Aspirin therapy is associated with a lower risk of pregnancy loss in both JAK2- and CALR-mutated essential thrombocythemia-A Mayo Clinic study of 200 pregnancies.

Two-hundred pregnancies involving 100 women with essential thrombocythemia (ET) were accessed from Mayo Clinic databases (1990-2023). Median platelet count displayed a decline during pregnancy, nadiring at 48% of baseline, in the third trimester: 704-369 × 109/L. Live birth rate was 72%. Of 53 (27%) unintentional pregnancy losses, 48 (24%) occurred in the first trimester. Other fetal complications included preterm birth 3%, intrauterine growth retardation 3%, and stillbirth 1%. Maternal complications included major hemorrhage (7%), preeclampsia (6%), thrombosis (1%), and placental abruption (0.5%). Antepartum management included no specific therapy in 52 (26%), aspirin alone in 112 (56%), aspirin combined with cytoreductive drugs or systemic anticoagulants in 23 (12%), and other permutations in the remaining. Postpartum systemic anticoagulation was documented in 29 (15%) pregnancies. Unintentional first-trimester loss was predicted by prior fetal loss (43% vs. 18%; p < .01), diabetes mellitus (DM; 67% vs. 23%; p = .02), and absence of aspirin therapy (45% vs. 14%; p < .01); the salutary effect of aspirin therapy was independent of the other two risk factors and apparent in both high (presence of ≥1 risk factor; 33% vs. 61%; p = .07) and low (absence of both risk factors; 10% vs. 34%; p < .01) risk scenarios. The benefit of aspirin therapy, in preventing first-trimester loss, was significant in both JAK2-mutated (18% vs. 50%; p < .01) and CALR-mutated (8% vs. 43%; p < .01) cases. Aspirin use was also associated with a lower risk of venous thrombosis (0% vs. 3%; p = .03). By contrast, the use of systemic anticoagulation, antepartum or postpartum, did not influence fetal or maternal complication rates. CALR mutation and DM predicted maternal hemorrhage (13% vs. 4%; p = .05) and preeclampsia (33% vs. 5%; p = .03), respectively. The current study demonstrates the protective role of aspirin in preventing first-trimester loss in ET, independent of driver mutation status or other risk factors.

Exploitation of green synthesized chromium doped zinc oxide nanorods (NRs) mediated by flower extract of Rhododendron arboreum for highly efficient photocatalytic degradation of cationic dyes Malachite green (MG) and Fuchsin basic (FB).

In this work, green method to synthesize chromium-doped zinc oxide (ZnO) nanorods (NRs) using an aqueous flower extract from Rhododendron arboretum is explored. Herein, chromium-doped ZnO NRs were prepared with different amount of chromium doping, varied as 2-10%. The green synthesized products underwent substantial analysis through X-ray diffraction (XRD), spectroscopic such as ultraviolet spectroscopy(UV-Vis) and scanning electron microscopy (SEM) methods. All samples were found to have hexagonal wurtzite ZnO, with average particle sizes of 52.41, 56.6, 54.44, 53.05, and 56.99 nm, respectively, for 2, 4, 6, 8, and 10% chromium doping in ZnO NRs. The Cr-doped ZnO NRs exhibited remarkable photocatalytic degradation activity of cationic dyes under UV-light, i.e., Malachite Green and Fuchsin Basic with degradation of 99.604 and 99.881%, respectively in 90 min. The reusability tests for these green synthesized Cr-doped ZnO NRs have also been carried out, showed 9-11 cycles with 85% of degradation efficiency. In addition, the Cr-doped ZnO NRs exhibited high selectivity for cationic dyes when experiments against mixture of dyes were performed. Photodegradation kinetics followed the pseudo-first-order model. The flower-extract-stabilized chromium-doped ZnO NRs demonstrated high photocatalytic activity toward malachite green and fuchsin basic dyes, potential material for pollution remediation.

Cr-doped ZnO NRs by green method using flower extract of Rhododendon arboretum were prepared for the first time under ambient reaction conditions.Effect of Dopant i.e. Cr on Photocatalytic activity have been exploited.Selective photocatalytic degradation of cationic dyes i.e. MG, and FB has been achieved in 60­90 minutes.Optimization of reaction condition and various parameters has also been carried out.Recyclability of Cr-doped ZnO NRs was also evaluated and were found to be reusable for 11 cycles for degradation.

[3+2]-Cycloaddition Reactions of gem-Difluorocyclopropenes with Azomethine Ylides - Access to Novel Fluorinated Scaffolds.

