First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3ß/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease.

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3ß (GSK-3ß). The synthesized compounds are highly potent GSK-3ß, HDAC2, and HDAC6 inhibitors with IC50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 µM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.

Implications of the Propagation Method for the Phytochemistry of Nepeta cataria L. throughout a Growing Season.

Catnip (Nepeta cataria L.) plants produce a wide array of specialized metabolites with multiple applications for human health. The productivity of such metabolites, including nepetalactones, and natural insect repellents is influenced by the conditions under which the plants are cultivated. In this study, we assessed how field-grown catnip plants, transplanted after being propagated via either single-node stem cuttings or seeds, varied regarding their phytochemical composition throughout a growing season in two distinct environmental conditions (Pittstown and Upper Deerfield) in the state of New Jersey, United States. Iridoid terpenes were quantified in plant tissues via ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-QqQ-MS), and phenolic compounds (phenolic acids and flavonoids) were analyzed via UHPLC with diode-array detection (UHPLC-DAD). The highest contents of total nepetalactones in Pittstown were found at 6 weeks after transplanting (WAT) for both seedlings and cuttings (1305.4 and 1223.3 mg/100 g, respectively), while in Upper Deerfield, the highest contents for both propagules were at 11 WAT (1247.7 and 997.1 mg/100 g, respectively) for seed-propagated and stem cuttings). The highest concentration of nepetalactones was associated with floral-bud to partial-flowering stages. Because plants in Pittstown accumulated considerably more biomass than plants grown in Upper Deerfield, the difference in nepetalactone production per plant was striking, with peak productivity reaching only 598.9 mg per plant in Upper Deerfield and 1833.1 mg per plant in Pittstown. Phenolic acids accumulated in higher contents towards the end of the season in both locations, after a period of low precipitation, and flavone glycosides had similar accumulation patterns to nepetalactones. In both locations, rooted stem cuttings reached their maximum nepetalactone productivity, on average, four weeks later than seed-propagated plants, suggesting that seedlings have, overall, better agronomic performance.

Towards the understanding of molecular motors and its relationship with local unfolding.

Molecular motors are machines essential for life since they convert chemical energy into mechanical work. However, the precise mechanism by which nucleotide binding, catalysis, or release of products is coupled to the work performed by the molecular motor is still not entirely clear. This is due, in part, to a lack of understanding of the role of force in the mechanical-structural processes involved in enzyme catalysis. From a mechanical perspective, one promising hypothesis is the Haldane-Pauling hypothesis which considers the idea that part of the enzymatic catalysis is strain-induced. It suggests that enzymes cannot be efficient catalysts if they are fully complementary to the substrates. Instead, they must exert strain on the substrate upon binding, using enzyme-substrate energy interaction (binding energy) to accelerate the reaction rate. A novel idea suggests that during catalysis, significant strain energy is built up, which is then released by a local unfolding/refolding event known as 'cracking'. Recent evidence has also shown that in catalytic reactions involving conformational changes, part of the heat released results in a center-of-mass acceleration of the enzyme, raising the possibility that the heat released by the reaction itself could affect the enzyme's integrity. Thus, it has been suggested that this released heat could promote or be linked to the cracking seen in proteins such as adenylate kinase (AK). We propose that the energy released as a consequence of ligand binding/catalysis is associated with the local unfolding/refolding events (cracking), and that this energy is capable of driving the mechanical work.

Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Adults with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. Therefore, the International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy and their representatives to develop minimum sets of standardized outcomes and outcomes measurement methods for clinical practice that support patient-clinician decision-making and quality improvement. Consensus methods identified 20 core outcomes. Measurement tools were recommended based on their evidence of strong clinical measurement properties, feasibility, and cross-cultural applicability. The essential outcomes included many non-seizure outcomes: anxiety, depression, suicidality, memory and attention, sleep quality, functional status, and the social impact of epilepsy. The proposed set will facilitate the implementation of the use of patient-centered outcomes in daily practice, ensuring holistic care. They also encourage harmonization of outcome measurement, and if widely implemented should reduce the heterogeneity of outcome measurement, accelerate comparative research, and facilitate quality improvement efforts.

