Robotic versus open mini-incision living donor nephrectomy: Single centre experience.

BACKGROUND: Robotic surgery is associated with less tissue manipulation and earlier recovery with minimal incision. The aim of this study was to compare the short-term clinical outcomes between robotic-assisted donor nephrectomy (RDN) and open mini-incision donor nephrectomy (ODN). METHODS: From 2016 to 2019, 141 cases involving RDN were analysed. Patient outcomes were compared with those of 191 patients who underwent ODN from 2010 to 2015. Demographics, operation factors, perioperative outcomes, and complications were retrospectively reviewed. RESULTS: The RDN group presented with less blood loss than the ODN group (p = 0.023). The length of hospital stay was significantly shorter in the RDN group than in the ODN group (p < 0.005). The overall rate of complications was low and there was no significant difference in complication rates between the groups. CONCLUSION: The robotic approach has benefits over the traditional open approach, including shorter length of hospital stay and reduced intraoperative blood loss.

Neuropsychological and social predictors of participation in a deep brain stimulation study of Parkinson's disease and dystonia.

Objectives: Participation is essential to DBS research, yet circumstances that affect diverse participation remain unclear. Here we evaluate factors impacting participation in an adaptive DBS study of Parkinson's disease (PD) and dystonia. Methods: Twenty participants were implanted with a sensing-enabled DBS device (Medtronic Summit RC+S) that allows neural data streaming in naturalistic settings and encouraged to stream as much as possible for the first five months after surgery. Using standardized baseline data obtained through neuropsychological evaluation, we compared neuropsychological and social variables to streaming hours. Results: Marital status and irritability significantly impacted streaming hours (estimate=136.7, bootstrapped ( b ) CI b =45.0 to 249.0, p b =0.016, and estimate=-95.1, CI b =-159.9 to -49.2, p b =0.027, respectively). These variables remained significant after multivariable analysis. Composite scores on verbal memory evaluations predicted the number of hours of data streamed (R 2 =0.284, estimate=67.7, CI b =20.1 to 119.9, p b =0.019). Discussion: Verbal memory impairment, irritability, and lack of a caregiver may be associated with decreased participation. Further study of factors that impact research participation is critical to the sustained inclusion of diverse participants.

Basal ganglia theta power indexes trait anxiety in people with Parkinson's disease.

Background: Neuropsychiatric symptoms are common and disabling in Parkinson's disease (PD), with troublesome anxiety occurring in one-third of patients. Management of anxiety in PD is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements, and largely ineffective treatments.In this study, we assessed the intracranial neurophysiological correlates of anxiety in PD patients treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety. Methods: We recorded local field potentials (LFP) from the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) DBS implants in three PD cohorts: 1) patients with recordings (STN) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON or OFF dopaminergic medication; 2) patients with recordings (STN or GPi) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic Percept™ device), ON dopaminergic medication, with stimulation both ON or OFF; 3) patients with recordings performed at home while engaging in a behavioral task via STN and GPi leads and electrocorticography paddles (ECoG) over premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both ON or OFF.Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges were extracted from the LFP recordings, and their relation with anxiety ratings was assessed using linear mixed-effects models. Results: In total, 33 PD patients (59 hemispheres) were included. Across three independent cohorts, with stimulation OFF, basal ganglia theta power was positively related to trait anxiety (all p<0.05). Also in a naturalistic setting, with individuals at home at rest with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (p<0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta-alpha power. There was no within-patient association between basal ganglia theta-alpha power and state anxiety. Conclusion: We showed that basal ganglia theta activity indexes trait anxiety in PD. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in PD, potentially suitable for guiding advanced DBS treatment tailored to the individual patient's needs, including non-motor symptoms.

Administration of 4% tetrasodium EDTA lock solution and central venous catheter complications in high-risk pediatric patients with intestinal failure: A retrospective cohort study.