The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.

Discovery and Visualization of the Hidden Relationships among N-Glycosylation, Disulfide Bonds, and Membrane Topology.

Membrane proteins (MPs) are functionally important but structurally complex. In particular, MPs often carry three structural features, i.e., transmembrane domains (TMs), disulfide bonds (SSs), and N-glycosylation (N-GLYCO). All three features have been intensively studied; however, how the three features potentially correlate has been less addressed in the literature. With the growing accuracy from computational prediction, we used publicly available information on SSs and N-GLYCO and analyzed the potential relationships among post-translational modifications (PTMs) and the predicted membrane topology in the human proteome. Our results suggested a very close relationship between SSs and N-GLYCO that behaved similarly, whereas a complementary relation between the TMs and the two PTMs was also revealed, in which the high SS and/or N-GLYCO presence is often accompanied by a low TM occurrence in a protein. Furthermore, the occurrence of SSs and N-GLYCO in a protein heavily relies on the protein length; however, TMs seem not to possess such length dependence. Finally, SSs exhibits larger potential dynamics than N-GLYCO, which is confined by the presence of sequons. The special classes of proteins possessing extreme or unique patterns of the three structural features are comprehensively identified, and their structural features and potential dynamics help to identify their susceptibility to different physiological and pathophysiological insults, which could help drug development and protein engineering.

Aging-related changes in metabolic indicators in female rats and their management with Tinospora cordifolia.

Conflicting reports of HRT necessitates exploration of therapeutic interventions with the least side effects to preserve metabolic homeodynamics in women later in life. The current study was designed to elucidate the cumulative effects of aging and/or high fat diet (HFD) on some metabolic indicators and their management by Tinospora cordifolia stem powder (TCP) using middle-aged acyclic and young adult cyclic female rats as the model system. Animals were fed on either normal chow or HFD supplemented with or without TCP. Blood and liver tissue were collected for biochemical, and histological studies as well as for expression of proteins regulating lipid metabolism. Animals fed with TCP supplemented normal chow feed showed bodyweight management over 12-weeks despite their high feed and calories intake compared to young and age-matched controls as well as HFD-fed animals. TCP dose used was not toxic and rather prevented age-associated liver dysfunctions and ameliorated dyslipidemia and oxidative stress, normalized blood glucose, insulin, leptin, and secretary pro-inflammatory cytokines. Further, bodyweight management effect of TCP was observed to target AMPK signalling pathway as the mediator of lipogenesis, sterol biosynthesis, lipolysis, and ß-oxidation of fatty acids. These findings suggest that TCP supplementation in diet may be a potential interventional strategy to ameliorate aging-associated hepatic and metabolic dysfunctions and to promote healthy aging.

Midostaurin therapy for advanced systemic mastocytosis: Mayo Clinic experience in 33 consecutive cases.

We retrospectively examined our experience with midostaurin therapy in 33 consecutive patients (median age 68 years; 58% females) with advanced systemic mastocytosis (adv-SM): aggressive SM (ASM; n = 17), SM associated with another hematologic neoplasm (SM-AHN; n = 14) and mast cell leukemia (MCL; n = 2). KITD816V mutation was detected in 84% of the patients and C findings in 91%. Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median time from diagnosis to initiation of midostaurin therapy was 2.2 months (range 0.3-41). Using modified valent criteria, overall response was 42% (53% ASM, 29% SM-AHN, 50% MCL; p = .22), all classified as being major. Responses included ≥50% reduction in bone marrow mast cells in 40% and normalization of serum tryptase in 29%, of evaluated cases. After a median follow-up of 14.6 months from initiation of midostaurin therapy, 7 (21%) deaths, 1 (3%) leukemic progression, and 18 (55%) treatment discontinuations were documented; median duration of midostaurin treatment was 7.9 months (range 0.5-123) and response duration 21.5 months (range 2.9-123). Most frequent side effect was gastrointestinal (51%) while grade 3/4 neutropenia or thrombocytopenia occurred in 12% of patients. Response to treatment was not predicted by KIT mutation (p = .67) or exposure to prior cytoreductive therapy (p = .44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs. 16 months; p = .15). Findings from the current study are broadly consistent with previously published clinical trial observations.

Five-Strand Versus Four-Strand Hamstring Autografts in Anterior Cruciate Ligament Reconstruction-A Prospective Randomized Controlled Study.