Characterization of the interaction between the Sec61 translocon complex and ppαF using optical tweezers.

The Sec61 translocon allows the translocation of secretory preproteins from the cytosol to the endoplasmic reticulum lumen during polypeptide biosynthesis. These proteins possess an N-terminal signal peptide (SP) which docks at the translocon. SP mutations can abolish translocation and cause diseases, suggesting an essential role for this SP/Sec61 interaction. However, a detailed biophysical characterization of this binding is still missing. Here, optical tweezers force spectroscopy was used to characterize the kinetic parameters of the dissociation process between Sec61 and the SP of prepro-alpha-factor. The unbinding parameters including off-rate constant and distance to the transition state were obtained by fitting rupture force data to Dudko-Hummer-Szabo models. Interestingly, the translocation inhibitor mycolactone increases the off-rate and accelerates the SP/Sec61 dissociation, while also weakening the interaction. Whereas the translocation deficient mutant containing a single point mutation in the SP abolished the specificity of the SP/Sec61 binding, resulting in an unstable interaction. In conclusion, we characterize quantitatively the dissociation process between the signal peptide and the translocon, and how the unbinding parameters are modified by a translocation inhibitor.

Loneliness, Dementia Status, and Their Association with All-Cause Mortality Among Older US Adults.

Background: Loneliness, dementia, and mortality are interconnected. Objective: We aimed at understanding mediating pathways and interactions between loneliness and dementia in relation to mortality risk. Methods: The study tested bi-directional relationships between dementia, loneliness, and mortality, by examining both interactions and mediating effects in a large sample of older US adults participating in the nationally representative Health and Retirement Study. Out of≤6,468 older participants selected in 2010, with mean baseline age of 78.3 years and a follow-up time up to the end of 2020, 3,298 died at a rate of 64 per 1,000 person-years (P-Y). Cox proportional hazards and four-way decomposition models were used. Results: Algorithmically defined dementia status (yes versus no) was consistently linked with a more than two-fold increase in mortality risk. Dementia status and Ln(odds of dementia) were strongly related with mortality risk across tertiles of loneliness score. Loneliness z-score was also linked to an elevated risk of all-cause mortality regardless of age, sex, or race or ethnicity, and its total effect (TE) on mortality was partially mediated by Ln(odds of dementia), z-scored, (≤40% of the TE was a pure indirect effect). Conversely, a small proportion (<5%) of the TE of Ln(odds of dementia), z-scored, on mortality risk was explained by the loneliness z-score. Conclusions: In sum, dementia was positively associated with all-cause mortality risk, in similar fashion across loneliness score tertiles, while loneliness was associated with mortality risk. TE of loneliness on mortality risk was partially mediated by dementia odds in reduced models.

Ventilatory Assistance Before Umbilical Cord Clamping in Extremely Preterm Infants: A Randomized Clinical Trial.

Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants. Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death. Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth. Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs. Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort. Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight. Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.

Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied. METHODS: We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator-gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV1) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6-10, 11-15, 16-20 and 21-25 years) to perform three analyses of younger versus older IVA initiation (6-10 vs 11-15, 11-15 vs 16-20 and 16-20 vs 21-25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA. FINDINGS: Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV1 than older initiators across all comparisons, and those initiating IVA between ages 6-10 and 11-15 years had significantly lower PEx rates. INTERPRETATION: Study findings showed the importance of early IVA initiation in people with CF.

Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study.

BACKGROUND: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk. METHODS: The present study involved 28,974 UK Biobank participants aged 50-74y (2006-2010) at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life's Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into "mediation only" or pure indirect effect (PIE), "interaction only" or interaction referent (INTREF), "neither mediation nor interaction" or controlled direct effect (CDE), and "both mediation and interaction" or mediated interaction (INTMED). RESULTS: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730). CONCLUSION: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained ∼ 54 % of the total effect.