BACKGROUND: Selection of central venous catheter (CVC) lock solution impacts catheter mechanical complications and central line-associated bloodstream infections (CLABSIs) in pediatric patients with intestinal failure. Disadvantages of the current clinical standards, heparin and ethanol lock therapy (ELT), led to the discovery of new lock solutions. High-risk pediatric patients with intestinal failure who lost access to ELT during a recent shortage were offered enrollment in a compassionate use trial with 4% tetrasodium EDTA (T-EDTA), a lock solution with antimicrobial, antibiofilm, and antithrombotic properties. METHODS: We performed a descriptive cohort study including 14 high-risk pediatric patients with intestinal failure receiving 4% T-EDTA as a daily catheter lock solution. CVC complications were documented (repairs, occlusions, replacements, and CLABSIs). Complication rates on 4% T-EDTA were compared with baseline rates, during which patients were receiving either heparin or ELT (designated as heparin/ELT). RESULTS: Patients initiated 4% T-EDTA at the time they were enrolled in the compassionate use protocol. Use of 4% T-EDTA resulted in a 50% reduction in CVC complications, compared with baseline rates on heparin/ELT (incidence rate ratio: 0.50; 95% CI, 0.25-1.004; P = 0.051). CONCLUSION: In a compassionate use protocol for high-risk pediatric patients with intestinal failure, the use of 4% T-EDTA reduced composite catheter complications, including those leading to emergency department visits, hospital admissions, additional procedures, and mortality. This outcome suggests 4% T-EDTA has benefits over currently available lock solutions.

A Scoping Review of PTSD and Depression in Adult Burn Patients: A Call for Standardized Screening and Intervention Research.

Despite the growing incidence of burn injuries globally and the advancements in physical recovery, the psychological aspect of burn trauma recovery remains inadequately addressed. This review aims to consolidate existing literature posttraumatic stress disorder (PTSD) and depression in adult burn survivors, recognizing the need for a holistic approach to burn recovery that encompasses both physical and mental health. The comprehensive analysis of 156 studies revealed significant variations in methodological approaches, leading to challenges in creating standardized protocols for mental health assessment in burn care. Key findings include the identification of a wide range of psychological assessment tools and a substantial research gap in low and middle-income countries, where the majority of burn injuries occur. Only 7.0% of the studies assessed interventions for PTSD or depression, indicating a lack of focus on treatment modalities. The studies identified demographic factors, patient history, psychosocial factors, burn injury characteristics, and treatment course as risk factors for PTSD and depression post-burn injury. The review highlights the need for early screening, intervention, and attention to subjective experiences related to burn injury, as these are strong predictors of long-term psychological distress. It also emphasizes the complexity of addressing psychological distress in burn survivors and the need for more standardized practices in assessing PTSD and depression specific to this population.

Hydroxocobalamin is not associated with methemoglobinemia in patients with inhalation injury and suspected cyanide toxicity and a proposed algorithm for hydroxocobalamin administration.