PURPOSE: To compare the clinical outcomes of the routine use of 5-strand hamstring grafts (where possible) with those of 4-strand grafts in primary anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 64 patients were enrolled in a prospective randomized controlled study comparing the use of 5-strand and 4-strand semitendinosus-gracilis autografts in single bundle ACL reconstruction (n = 32 in each group). Four participants in each group were lost to follow-up and were excluded from the outcome analysis. The outcomes of 28 patients in the 5-strand group and 28 patients in the 4-strand group were analyzed. The diameters of all grafts were measured intraoperatively. Patients were assessed postoperatively at 2 years with objective assessments (anterior knee laxity using the KT-2000 arthrometer, Lachman test, pivot-shift test, hop test) and patient-reported outcome scores (Lysholm knee score, Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee subjective knee score, SF-36 physical and mental components, Tegner activity scale). Postoperative graft ruptures were also noted. RESULTS: There were improvements in all outcome measures postoperatively regardless of the number of graft strands. When we compared the study and control groups, there were no significant differences in all subjective and objective outcome measures except the Knee Injury and Osteoarthritis Outcome Score symptoms score (5-strand group 93.3 ± 9.2 vs 4-strand group 86.2 ± 14.7, P = .04). The KT-2000 side-to-side difference was 2.79 ± 2.11 mm in the 5-strand group and 2.54 ± 1.75 mm in the 4-strand group (P = .63). The 5-strand study group had 2 graft ruptures at 1 year, whereas the 4-strand control group had one partial graft rupture at 6 months. CONCLUSIONS: At 2-year follow-up, the routine use of the 5-strand hamstring tendon autograft was not superior to that of the quadrupled or 4-strand graft in primary ACL reconstruction. LEVEL OF EVIDENCE: Level I, prospective randomized controlled trial.

Engineering Bacterial Cellulose by Synthetic Biology.

Synthetic biology is an advanced form of genetic manipulation that applies the principles of modularity and engineering design to reprogram cells by changing their DNA. Over the last decade, synthetic biology has begun to be applied to bacteria that naturally produce biomaterials, in order to boost material production, change material properties and to add new functionalities to the resulting material. Recent work has used synthetic biology to engineer several Komagataeibacter strains; bacteria that naturally secrete large amounts of the versatile and promising material bacterial cellulose (BC). In this review, we summarize how genetic engineering, metabolic engineering and now synthetic biology have been used in Komagataeibacter strains to alter BC, improve its production and begin to add new functionalities into this easy-to-grow material. As well as describing the milestone advances, we also look forward to what will come next from engineering bacterial cellulose by synthetic biology.

Melatonin and serotonin: Mediators in the symphony of plant morphogenesis.

Melatonin and serotonin are important signaling and stress mitigating molecules that play important roles across growth and development in plants. Despite many well-documented responses, a systematic investigation of the entire metabolic pathway (tryptophan, tryptamine, and N-acetylserotonin) does not exist, leaving many open questions. The objective of this study was to determine the responses of Hypericum perforatum (L.) to melatonin, serotonin, and their metabolic precursors. Two well-characterized germplasm lines (#4 and 112) created by mutation and a haploid breeding program were compared to wild type to identify specific responses. Germplasm line 4 has lower regenerative and photosynthetic capacity than either wild type or line 112, and there are documented significant differences in the chemistry and physiology of lines 4 and 112. Supplementation of the culture media with tryptophan, tryptamine, N-acetylserotonin, serotonin, or melatonin partially reversed the regenerative recalcitrance and growth impairment of the germplasm lines. Quantification of phytohormones revealed crosstalk between the indoleamines and related phytohormones including cytokinin, salicylic acid, and abscisic acid. We hypothesize that melatonin and serotonin function in coordination with their metabolites in a cascade of phytochemical responses including multiple pathways and phytohormone networks to direct morphogenesis and protect photosynthesis in H. perforatum.

Use of the 5-Strand Hamstring Autograft Technique in Increasing Graft Size in Anterior Cruciate Ligament Reconstruction.