Frailty in intracranial meningioma resection: the risk analysis index demonstrates strong discrimination for predicting non-home discharge and in-hospital mortality.

PURPOSE: Frailty is an independent risk factor for adverse postoperative outcomes following intracranial meningioma resection (IMR). The role of the Risk Analysis Index (RAI) in predicting postoperative outcomes following IMR is nascent but may inform preoperative patient selection and surgical planning. METHODS: IMR patients from the Nationwide Inpatient Sample were identified using diagnostic and procedural codes (2019-2020). The relationship between preoperative RAI-measured frailty and primary outcomes (non-home discharge (NHD), in-hospital mortality) and secondary outcomes (extended length of stay (eLOS), complication rates) was assessed via multivariate analyses. The discriminatory accuracy of the RAI for primary outcomes was measured in area under the receiver operating characteristic (AUROC) curve analysis. RESULTS: A total of 23,230 IMR patients (mean age = 59) were identified, with frailty statuses stratified by RAI score: 0-20 "robust" (R)(N = 10,665, 45.9%), 21-30 "normal" (N)(N = 8,895, 38.3%), 31-40 "frail" (F)(N = 2,605, 11.2%), and 41+ "very frail" (VF)(N = 1,065, 4.6%). Rates of NHD (R 11.5%, N 29.7%, F 60.8%, VF 61.5%), in-hospital mortality (R 0.5%, N 1.8%, F 3.8%, VF 7.0%), eLOS (R 13.2%, N 21.5%, F 40.9%, VF 46.0%), and complications (R 7.5%, N 11.6%, F 15.7%, VF 16.0%) significantly increased with increasing frailty thresholds (p < 0.001). The RAI demonstrated strong discrimination for NHD (C-statistic: 0.755) and in-hospital mortality (C-statistic: 0.754) in AUROC curve analysis. CONCLUSION: Increasing RAI-measured frailty is significantly associated with increased complication rates, eLOS, NHD, and in-hospital mortality following IMR. The RAI demonstrates strong discrimination for predicting NHD and in-hospital mortality following IMR, and may aid in preoperative risk stratification.

Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Infants, Children, and Adolescents with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. The International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy, and their representatives to develop minimum sets of standardized outcomes and outcome measurement methods for clinical practice. Using modified Delphi consensus methods with consecutive rounds of online voting over 12 months, a core set of outcomes and corresponding measurement tool packages to capture the outcomes were identified for infants, children, and adolescents with epilepsy. Consensus methods identified 20 core outcomes. In addition to the outcomes identified for the ICHOM Epilepsy adult standard set, behavioral, motor, and cognitive/language development outcomes were voted as essential for all infants and children with epilepsy. The proposed set of outcomes and measurement methods will facilitate the implementation of the use of patient-centered outcomes in daily practice.

Outcomes and Complications of Revision Reverse Shoulder Arthroplasty Following Failed Primary Anatomical Shoulder Arthroplasty or Hemiarthroplasty: A Systematic Review.