BACKGROUND: Cyanide poisoning poses a significant threat to burn patients exposed to smoke in residential or workplace fires, leading to central nervous system dysfunction, hemodynamic instability, cardiovascular collapse, and death. Prompt administration of an effective antidote is critical. Hydroxocobalamin, a form of vitamin B12, is the gold standard treatment for cyanide toxicity, by binding to cyanide molecules and converting them into non-toxic cyanocobalamin that is eliminated by the kidneys. This mechanism is distinct from previous cyanide antidotes, which induce the formation of methemoglobin to bind to cyanide. Recent case studies have reported elevated methemoglobin levels after hydroxocobalamin administration, raising concerns regarding its safety. The current study investigates smoke inhalation patients treated with hydroxocobalamin at a single institution Burn Unit in hopes of enhancing our understanding of the complexities surrounding cyanide antidote therapy. METHODS: After Institutional Board Approval, a retrospective cohort study was conducted. Our sample comprised burn patients with inhalation injury admitted to a single institution from 2013 to 2023 and treated with hydroxocobalamin for suspected cyanide toxicity. We also analyzed a matched control cohort of similar patients with inhalation injury not treated with hydroxocobalamin. We analyzed changes and peaks in methemoglobin levels, lactate levels, blood urea nitrogen (BUN) and creatinine, ventilator days, % total body surface area (TBSA), various types of medications and dressings, and mortality. Statistical analyses included t-tests, chi-square, linear and logistic regressions, and correlation analysis. RESULTS: In the study, 36 patients with suspected inhalation injury were treated with hydroxocobalamin at the Los Angeles General (LAG) Burn Unit from 2013 to 2023, who were matched to 32 control patients with inhalation injury who were not treated with hydroxocobalamin. Demographic and baseline characteristics showed no statistically significant differences between the groups, including age, gender, BMI, and %TBSA. No significant differences were found in initial, final, peak, or change in methemoglobin levels. The study also revealed no significant disparities in initial lactate levels, mortality, kidney function tests, ventilator days, surgeries, or use of medications/treatments (e.g., Silvadene dressings, Vitamin C) between the two groups. When controlling for covariates, multiple linear regression analysis (age, gender, and %TBSA) indicated that hydroxocobalamin administration was not significantly associated with changes in methemoglobin or mortality. Increased %TBSA, however, was linked to elevated lactate levels. CONCLUSIONS: Our investigation sought to assess the potential risks associated with hydroxocobalamin administration in burn patients with concomitant inhalation injury. Contrary to our initial hypothesis, we found no statistically significant differences in methemoglobinemia, lactate levels, mortality, or kidney function. The influence of other factors, such as methemoglobinemia-inducing drugs or hydroxocobalamin's interference with co-oximetry, adds complexity. Although elevated methemoglobin levels were observed in some cases, their clinical significance was limited. However, this study's limitations, particularly the rarity of inhalation injury cases with concern for cyanide toxicity, warrant consideration. Further research is required to comprehensively elucidate the impact of hydroxocobalamin administration on burn patients' outcomes.

Plan-do-study-act (PDSA) interventions to improve real-world endoscopy unit productivity.

Background and study aims The Plan-Do-Study Act (PDSA) ramp is a framework that uses initial small changes to build consensus and momentum for subsequent, iterative process improvement. Our aim was to study its impact on endoscopy unit efficiency and throughput. Methods Following a granular time-and-motion analysis to evaluate baseline performance (phase 1) we instituted successive interventions and measured their impact on core efficiency metrics including procedure volume and turnover time (phases 2-3). Results We identified that inefficiency in turnover of anesthesia-supported endoscopy was the most crucial issue. Implementation of a pre-procedure anesthesia visit in phase 2 reduced turnover time by 15.5 minutes (95% confidence interval 3.9-27.1 minutes). Subsequent changes (phase 3) including front-loaded procedure scheduling and parallel in-room preparation resulted in an 18% increase in procedure volume. Conclusions The PDSA ramp model is an effective means of assessing operational processes, developing novel interventions, and building consensus to improve the real-world productivity in a resource-conscious manner.

Assessment of a Decade of Change in U.S. Assisted Reproductive Technology Cumulative Live-Birth Rates: 2004-2009 Compared With 2014-2020.

OBJECTIVE: To assess the effects of demographic shifts, changes in contemporaneous clinical practices, and technologic innovation on assisted reproductive technology (ART) success rates by conducting an analysis of cumulative live-birth rates across different time periods, age groups, and infertility diagnoses. METHODS: We conducted a retrospective cohort study of autologous linked cycles comparing cumulative live-birth rates over successive cycles from patients undergoing their first retrieval between 2014 and 2019 in the SART CORS (Society for Assisted Reproductive Technology Clinic Outcome Reporting System) database. All cycles reported for these individuals up to 2020 were included for analysis. We compared cumulative live-birth rates stratified by age and infertility cause with published data from the 2004-2009 SART CORS database. RESULTS: From 2014 to 2019, 447,042 patients underwent their first autologous index retrieval, resulting in 1,007,374 cycles and 252,215 live births over the period of 2014 to 2020. In contrast, between 2004 and 2008, 246,740 patients underwent 471,208 cycles, resulting in 140,859 births by 2009. Noteworthy shifts in demographics were observed, with an increase in people of color seeking reproductive technology (57.9% vs 51.7%, P <.001). There was also an increase in patients with diminished ovarian reserve and ovulatory disorders and a decrease in endometriosis, tubal, and male factor infertility ( P <.001). Previously associated with decreased odds of live birth, frozen embryo transfer and preimplantation genetic testing showed increased odds in 2014-2020. Preimplantation genetic testing rose from 3.4% to 36.0% and was associated with a lower cumulative live-birth rate for those younger than age 35 years ( P <.001) but a higher cumulative live-birth rate for those aged 35 years or older ( P <.001). Comparing 2014-2020 with 2004-2009 shows that the overall cumulative live-birth rate improved for patients aged 35 years or older and for all infertility diagnoses except ovulatory disorders ( P <.001). CONCLUSION: This analysis provides insights into the changing landscape of ART treatments in the United States over the past two decades. The observed shifts in demographics, clinical practices, and technology highlight the dynamic nature of an evolving field of reproductive medicine. These findings may offer insight for clinicians to consider in counseling patients and to inform future research endeavors in the field of ART.

