II (p = 0.001). However, there was no difference in OS when adjusting for potential confounders (HR 1.00 [0.77-1.33]; p = 0.998). CONCLUSIONS: Hmong individuals are nearly a decade younger at the time of diagnosis of CRC compared to the NHW individuals. However, these data do not suggest an association between Hmong ethnicity and overall survival, when compared to the NHW population.

Acute kidney injury in children undergoing cardiac surgery: predictive value of kidney arterial Doppler-based variables.

BACKGROUND: Acute kidney injury (AKI) is a common condition in critically ill children and is associated with increased morbidity and mortality. This study aimed to assess the performance of point-of-care ultrasonography to predict AKI in children undergoing cardiac surgery. METHODS: In this prospective study, consecutive children underwent kidney Doppler ultrasound examination within 24 h following cardiac surgery, and an experienced operator obtained both renal resistive index (RRI) and renal pulsatility index (RPI). AKI was defined by the Kidney Disease Improving Global Outcome (KDIGO) criteria. The primary outcome was the diagnosis of severe AKI (KDIGO stage 2 or 3) on day 3. RESULTS: A total of 58 patients were included. Median age and weight were 12.9 months (IQR 6.0-37.9) and 7.36 kg (IQR 5.19-11.40), respectively. On day 3, 13 patients were classified as having AKI, of which 11 were severe. RRI could effectively predict AKI (area under the ROC curve [AUC] 0.83, 95% CI 0.71-0.92; p < 0.001) as well as RPI (AUC 0.81, 95% CI 0.69-0.90; p < 0.001). The optimal cutoff value for RRI was 0.85 (sensitivity, 73%; specificity, 83%; positive predictive value [PPV], 50%; and negative predictive value [NPV], 93%), while for RPI was 1.95 (sensitivity, 73%; specificity, 78%; PPV, 44%; and NPV, 92%). Similar results were found in the analysis for prediction on day 5. Significant correlations were found between Doppler-based variables and estimated GFR and furosemide dose on day 3. CONCLUSIONS: Kidney Doppler ultrasound may be a promising tool for predicting AKI in children undergoing cardiac surgery.

The ants of the genus Rhopalothrix Mayr, 1870 (Hymenoptera, Formicidae, Myrmicinae) in Colombia.

The ants of the genus Rhopalothrix are diverse in the Neotropical region, with 14 of the 16 described species. Based on museum material and recent fieldwork, Rhopalothrix ants in Colombia were reviewed. Morphological analysis of the workers allowed delimitation of six species, including two new species, Rhopalothrixmandibularis Guerrero & Grajales, sp. nov. and Rhopalothrixmariaemirae Tocora, Fiorentino & Fernández, sp. nov. A new combination Rhopalothrixamaticomb. nov. is proposed for Eurhopalothrixamati. A worker-based taxonomic key, high-definition images of the workers, and a distribution map of all Rhopalothrix species present in Colombia are provided.

Upcycling Romaine lettuce outer leaves by infrared blanching and hot air drying.

Romaine lettuce outer leaves, as opposed to the more commonly marketed heart, are typically discarded and present an opportunity for upcycling as dried powders. Duquesne Romaine lettuce was evaluated to quantify and compare quality attributes of fresh outer and heart leaves, dried powders following hot air drying, and dried powders following an infrared (IR) blanching pretreatment before drying. Attributes measured for fresh leaves included moisture, water activity (Aw), color, total soluble phenolics (TSP), and antioxidant capacity (AC). Drying kinetics and time/energy saving through IR blanching were evaluated. Attributes measured for dried powders included moisture, Aw, color, true density, water vapor isotherms, TSP, AC, cadmium (Cd) content, and pesticide residues. TSP, AC, Cd, and pesticide residues were higher, whereas moisture content and Aw were lower in fresh outer versus heart leaves. Hot air drying reduced TSP and AC to 63.6% and 35.2% of fresh values, respectively, whereas IR blanching further reduced TSP and AC to 37.3% and 25.4% in outer leave powders. On the other hand, TSP and AC increased 237% and 151%, respectively, for unblanched heart powders. Higher increase of TSP than AC in heart leaf powder may indicate synthesis of phenolic compounds activated by abiotic stresses such as cutting and high temperatures at the initial drying stage. IR blanching resulted in significant time/energy savings for drying of outer leaves. Microbial loads were substantially reduced during drying, although microbial population on outer leaves were more resistant. Safe to eat outer leaf Romaine lettuce powders can be produced, assuming appropriate agricultural practices.

Pickering emulsions of thyme oil in water using oxidized cellulose nanofibers: Towards bio-based active packaging.

The antioxidant and antimicrobial properties of thyme essential oil (TEO) are useful for active food packaging, but its poor aqueous solubility restricts its applications. This work involves anionic cellulose nanofibers (CNFs) as the sole stabilizing agent for TEO-in-water emulsions, with oil concentrations ranging from 10 mL/L to 300 mL/L. A double mechanism was proposed: the adsorption of CNFs at oil/water interfaces restricted coalescence to a limited extent, while thickening (rheological stabilization) was required to avoid the buoyance of large droplets (>10 µm). Thickening effects comprised both higher viscosity (over 0.1 Pa·s at 10 s-1) and yield stress (approximately 0.9 Pa). Dilute emulsions had good film-forming capabilities, whereas concentrated emulsions were suitable for paper coating. Regarding antimicrobial activity, CNF-stabilized TEO-in-water emulsions successfully inhibited the growth of both Gram-negative (E. coli, S. typhimurium) and Gram-positive bacteria (L. monocytogenes). As for the antioxidant properties, approximately 50 mg of paper or 3-5 mg of film per mL of food simulant D1 were required to attain 50 % inhibition in radical scavenging tests. Nonetheless, despite the stability and the active properties of these bio-based hydrocolloids, providing this antioxidant and antimicrobial activity was incompatible with maintaining the organoleptic properties of the foodstuff unaltered.