BACKGROUND: The purpose of this study is to systematically review the evidence in the literature to ascertain the functional outcomes, range of motion (ROM) and complication and reoperation rates following revision reverse shoulder arthroplasty (RSA) for a failed primary total shoulder arthroplasty (TSA) or hemiarthroplasty (HA). METHODS: Two independent reviewers performed the literature search based on PRISMA guidelines, utilizing the EMBASE, MEDLINE, and The Cochrane Library Databases. Studies were included if they reported clinical outcomes for revision RSA for a failed primary TSA or HA. RESULTS: Our review found 23 studies including 1,041 shoulders (627 TSA, 414 HA) meeting our inclusion criteria. The majority of patients were female (66.1%), with an average age of 69.0 years (range 39-93) with a mean follow-up of 46.3 months. ASES and VAS pain scores improved from 32.6 to 61.9 and 6.7 to 2.7, respectively. ROM results including forward flexion, abduction and external rotation that improved from 59.4° to 107.7°, 50.7° to 104.4°, and 19.8° to 26.3° respectively. Only one out of the ten studies reporting internal rotation found a statistically significant difference with mean internal rotation improving from S1-S3 preoperatively to L4-L5 postoperatively for patients undergoing HA. The overall complication rate and reoperation rate were 23.4% and 12.5% respectively. The most common complications were glenoid component loosening (6.0%), fracture (periprosthetic, intraoperative, or other scapula fractures) (n=4.7%), and infection (n=3.3%). CONCLUSION: Revision RSA for a failed primary TSA and HA has been shown to result in excellent functional outcomes and improved ROM suggesting patients who have failed TSA or HA may benefit from a revision RSA.

Debunking the July Effect in lung transplantation recipients.

Objective: The "July Effect" is a theory that the influx of trainees from July to September negatively impacts patient outcomes. We aimed to study this theoretical phenomenon in lung transplant recipients given the highly technical nature of thoracic procedures. Methods: Adult lung transplant hospitalizations were identified within the National Inpatient Sample (2005-2020). Recipients were categorized as academic Q1 (July to September) or Q2-Q4 (October to June). In-hospital mortality, operator-driven complications (pneumothorax, dehiscence including wound dehiscence, bronchial anastomosis, and others, and vocal cord/diaphragm paralysis, all 3 treated as a composite outcome), length of stay, and inflation-adjusted hospitalization charges were compared between both groups. Multivariable logistic regression was performed to assess the association between academic quarter and in-hospital mortality and operator-driven complications. The models were adjusted for recipient demographics and transplant characteristics. Subgroup analysis was performed between academic and nonacademic hospitals. Results: Of 30,788 lung transplants, 7838 occurred in Q1 and 22,950 occurred in Q2-Q4. Recipient demographic and clinical characteristics were similar between groups. Dehiscence (n = 922, 4% vs n = 236, 3%), post-transplant cardiac arrest (n = 532, 2% vs n = 113, 1%), and pulmonary embolism (n = 712, 3% vs n = 164, 2%) were more common in Q2-Q4 versus Q1 recipients (all P < .05). Other operator-driven complications, in-hospital mortality, and resource use were similar between groups (P > .05). These inferences remained unchanged in adjusted analyses and on subgroup analyses of academic versus nonacademic hospitals. Conclusions: The "July Effect" is not evident in US lung transplantation recipient outcomes during the transplant hospitalization. This suggests that current institutional monitoring systems for trainees across multiple specialties, including surgery, anesthesia, critical care, nursing, and others, are robust.

Knockdown of INPP5K compromises the differentiation of N2A cells.

Inositol polyphosphate 5-phosphatase K (INPP5K), also known as SKIP (skeletal muscle and kidney-enriched inositol phosphatase), is a cytoplasmic enzyme with 5-phosphatase activity toward phosphoinositides (PIs). Mutations in INPP5K are associated with autosomal recessive congenital muscular dystrophy with cataracts and intellectual disability (MDCCAID). Notably, muscular dystrophy is characterized by the hypoglycosylation of dystroglycan. Thus, far, the underlying mechanisms are only partially understood. In this study, we show that INPP5K expression increases during brain development. Knockdown of INPP5K in the neuroblastoma-derived cell line N2A impaired their neuronal-like differentiation and interfered with protein glycosylation.