Movement of the endoplasmic reticulum is driven by multiple classes of vesicles marked by Rab-GTPases.

Peripheral endoplasmic reticulum (ER) tubules move along microtubules to interact with various organelles through membrane contact sites (MCS). Traditionally, ER moves by either sliding along stable microtubules via molecular motors or attaching to the plus ends of dynamic microtubules through tip attachment complexes (TAC). A recently discovered third process, hitchhiking, involves motile vesicles pulling ER tubules along microtubules. Previous research showed that ER hitchhikes on Rab5- and Rab7-marked endosomes, but it is uncertain if other Rab-vesicles can do the same. In U2OS cells, we screened Rabs for their ability to cotransport with ER tubules and found that ER hitchhikes on post-Golgi vesicles marked by Rab6 (isoforms a and b). Rab6-ER hitchhiking occurs independently of ER-endolysosome contacts and TAC-mediated ER movement. Disrupting either Rab6 or the motility of Rab6-vesicles reduces overall ER movement. Conversely, relocating these vesicles to the cell periphery causes peripheral ER accumulation, indicating that Rab6-vesicle motility is crucial for a subset of ER movements. Proximal post-Golgi vesicles marked by TGN46 are involved in Rab6-ER hitchhiking, while other post-Golgi vesicles (Rabs 8/10/11/13/14) are not essential for ER movement. Our further analysis finds that ER to Golgi vesicles marked by Rab1 are also capable of driving a subset of ER movements. Taken together, our findings suggest that ER hitchhiking on Rab-vesicles is a significant mode of ER movement. SIGNIFICANCE STATEMENT: Peripheral endoplasmic reticulum tubules move on microtubules by either attaching to motors (cargo adaptor-mediated), dynamic microtubule-plus ends (tip attachment complexes) or motile vesicles (hitchhiking) but the prevalence of each mode is not clearPost-Golgi vesicles marked by Rab6/TGN46 and ER to Golgi vesicles marked by Rab1 drive ER movementsER hitchhiking on multiple classes of vesicles (endolysosomal, post-Golgi and ER to Golgi) marked by Rabs plays a prominent role in ER movement.

Age-related increase in live-birth rates of first frozen thaw embryo versus first fresh transfer in initial assisted reproductive technology cycles without PGT.