BACKGROUND: To determine the extent to which a strategy of routinely preparing a 5-strand hamstring autograft would increase graft size in anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 64 patients were enrolled in a prospective randomized controlled study comparing 5-strand and quadrupled semitendinosus-gracilis autografts in single-bundle ACL reconstruction (5-strand group, n = 32; 4-strand group, n = 32). In the 5-strand group, the diameter of the 4-strand construct and the subsequent 5-strand graft used were measured, whereas in the 4-strand group, the diameter of the quadrupled graft used was measured. Quadrupled graft diameter and hamstring tendon lengths were correlated with patient gender, height, weight, and body mass index (BMI). RESULTS: The mean diameter of the final graft used in the 5-strand group was 8.8 ± 0.8 mm, whereas that in the 4-strand group was 7.8 ± 0.7 mm (P < .001). The mean increase in graft size achieved with the use of the 5-strand technique was 1.4 ± 0.3 mm. In the 5-strand group, 24 of 32 (75%) patients had graft diameters exceeding 8 mm compared with 9 of 32 (28%) patients in the 4-strand group (P < .001). Quadrupled graft diameter was significantly correlated with patient height and BMI, whereas the gracilis and semitendinosus lengths were significantly correlated with patient height. CONCLUSIONS: The 5-strand hamstring autograft provides a significantly larger diameter graft compared with the quadrupled hamstring autograft in ACL reconstruction. Graft sizes exceeding 8 mm are achievable in 75% of patients with the routine application of this technique. This is significantly more than that obtained with the standard quadrupled hamstring graft. Hamstring tendon length and quadrupled hamstring graft diameter are also significantly correlated with patient height. LEVEL OF EVIDENCE: Level 1, prospective randomized controlled trial.

Concomitant meniscal injury in anterior cruciate ligament reconstruction does not lead to poorer short-term post-operative outcomes.

PURPOSE: The main objective was to compare post-operative outcomes in patients undergoing anterior cruciate ligament (ACL) reconstruction both with and without concomitant meniscus injury at a mean follow-up of 3.5 years. The secondary objective was to study the effect of different meniscal injury sites and treatment modalities on post-operative outcomes (PROS). METHODS: This is a retrospective analysis of a prospectively maintained database of patients undergoing ACL reconstruction at our tertiary institution between 2009 and 2012. Age, sex, graft type, graft fixation modality, location of meniscal tear and treatment (meniscal repair or meniscectomy) were recorded in the database. PROS used included the Tegner activity scale and the Lysholm score. RESULTS: There were no significant differences between patients with or without meniscal injury in terms of age, BMI or preoperative PROS. There was no significant difference in the post-operative outcome scores between patients with or without meniscal injury at a mean follow-up of 3.5 years. Regardless of the location of meniscal injury, the post-operative scores improved as compared to preoperative scores. CONCLUSION: Concomitant meniscal injury in cases of ACL reconstruction is not associated with poorer short-term post-operative PROS (mean follow-up time: 3.5 years). These findings may influence management decisions and help in preoperative counselling. LEVEL OF EVIDENCE: IV.

Exploring the Role of TRPV and CGRP in Adenosine Preconditioning and Remote Hind Limb Preconditioning-Induced Cardioprotection in Rats.

The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dtmax and -dp/dtmin. Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.

Outcome of Single-Bundle Hamstring Anterior Cruciate Ligament Reconstruction Using the Anteromedial Versus the Transtibial Technique: A Systematic Review and Meta-analysis.

PURPOSE: To compare the clinical outcomes of single-bundle hamstring anterior cruciate ligament (ACL) reconstruction between the anteromedial (AM) and transtibial (TT) techniques. METHODS: We performed a comprehensive systematic review and meta-analysis of the English-language literature in the PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases for articles that compared clinical outcomes of AM versus TT ACL reconstruction. The outcome measures analyzed included postoperative Lachman test, pivot-shift test, International Knee Documentation Committee (IKDC), and Lysholm scores. RESULTS: We included 10 articles from an initial 308 abstracts for the systematic review and included 6 studies for the meta-analysis. The study population consisted of a total of 733 patients, of whom 366 (49.9%) underwent the AM technique and 367 (50.1%) underwent the TT technique for ACL reconstruction. For postoperative knee stability, the AM technique yielded superior results in terms of the proportion of negative Lachman test results (n = 243; odds ratio [OR], 2.98 [95% confidence interval (CI), 1.29 to 6.88]) and proportion of negative pivot-shift test results (n = 238; OR, 3.67 [95% CI, 1.80 to 7.52]). For postoperative functional status, the AM technique yielded superior results in terms of objective IKDC grading (proportion with IKDC grade A) (n = 269; OR, 2.19 [95% CI, 1.23 to 3.88]) but had comparable Lysholm scores (n = 478; mean difference, 1.43 [95% CI, 0.01 to 2.84]). CONCLUSIONS: Single-bundle hamstring ACL reconstruction using the AM technique showed superior surgeon-recorded stability according to the IKDC knee score, Lachman test, and pivot-shift test. However, there was no difference in patient-reported functional outcome (Lysholm score). LEVEL OF EVIDENCE: Level III, systematic review and meta-analysis of Level I, II, and III studies.