Risk Analysis Index as a preoperative frailty tool for elective ventriculoperitoneal shunt surgery for idiopathic normal pressure hydrocephalus.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) predominantly occurs in older patients, and ventriculoperitoneal shunt (VPS) placement is the definitive surgical treatment. VPS surgery carries significant postoperative complication rates, which may tip the risk/benefit balance of this treatment option for frail, or higher-risk, patients. In this study, the authors investigated the use of frailty scoring for preoperative risk stratification for adverse event prediction in iNPH patients who underwent elective VPS placement. METHODS: The Nationwide Readmissions Database (NRD) was queried from 2018 to 2019 for iNPH patients aged ≥ 60 years who underwent VPS surgery. Risk Analysis Index (RAI) and modified 5-item Frailty Index (mFI-5) scores were calculated and RAI cross-tabulation was used to analyze trends in frailty scores by the following binary outcome measures: overall complications, nonhome discharge (NHD), extended length of stay (eLOS) (> 75th percentile), and mortality. Area under the receiver operating characteristic curve analysis was performed to assess the discriminatory accuracy of RAI and mFI-5 for primary outcomes. RESULTS: A total of 9319 iNPH patients underwent VPS surgery, and there were 685 readmissions (7.4%), 593 perioperative complications (6.4%), and 94 deaths (1.0%). Increasing RAI score was significantly associated with increasing rates of postoperative complications: RAI scores 11-15, 5.4% (n = 80); 16-20, 5.6% (n = 291); 21-25, 7.6% (n = 166); and ≥ 26, 11.6% (n = 56). The discriminatory accuracy of RAI was statistically superior (DeLong test, p < 0.05) to mFI-5 for the primary endpoints of mortality, NHD, and eLOS. All RAI C-statistics were > 0.60 for mortality within 30 days (C-statistic = 0.69, 95% CI 0.68-0.70). CONCLUSIONS: In a nationwide database analysis, increasing frailty, as measured by RAI, was associated with NHD, 30-day mortality, unplanned readmission, eLOS, and postoperative complications. Although the RAI outperformed the mFI-5, it is essential to account for the potentially reversible clinical issues related to the underlying disease process, as these factors may inflate frailty scores, assign undue risk, and diminish their utility. This knowledge may enhance provider understanding of the impact of frailty on postoperative outcomes for patients with iNPH, while highlighting the potential constraints associated with frailty assessment tools.

100 anastomoses: a two-year single-center experience with robotic-assisted micro- and supermicrosurgery for lymphatic reconstruction.

Robotic-assisted microsurgery has gained significant attention in recent years following the introduction of two dedicated microsurgical robotic systems specifically designed for this purpose. These feature higher degrees of movement and motion scaling which are useful tools, especially when performing surgery in areas of the body which are difficult to access. Robotic-assisted microsurgery has been implemented in lymphatic surgery as well as soft tissue reconstructive surgery at our institution over the past 2.5 years. Our study gives an insight into the details and outcomes of the first 100 consecutive (super-) microsurgical anastomoses in peripheral and central lymphatic reconstruction performed with the Symani® Surgical System between 2021 and 2024. In total, 67 patients were treated, receiving robotic-assisted lymphatic reconstruction with lymphatic tissue transfer (LTT) and/or lymphovenous anastomoses (LVA)/lympholymphatic anastomoses (LLA). No anastomosis-associated complications were recorded postoperatively. The majority of patients reported a postoperative improvement of their lymphedema or central lymphatic disorder. In conclusion, we show the successful implementation of the Symani® Surgical System into our clinical practice of lymphatic reconstruction. Although the necessary intraoperative setup and the use of intrinsic motion scaling lead to a slight increase in operating time, the presented study demonstrates the advantages of robotic assistance which becomes particularly evident in lymphatic surgery due to the involved deep surgical sites and the need for supermicrosurgical techniques.

Outcomes of Patients with Preoperative Thrombocytosis After Hip Fracture Surgery.