BACKGROUND: The landscape of assisted reproductive technology (ART) has seen a significant shift towards frozen-thawed embryo transfers (FET) over fresh transfers, driven by technological advancements and clinical considerations. This study aimed to compare live birth outcomes between primary FET and fresh transfers, focusing on cycles without preimplantation genetic testing (PGT), using United States national data from the SART CORS database spanning from 2014 to 2020. METHODS: We performed a retrospective cohort study of autologous first ART cycles without PGT comparing primary embryo transfer (frozen thaw vs. fresh) success rates from the 2014-2020 SARTCORS database. Live-birth rates (LBR) and cumulative live-birth rates (CLBR) were compared between first FET versus first fresh embryo transfer from an index retrieval. Multivariate logistic regression (MLR) determined association between live birth outcomes and method of transfer. In a subsequent sub-analysis, we compared these two embryo transfer methods among patients with either diminished ovarian reserve (DOR) or male factor infertility. RESULTS: 228,171 first ART cycles resulted in primary embryo transfer. 62,100 initial FETs and 166,071 fresh transfers were compared. Initial FETs demonstrated higher LBR and CLBR compared to fresh transfers (LBR 48.3% vs. 39.8%, p < 0.001; CLBR 74.0% vs. 60.0%, p < 0.0001). MLR indicated greater chances of live birth with FET across all age groups, with adjusted odds ratio (aOR) of live-birth incrementally increasing with advancing age groups. For DOR cycles, LBR and CLBR were significantly higher for FET compared to fresh (33.9% vs. 26.0%, p < 0.001, 44.5% vs. 37.6%, p < 0.0001), respectively. MF cycles also demonstrated higher LBR and CLBR with FET (52.3% vs. 44.2%, p < 0.001, 81.2% vs. 68.9%, p < 0.0001), respectively. MLR demonstrated that in DOR cycles, initial FET was associated with greater chance of live birth in age groups ≥ 35yo (p < 0.01), with aOR of live birth increasingly considerably for those > 42yo (aOR 2.63, p < 0.0001). CONCLUSIONS: Overall LBR and CLBR were greater for first FET than fresh transfers with incremental increases in odds of live birth with advancing age, suggesting the presence of a more favorable age-related change in endometrial receptivity present in frozen-thawed cycles. For both DOR and MF cycles, LBR and CLBR after primary transfer were greater for first FET than fresh. However, this was particularly evident in older ages for DOR cycles. This suggests that supraphysiologic stimulation in older DOR cycles may be detrimental to endometrial receptivity, which is in part corrected for in FET cycles.

Protocol for combined N-of-1 trials to assess cerebellar neurostimulation for movement disorders in children and young adults with dyskinetic cerebral palsy.

Background: Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders. Methods: Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS. Discussion: Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies. Trial registration: ClinicalTrials.gov NCT06122675, first registered November 7, 2023.

Fat malabsorption in short bowel syndrome: A review of pathophysiology and management.

Fat malabsorption is central to the pathophysiology of short bowel syndrome (SBS). It occurs in patients with insufficient intestinal surface area and/or function to maintain metabolic and growth demands. Rapid intestinal transit and impaired bile acid recycling further contribute to fat malabsorption. A significant portion of patients require parenteral nutrition (PN) for their survival but may develop sepsis and liver dysfunction as a result. Despite advancements in the treatment of SBS, fat malabsorption remains a chronic issue for this vulnerable patient population. Peer-reviewed literature was assessed on the topic of fat malabsorption in SBS. Current management of patients with SBS involves dietary considerations, PN management, antidiarrheals, glucagon-like peptide 2 agonists, and multidisciplinary teams. Clinical trials have focused on improving intestinal fat absorption by facilitating fat digestion with pancreatic enzymes. Targeting fat malabsorption in SBS is a potential pathway to improving lifestyle and reducing morbidity and mortality in this rare disease.

Whole-genome bisulfite sequencing identifies stage- and subtype-specific DNA methylation signatures in pancreatic cancer.

In pancreatic ductal adenocarcinoma (PDAC), no recurrent metastasis-specific mutation has been found, suggesting that epigenetic mechanisms, such as DNA methylation, are the major contributors of late-stage disease progression. Here, we performed the first whole-genome bisulfite sequencing (WGBS) on mouse and human PDAC organoid models to identify stage-specific and molecular subtype-specific DNA methylation signatures. With this approach, we identified thousands of differentially methylated regions (DMRs) that can distinguish between the stages and molecular subtypes of PDAC. Stage-specific DMRs are associated with genes related to nervous system development and cell-cell adhesions, and are enriched in promoters and bivalent enhancers. Subtype-specific DMRs showed hypermethylation of GATA6 foregut endoderm transcriptional networks in the squamous subtype and hypermethylation of EMT transcriptional networks in the progenitor subtype. These results indicate that aberrant DNA methylation contributes to both PDAC progression and subtype differentiation, resulting in significant and reoccurring DNA methylation patterns with diagnostic and prognostic potential.

Bilateral exploration in primary hyperparathyroidism: Double adenoma distribution and biochemical patterns over two decades.