Variation and correlation of properties in different grades of maple syrup.

Thirty five commercial maple syrups from twelve producers in Southern Ontario were evaluated for properties including light transmittance, autofluorescence, density, pH, total soluble solids (TSS), glucose and fructose content, total phenol content, antioxidant potential and mineral content (Mg, Mn, P, Zn, Ca, K, Fe and Pb). A high degree of variability was found in many characteristics, often exceeding an order of magnitude. Syrups were categorized based on light transmission at 560 nm into amber (12), dark (13) and very dark (10) using International Maple Syrup Institute (IMSI) guidelines. No statistical differences were found among grades of syrup for density, pH, TSS, glucose, fructose, total reducing sugars, glucose:fructose ratio, magnesium, manganese or potassium. Darker syrups showed significantly higher autofluorescence, total phenol content, antioxidant potential, phosphorous, calcium and total mineral content. Significant negative correlations of percent transmission with total phenol content, antioxidant potential and total mineral content are reported. Significant positive correlations among total phenol content, antioxidant potential and total mineral content are also described. The results from this study suggest that darker syrups tend to contain more beneficial traits and may be applied in developing functional foods and value added products.

Opioid Prescription Trends Among Sleep Surgeons in the United States.

OBJECTIVE: This study aimed to describe trends in opioid prescriptions among US sleep surgeons between 2013 and 2021 via a retrospective analysis conducted using publicly available data. METHODS: Utilizing the CMS part D database, we analyzed data from 82 sleep surgeons, focusing on metrics including number of opioid beneficiaries and claims, opioid cost, and opioid day supply per beneficiary. We employed statistical methods including ANOVA, t-tests, Fisher's exact test with Monte Carlo Simulation, and regression models. RESULTS: There were no significant changes in the number of opioid claims (p = 0.782) or beneficiaries per provider (p = 0.590) nor was there a decrease in opioid day supply per beneficiary (p = 0.489) over time. Surgeons who graduated residency before 2000 prescribed significantly more opioids over the course of the study period compared to those graduating after 2000 with higher opioid day supply per beneficiary (13.34 vs. 7.42, p < 0.001), higher opioid beneficiaries per provider (21.62 vs. 19.36, p = 0.028), and higher opioid claims per provider (30.30 vs. 21.78, p < 0.001). A significant annual decrease in opioid cost per beneficiary (ANOVA, p = 0.006) was noted. CONCLUSIONS: This study illuminates a significant impact of provider years in practice on opioid prescribing trends, alongside a decreasing trend in opioid cost per beneficiary. Despite the evolving paradigm emphasizing opioid reduction and evidence of decreasing opioid prescriptions in other otolaryngology subspecialties, our findings depict that opioid prescriptions among sleep surgeons remained stable from 2013 to 2021. LEVEL OF EVIDENCE: III Laryngoscope, 2024.

Sociodemographic and Healthcare System Barriers to PAP Alternatives for Adult OSA: A Scoping Review.

OBJECTIVE: To investigate sociodemographic and healthcare system barriers to access and utilization of alternative treatments to positive airway pressure (PAP) in the management of adult obstructive sleep apnea (OSA). DATA SOURCES: PubMed, Embase, and Web of Science databases were searched from 2003 to 2023 for English-language studies containing original data on sociodemographic and healthcare system barriers to PAP-alternative treatments for adult OSA. REVIEW METHODS: Studies were assessed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Title and abstract screening, full-text review, and data collection were conducted by two investigators independently. RESULTS: Out of 1,615 studies screened, 13 studies met inclusion criteria and reported on a total of 1,206,115 patients who received PAP alternative treatments, including surgery (n = 9 studies), and oral appliances (OAs) (n = 3 studies). The chance of receiving a PAP-alternative treatment such as surgery was greater among patients aged 39 years or younger, had body mass index below 30 kg/m2, fewer comorbidities, private insurance, and a higher occupational and income status. The decision of individuals to receive PAP alternative treatments was influenced by increased patient education from providers, as well as improvements in daytime sleepiness and partner perception of snoring and apnea. CONCLUSION: Cumulative evidence suggests that several sociodemographic and healthcare system factors are associated with decreased use of PAP alternatives when PAP therapy fails. Investigation of interventions to eliminate these potential barriers may improve access and treatment outcomes. Laryngoscope, 2024.