INTRODUCTION: Low platelet counts have clinically relevant effects on patient outcomes after hip fracture surgery; however, the relationship between abnormally high platelet counts and postoperative outcomes in this population is unknown. METHODS: The ACS-NSQIP database was queried for patients who underwent hip fracture surgery between 2015 and 2019. Outcomes were compared between patients with normal platelet counts (150,000 to 450,000/µL) and thrombocytosis (>450,000/µL). RESULTS: Eighty-six thousand three hundred eleven hip fracture patients were identified, of which 1067 (1.2%) had preoperative thrombocytosis. Compared with patients with normal platelet counts, patients with preoperative thrombocytosis had increased rates of 30-day mortality (6.4% vs 4.5%, P = 0.004; OR 1.15 [95% CI 0.88 to 1.50], P = 0.322) as well as increased rates and odds of readmission (11.4% vs 7.8%, P < 0.001; OR 1.35 [95% CI 1.10 to 1.65], P = 0.004) and venous thromboembolic events (3.2% vs 1.7%, P < 0.001; OR 1.88 [95% CI 1.31 to 2.71], P < 0.001). CONCLUSIONS: Hip fracture patients with preoperative thrombocytosis had increased rates of early mortality as well as increased odds of venous thromboembolic events and readmission. A patient with thrombocytosis may benefit from close postoperative surveillance and careful follow-up. Future prospective studies are needed to verify causation and investigate how to mitigate adverse outcomes in hip fracture patients with preoperative thrombocytosis.

Andexanet alfa therapy showed No increased rate of thromboembolic events in spontaneous intracranial hemorrhage patients: A multicenter electronic health record study.

•Intracranial hemorrhage accounts for two out of every three major intracranial hemorrhages.•Systemic anticoagulation is routinely prescribed for prevention of cerebrovascular accidents.•The FDA approved Andexanet alfa to treat life-threatening bleeding.•Andexanet alfa relationship to outcomes requires further investigation.

Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome.

We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist for participants with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤400/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. Primary endpoint was time (hours) above ANC threshold ≥500/µL (TATANC; over 24 hours). Secondary endpoints included TAT absolute lymphocyte count ≥1000/µL (TATALC; defined similar to TATANC); absolute changes in white blood cell (WBC), ANC, and ALC from baseline; annualized infection rate; infection duration and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n=14; placebo, n=17), mavorixafor least squares (LS) mean TATANC was 15.0 hours, placebo 2.8 hours (P<0.001). Mavorixafor LS mean TATALC was 15.8 hours, placebo 4.6 hours (P<0.001). Higher absolute WBC, ANC, and ALC levels were seen with mavorixafor than placebo at each timepoint assessed. Annualized infection rates were 60% lower with mavorixafor versus placebo (LS mean 1.7 versus 4.2; nominal P=0.007) and total infection scores were 40% lower (7.4 [95% CI, 1.6-13.2] versus 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor-treated participants showed significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration. Mavorixafor was well tolerated in participants with WHIM syndrome. Trial was registered at ClinicalTrials.gov NCT03995108.

Upconversion electroluminescence in 2D semiconductors integrated with plasmonic tunnel junctions.

Plasmonic tunnel junctions are a unique electroluminescent system in which light emission occurs via an interplay between tunnelling electrons and plasmonic fields instead of electron-hole recombination as in conventional light-emitting diodes. It was previously shown that placing luminescent molecules in the tunneling pathway of nanoscopic tunnel junctions results in peculiar upconversion electroluminescence where the energy of emitted photons exceeds that of excitation electrons. Here we report the observation of upconversion electroluminescence in macroscopic van der Waals plasmonic tunnel junctions comprising gold and few-layer graphene electrodes separated by a ~2-nm-thick hexagonal boron nitride tunnel barrier and a monolayer semiconductor. We find that the semiconductor ground exciton emission is triggered at excitation electron energies lower than the semiconductor optical gap. Interestingly, this upconversion is reached in devices operating at a low conductance (<10-6 S) and low power density regime (<102 W cm-2), defying explanation through existing proposed mechanisms. By examining the scaling relationship between plasmonic and excitonic emission intensities, we elucidate the role of inelastic electron tunnelling dipoles that induce optically forbidden transitions in the few-layer graphene electrode and ultrafast hot carrier transfer across the van der Waals interface.