BACKGROUND: We investigated if anatomic patterns of abnormal parathyroid glands have ch anged for primary hyperparathyroidism (pHPT) as atypical biochemical presentation (normohormonal and normocalcemic) has increased. METHODS: Retrospective review of patients with pHPT who underwent routine bilateral neck exploration. RESULTS: 2762 patients were included. The "late" cohort (2014-2020) exhibited lower preoperative calcium (10.8 vs 11.1 â€‹mg/dL; P â€‹= â€‹0.001) and PTH levels (101 vs. 146 â€‹pg/mL; P â€‹= â€‹0.001) compared to the "early" cohort (2000-2006). Patients with atypical biochemical profiles increased from 25.5% to 31.3% (P â€‹< â€‹0.001). The prevalence of single adenoma (SA) decreased (66.1% vs 58.9%, P â€‹= â€‹0.02) while the proportion of double adenoma (DA) increased (17.3% vs. 22.6%, P â€‹< â€‹0.01). Upper parathyroid adenoma(s) remained the most common finding for SA and DA in both time points. CONCLUSIONS: Despite changes in patient characteristics, single upper adenoma and bilateral double upper adenomas remain the most common findings for patients with pHPT.

PTEN-restoration abrogates brain colonisation and perivascular niche invasion by melanoma cells.

BACKGROUND: Melanoma brain metastases (MBM) continue to be a significant clinical problem with limited treatment options. Highly invasive melanoma cells migrate along the vasculature and perivascular cells may contribute to residual disease and recurrence. PTEN loss and hyperactivation of AKT occur in MBM; however, a role for PTEN/AKT in perivascular invasion has not been described. METHODS: We used in vivo intracranial injections of murine melanoma and bulk RNA sequencing of melanoma cells co-cultured with brain endothelial cells (brECs) to investigate brain colonisation and perivascular invasion. RESULTS: We found that PTEN-null melanoma cells were highly efficient at colonising the perivascular niche relative to PTEN-expressing counterparts. PTEN re-expression (PTEN-RE) in melanoma cells significantly reduced brain colonisation and migration along the vasculature. We hypothesised this phenotype was mediated through vascular-induced TGFß secretion, which drives AKT phosphorylation. Disabling TGFß signalling in melanoma cells reduced colonisation and perivascular invasion; however, the introduction of constitutively active myristolated-AKT (myrAKT) restored overall tumour size but not perivascular invasion. CONCLUSIONS: PTEN loss facilitates perivascular brain colonisation and invasion of melanoma. TGFß-AKT signalling partially contributes to this phenotype, but further studies are needed to determine the complementary mechanisms that enable melanoma cells to both survive and spread along the brain vasculature.

Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

Beta and theta oscillations track effort and previous reward in human basal ganglia and prefrontal cortex during decision making.

Choosing whether to exert effort to obtain rewards is fundamental to human motivated behavior. However, the neural dynamics underlying the evaluation of reward and effort in humans is poorly understood. Here, we investigate this with chronic intracranial recordings from prefrontal cortex (PFC) and basal ganglia (BG; subthalamic nuclei and globus pallidus) in people with Parkinson's disease performing a decision-making task with offers that varied in levels of reward and physical effort required. This revealed dissociable neural signatures of reward and effort, with BG beta (12-20 Hz) oscillations tracking subjective effort on a single trial basis and PFC theta (4-7 Hz) signaling previous trial reward. Stimulation of PFC increased overall acceptance of offers in addition to increasing the impact of reward on choices. This work uncovers oscillatory mechanisms that guide fundamental decisions to exert effort for reward across BG and PFC, as well as supporting a causal role of PFC for such choices.

A chair-stand time of greater than 15 seconds is associated with an increased risk of death and hospitalization in cirrhosis.