Lysosome identity crisis: Phosphoinositides and mTORC1 negotiate lysosomal behavior.

Ebner et al.1 discovered a nutrient-dependent molecular feedback circuit that employs mTORC1, lipid kinases, and phosphatases to generate phosphatidylinositol-3-phosphate [PI(3)P] or phosphatidylinositol-4-phosphate [PI(4)P] in a mutually exclusive manner on lysosomes, which respectively convert lysosomes into organelles that support anabolism or catabolism.

Modified Frailty Index Predicts Postoperative Complications Following Parastomal Hernia Repair.

BACKGROUND: The 5-factor frailty index (5-mFI), validated frailty index with Spearmen rho correlation of .95 and C statistic >.7 for predicting postoperative complications, can be preoperatively used to stratify patients prior to parastomal hernia repairs. METHODS: Retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database identified patients from 2015 to 2020. 5-mFI scores were calculated by adding one point for each comorbidity present: diabetes mellitus, congestive heart failure (CHF), hypertension requiring medication, severe chronic obstructive pulmonary disease (COPD), non-independent functional status. Primary endpoint was 30-day overall complications; secondary endpoints were 30-day readmission, reoperation, and discharge to care facility. RESULTS: 2924 (52.2% female) patients underwent elective parastomal hernia repair. Univariate analysis showed 5-mFI > 2 had higher rates of overall (P = .008), pulmonary (P = .002), cardiovascular (P = .003)), hematologic (P = .003), and renal (P = .002) complications and higher rates of readmission (P = .009), reoperation (P = .001), discharge to care facility (P < .001), and death (P < .001). Multivariate analysis identified a 5-mFI of 2 or more as an independent risk factor for overall complications [OR: 1.40, 1.03-1.78; P = .032], pulmonary complications [2.97, 1.63-5.39; P < .001], hematological complications [1.60, 1.03-2.47; P = .035], renal complications [2.04, 1.19-3.46; P = .009], readmission [1.54, 1.19-1.99; P < .001], and discharge to facility [2.50, 1.66-3.77; P < .001]. Reoperation was not signification on multivariate analysis. CONCLUSIONS: Parastomal hernia repair patients with 5-mFI score of >2 had higher risk of renal, cardiovascular, pulmonary, and hematologic complications, readmissions, longer hospitalization, discharge to care facility, and mortality, and can be useful during preoperative risk stratification.

Rapid Formation of Non-canonical Phospholipid Membranes by Chemoselective Amide-Forming Ligations with Hydroxylamines.

There has been increasing interest in methods to generate synthetic lipid membranes as key constituents of artificial cells or to develop new tools for remodeling membranes in living cells. However, the biosynthesis of phospholipids involves elaborate enzymatic pathways that are challenging to reconstitute in vitro. An alternative approach is to use chemical reactions to non-enzymatically generate natural or non-canonical phospholipids de novo. Previous reports have shown that synthetic lipid membranes can be formed in situ using various ligation chemistries, but these methods lack biocompatibility and/or suffer from slow kinetics at physiological pH. Thus, it would be valuable to develop chemoselective strategies for synthesizing phospholipids from water-soluble precursors that are compatible with synthetic or living cells Here, we demonstrate that amide-forming ligations between lipid precursors bearing hydroxylamines and α-ketoacids (KAs) or potassium acyltrifluoroborates (KATs) can be used to prepare non-canonical phospholipids at physiological pH conditions. The generated amide-linked phospholipids spontaneously self-assemble into cell-like micron-sized vesicles similar to natural phospholipid membranes. We show that lipid synthesis using KAT ligation proceeds extremely rapidly, and the high selectivity and biocompatibility of the approach facilitates the in situ synthesis of phospholipids and associated membranes in living cells.

Salmonella actively modulates TFEB in murine macrophages in a growth-phase and time-dependent manner.

IMPORTANCE: Activation of the host transcription factor TFEB helps mammalian cells adapt to stresses such as starvation and infection by upregulating lysosome, autophagy, and immuno-protective gene expression. Thus, TFEB is generally thought to protect host cells. However, it may also be that pathogenic bacteria like Salmonella orchestrate TFEB in a spatio-temporal manner to harness its functions to grow intracellularly. Indeed, the relationship between Salmonella and TFEB is controversial since some studies showed that Salmonella actively promotes TFEB, while others have observed that Salmonella degrades TFEB and that compounds that promote TFEB restrict bacterial growth. Our work provides a path to resolve these apparent discordant observations since we showed that stationary-grown Salmonella actively delays TFEB after infection, while late-log Salmonella is permissive of TFEB activation. Nevertheless, the exact function of this manipulation remains unclear, but conditions that erase the conditional control of TFEB by Salmonella may be detrimental to the microbe.