Background: Frailty is a clinical state of increased vulnerability and is common in patients with cirrhosis. The liver frailty index (LFI) is a validated tool to evaluate frailty in cirrhosis, comprising of grip strength, chair stands, and balance tests. The chair-stand test is an easy to conduct frailty subcomponent that does not require specialized equipment and may be valuable to predict adverse clinical outcomes in cirrhosis. The objective of this study was to determine if the chair-stand test is an independent predictor of mortality and hospitalization in cirrhosis. Methods: A retrospective review of 787 patients with cirrhosis was conducted. Chair-stand times were collected at baseline in person and divided into three groups: <10 seconds (n = 276), 10-15 seconds (n = 290), and >15 seconds (n = 221). Fine-Gray proportional hazards regression models were used to evaluate the association between chair-stand times and the outcomes of mortality and non-elective hospitalization. Results: The hazard of mortality (HR 3.21, 95% CI 2.16%-4.78%, p <0.001) and non-elective hospitalization (HR 2.24, 95% CI 1.73%-2.91%, p <0.001) was increased in group 3 in comparison to group 1. A chair-stand test time >15 seconds had increased all-cause mortality (HR 2.78, 95% CI 2.01%-3.83%, p <0.001) and non-elective hospitalizations (HR 1.84, 95% CI 1.48%-2.29%, p <0.001) compared to <15 seconds. Conclusions: A chair-stand test time of >15 seconds is independently associated with mortality and non-elective hospitalizations. This test holds promise as a rapid prognostication tool in cirrhosis. Future work will include external validation and virtual assessment in this population.

Cumulative live birth rates with autologous oocytes plateau with fewer number of cycles for each year of age > 42.

OBJECTIVE: To disaggregate the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) age category of " > 42" and compare age-stratified cumulative live birth rates (CLBR) > 42 years old. DESIGN: Retrospective cohort study of autologous linked ART cycles. SETTING: United States (US) National ART Database. PATIENT(S): Women > 42 years old without a history of prior ART cycles who underwent ART between 2014-2020 as reported to the SART CORS database. INTERVENTION(S): Disaggregate the SART CORS age category of " > 42" into age-stratified cumulative live birth rates (CLBR). MAIN OUTCOME MEASURE(S): Age-stratified cumulative live birth rates (CLBR) for women ≥ 43 years old. RESULTS: Between 2014-2020, 24,650 women > 42 years old without history of prior ART underwent 58,132 cycles, resulting in 1,982 live births. Women ages 43, 44, 45, 46, 47, 48, 49, ≥ 50 achieved maximal CLBR of 9.7%, 8.6%, 5.0%, 3.6%, 2.5%, 1.5%, 2.7%, 1.3%, respectively. CLBR for women between 43-45 were significantly higher compared to those 46 and older (p < 0.05). Among women 46 and older, CLBR were not significantly different. Women ages 43 and 44 did not exhibit a significant increase in CLBR beyond the 5th cycle. Age 45 and 46 reached CLBR plateau by the 3rd cycle. Age ≥ 47 CLBR plateaued after the first cycle. After adjusting for age, race/ethnicity, BMI, nulliparity, etiology of infertility, number of oocytes retrieved, embryos transferred, blastocyst transfer, use of ICSI, PGT, and ART treatment cycle number, there was no association between markers of ovarian reserve (day 3 FSH and random AMH levels) and live birth for women > 42. CONCLUSIONS: While CLBR of autologous cycles from women 42 or younger generally plateau by cycle number 5, age-stratified cycles from women > 42 plateau after fewer cycles to maximize CLBR. Patient and physician expectations for maximum CLBR beyond 42 may be practically based on fewer planned cycles before reaching an age-specific CLBR plateau than may have been previously expected.

Personalized chronic adaptive deep brain stimulation outperforms conventional stimulation in Parkinson's disease.

Deep brain stimulation is a widely used therapy for Parkinson's disease (PD) but currently lacks dynamic responsiveness to changing clinical and neural states. Feedback control has the potential to improve therapeutic effectiveness, but optimal control strategy and additional benefits of "adaptive" neurostimulation are unclear. We implemented adaptive subthalamic nucleus stimulation, controlled by subthalamic or cortical signals, in three PD patients (five hemispheres) during normal daily life. We identified neurophysiological biomarkers of residual motor fluctuations using data-driven analyses of field potentials over a wide frequency range and varying stimulation amplitudes. Narrowband gamma oscillations (65-70 Hz) at either site emerged as the best control signal for sensing during stimulation. A blinded, randomized trial demonstrated improved motor symptoms and quality of life compared to clinically optimized standard stimulation. Our approach highlights the promise of personalized adaptive neurostimulation based on data-driven selection of control signals and may be applied to other neurological disorders.